WO2019126768A1

WO2019126768A1 - Composite, multidomain, genomically engineered molecules (gem)

Info

Publication number: WO2019126768A1
Application number: PCT/US2018/067320
Authority: WO
Inventors: Marek Malecki; Bianka Kathryn SAETRE
Original assignee: Phoenix Biomolecular Engineering Foundation
Priority date: 2017-12-24
Filing date: 2018-12-21
Publication date: 2019-06-27
Also published as: WO2019126768A4

Abstract

Viral infections cause debilitating diseases and deaths World-wide. While vaccines (e.g., HBV Vaccine) prevent some of them, new viruses (e.g., HIV) or new strains evading vaccination acquired immunity or therapy (e.g., influenza) emerge. Moreover, currently approved therapies cause serious adverse effects, but do not remove the virus and virus infected cells from the patients. Therefore, the patients may suffer progression of the disease with flares and potentially infect other people. Herein, we disclose and claim designs, composition, manufacturing processes, and utility of not reported before, not obvious, not occurring in nature, genomically engineered molecules (GEMs) for removing of the viruses from the patients' bodies by GEMs-aided apheresis, as a therapy of the patients with viremia.

Description

COMPOSITE, MULTIDOMAIN, GENOMICALLY ENGINEERED MOLECULES

(GEM)

[0001] Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57. This application claims priority to U.S. Provisional Patent Application No. 62/610,205, filed December 24, 2017 and U.S. Provisional Patent Application No. 62/612,470, filed December 31 2017, which are incorporated herein by reference in their entireties.

SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled PBEF003WO Final.txt, created December 21, 2018, which is 460,902 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

FIELD

[0003] The present application relates to compositions of genomically engineered molecules (GEM) and methods of using and manufacturing said genomically engineered molecules (GEM).

BACKGROUND

[0004] Viral infections cause debilitating diseases and deaths World-wide.

While preventive vaccines (e.g., HBV Vaccine) prevent some of them, new viruses emerge (e.g., HIV) or new strains evade vaccination acquired immunity or therapy (e.g., influenza). A good example is a natural history of HIV, which emerged in 80s. [0005] According to the World Health Organization, approximately 36,7 million people suffered from AIDS in 2016 and approximately 1 million of them died that year, while almost 1.8 million became newly infected. [1]

[0006] Currently, there are no prophylactic and / or therapeutic HIV vaccines approved and / or recommended neither by WHO, nor by FDA in the United States. [2-4] ] Attempts to develop vaccines have not been satisfactory so far. [18, 19]

[0007] Ongoing research on alternative therapies is primarily stemmed from the reports that CD4 is the HIV attaching molecules and entry port and gpl20 is the HIV targeting molecule, whereas the infection may spread through cytolysis, budding, and syncytium. [8-10] Hence, soluble, recombinant CD4 may reduce HIV attaching; thus entry. [11-12] Similar effects may have gpl20 neutralizing antibodies, which initially are effective, but may be quickly evaded by HIV due to mutations. [13-14] Those therapeutic attempts, which were further expanded by CD4-IgG fusions, all failed. [15, 16, 17]

[0008] At the present time (December 2017), the FDA and WHO approved therapies of the HIV+ patients rely upon administration of drugs repressing the HIV propagation mechanisms: entry inhibitors (e.g., enfuvirtide or maraviroc), reverse transcriptase inhibitors (e.g., zidovudine or tenofovir), integrase inhibitors (e.g., elvitegravir), or protease inhibitors (e.g., darunavir). [2, 5]

[0009] The main problems with all those aforementioned and currently approved therapies are: they cause very serious adverse effects, they do not remove the virus from the patients’ bodies, and they do not remove the HIV-infected and HIV-producing cells. [2, 6] Therefore, the HIV+ patients keep suffering progression of the disease and continue infecting others through blood and lymph (primarily by sharing needles), as well as, saliva, semen, vaginal fluids, and all physiological secretions (primarily by sex), as detected by the FDA approved diagnostic tests. [7].

SUMMARY OF THE INVENTION

[0010] Provided herein are genomically engineered molecules (GEM) compositions rendered with superparamagnetic properties as well as their utility as a therapeutics facilitating rapid removal of HIV and other viremia-causing viruses from blood lymph, or cerebrospinal fluid of the virus positive (+) patients. Also provided herein are genomically engineered molecules (GEM) compositions rendered with fluorescent properties as well as their utility as therapeutics facilitating rapid removal of HIV and other viremia- causing viruses from blood, lymph, or cerebrospinal fluid of the virus positive (+) patients.

[0011] For a person skilled in art and science of biotechnology, genomics, immunology, and molecular and genomic medicine, this invention can be utilized for the treatment of patients with HIV viremia as well as other viremias upon the selection of the virus- specific genomically engineered molecule (GEM), as outlined below.

[0012] In some embodiments, a genetically engineered molecule (GEM) composition comprises a soluble virus-attaching molecule (VAM), an apheresis initiating molecule (AIM), and a superparamagnetic (SPM) nanoparticle. The virus-attaching molecule (VAM) is linked to the apheresis initiating molecule (AIM), and the apheresis initiating molecule (AIM) is linked to the superparamagnetic (SPM) nanoparticle.

[0013] In some embodiments, the SPM can be attached in different manners. In some embodiments, a DNA coding sequences for VAM with no STOP codon is synthesized merged with the DNA coding sequence for AIM followed by STOP codon. They are inserted into the dsDNA p_CMV-INS-SV40 plasmids. Therefore, they form the integrated DNA coding sequence that facilitates expression of genomically engineered molecule (GEM) as one fusion protein in human Multiple myelomas grown in sera free media in spinning incubators. At this point GEM has a metal binding domain (MBD) incorporated into its structure, so GEM, after MBD harbors SPM, acquires superparamagnetic properties, so it is sensitive to magnetic field, while becoming GEM (with a SPM).

[0014] In some embodiments, the unmodified DNA sequences coding for virus attaching molecule (VAM), per NCBI sequence data base, is transgenically expressed in human Multiple myelomas in serum free media as transgenically expressed VAM (tgVAM). These tgVAM are functionalized with hetero-bifunctional linkers according to the protocols provided herein. Depending on the chemistry outlined herein the core-shell superparamagnetic particlesare also functionalized by the linkers (as provided herein) according to the protocols provided herein. Click chemistry in the reactions developed and described in the detailed protocols provided herein, facilitates stable, covalent conjugation of tgVAM with SPM rendering their superparamagnetic features. [0015] In some embodiments, a genetically engineered molecule (GEM) composition comprising a virus-attaching molecule (VAM), an apheresis initiating molecule (AIM), and a fluorescent (F) molecule is provided. The virus -attaching molecule (VAM) is linked to the apheresis initiating molecule (AIM) and the apheresis initiating molecule (AIM) is linked to the fluorescent (F) molecule.

[0016] In some embodiments, a method of manufacturing the genomically enigineered molecule (GEM) composition is provided. The method comprises amplifying DNA sequences encoding the VAM and the AIM, synthesizing DNA sequences by extension overlap with cloning overhangs, cloning DNA sequences coding VAM and AIM into p_CMV- INS-SV40 DNA vector, transfecting human myeloma cells, and expressing in human myeloma cells, and applying biochemical affinity isolation and/or purification.

[0017] In some embodiments, a method of treatment comprises administering any one of the GEM composition described herein, to a patient. In some embodiments, the method comprises intra-venous (i.v.) infusion, intra-lymphatic (i.l.) infusion, subcutaneous (s.c.) injection, intra-muscular (i.m.) injection, or intra-cerebrospinal (i.c.s.) fluid injection.

[0018] In some embodiments, a use of the GEM composition described herein or produced by the method described herein for the treatment of a disease related to a virus occurring in a patient’s body, such that the virus causes viremia, is provided.

[0019] In some embodiments, a method of treating a subject is provided. The method comprises providing a subject to be treated and administering at least one of the GEM composition as described herein to the subject in an amount sufficient to allow binding of the GEM in the composition to a target protein (e.g., virus particle) in the subject, and removing the target protein and any associated biological material with the target protein, from the subject via a magnetic action on the SPM in the composition. In some embodiments, if the target material is removed ex vivo, the method comprises cleaning of subject’s blood, lymph, or cerebrospinal fluid of the SPM and material associated therewith.

[0020] In some embodiments, a method of treating a subject is described. The method comprises administering to the subject of any one of the GEM composition as described herein as a sterile composition, removing from the subject’s body a portion of the subject’s blood, conducting apheresis via a magnetic field on the portion of the subject’s blood to provide a cleaned portion of the blood, lymph, or cerebrospinal fluid and optionally returning the cleaned portion of the blood to the patient.

[0021] In some embodiments, a GEM composition is provided. The composition comprises a virus-attaching-molecule (VAM), wherein the VAM is soluble; a chemical linker; and a superparamagnetic (SPM) nanoparticle or a fluorescent molecule (F). The VAM is conjugated to the SPM or the fluorescent molecule via the chemical linker.

[0022] In some embodiments, a method of treating a subject having a virus- induced disease is provided. The method comprises removing one or more virus -infected cells and/or an infecting virus from a subject by magnetic apheresis. Apheresis is performed using a genomically engineered molecule (GEM), wherein the GEM comprises any one of the GEMs from claims 1-8, and wherein the SPM within the GEM allows for the use of a magnetic field to achieve apheresis to remove the virus-infected cells and/or virus from the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIGs. 1A-1C illustrate the effect of the VAM or the modified GEM against the infection of virus. Specifically, FIG. 1A illustrates a scenario that occurs upon the natural infection of a patient with a virus, that is attaching to a wild-type VAM displayed by human cells. FIG. IB illustrates the components used in genomic engineering of the composite, multidomain, Gemomically Engineered Molecule (GEM): VAM - Virus Attaching Molecule, AIM - Apheresis Initiating Molecule, and SPM - Superparamagnetic Particle. In some embodiments, the AIM can be replaced with a hetero-bifunctional linker system. FIG. 1C illustrates the GEM capturing the virus. This can be followed by apheresis of the GEM-virus complex, thus elimination of the virus from blood, lymph, or cerebrospinal fluid.

[0024] FIG. 2 illustrates the rapid reduction of the various heights of HIV viremia in blood of the HIV+ patients by means of GEM aided apheresis.

[0025] FIG. 3 illustrates that the reduction of the HIV viremia in blood of the HIV+ patients was maintained over time by means of GEM aided apheresis.

[0026] FIG. 4 illustrates the preventive administration of GEM prior to the HIV infection resulted in significant reduction of the HIV viremia upon infection. [0027] FIG. 5 illustrates the reduced number of CD4+ lymphocytes, which became newly infected with HIV, if infection occurred after administration of GEM. The CD4+ lymphocyte count was conducted by flow cytometry after labeling with anti-CD4 antibodies rendered fluorescent with phycoerythrin.

[0028] FIG. 6 illustrates that the CD4+ lymphocyte population is protected by administration of GEM, which is repressing the viral count, therefore is reducing CD4+ lymphocyte cytopathic depletion. The CD4+ lymphocyte count was conducted by flow cytometry after labeling with anti-CD4 antibodies rendered fluorescent with phycoerythrin.

[0029] FIG. 7 illustrates an energy dispersive X-ray spectroscopy of the elemental composition of genomically engineered molecules (GEM). GEM (including SPM ( VAM=CD4; AIM=Cys6; SPM= {Fe304}Si02).

[0030] FIG. 8 displays a p_CMV-INS-SV4 map which supplements the sequence of cloning vector sequence (SEQ ID NO: 30).

[0031] FIG. 9 displays an immediate reduction of the HIV-infected cells’ counts in blood of the HIV+ patients was attained by the GEM (CD4-SPM) aided apheresis.

[0032] FIG. 10 displays immediate reduction of the HIV-infected cells’ counts in blood of the HIV+ patients that was attained by the GEM (anti-gpl20-SPM) aided apheresis.

[0033] FIG. 11 displays long-term protection of the CD4+ cells’ population that was attained by cycles of the GEM (CD4-SPM) aided apheresis.

[0034] FIG. 12 displays long-term protection of the CD4+ cells’ population was attained by means of cycles of the GEM (anti-gpl20-SPM) aided apheresis.

[0035] FIG. 13 displays a gel showing specificity of GEM (CD4-SPM) in pulling out the HIV-infected and HIV-producing cells was assessed by Western blotting with anti-p24. Lanes: 1 - healthy volunteer’s blood; GEM (CD4-mutant-SPM); 3 - ; 4-5 - HIV+ patients’ 1st- 2nd blood; 6-7 - HIV+ patients’ lst-2nd lymph; 8 - reference p24; 9 - HIV+ patient 1^st blood after 3 cycles of GEM (CD4-aided) apheresis (no actively HIV-producing cells detected).

[0036] FIGs. 14 and 15 are spectra of the SPM {Fe304}Au used in Example 4. DETAILED DESCRIPTION

[0037] FIGs. 1A-1C illustrate various aspects relating to VAM or GEM components against the infection of a virus.

[0038] FIG. 1A is a diagram that illustrates a scenario that occurs upon the natural infection of a patient with a virus. The virus attaches to the specific virus attaching molecule (VAM) displayed on cells as the very first step of the natural infection. This step is followed by entry into the cytoplasm. The next step may occur in cytoplasm or nucleus. The outcome is virus propagation leading to massive presence of viruses in blood and lymph, also known as viremia. This leads to disease progression and potentially death, while also carrying the risk of spreading the viral disease to other people.

[0039] FIG. 1B is a diagram that illustrates steps in manufacturing Genomically Engineered Molecules (GEM). The DNA coding sequence for VAM, that is specific for a virus under consideration is extracted from the cells’ genome, is cloned into an expression vector and expressed in human Multiple Myelomas as transgenically expressed VAM (tgVAM). The genomically engineered molecule (GEM) is designed and expressed to comprise two domains: VAM domain that is attaching to the virus and apheresis initiating molecule (AIM) domain that is harboring superparamagnetic (SPM) particle or fluorescent (F) molecule. Through genomic engineering, the GEM is formed comprising VAM, AIM and SPM or is formed comprising VAM, AIM and F.

[0040] FIG. 1C is a diagram that illustrates a scenario that occurs upon the infection with virus, but with administration of genomically engineered molecules (GEM) saturated with superparamagnetic (SPM). GEM comprises VAM domain that anchors the virus and AIM domain that harbors SPM making GEM responsive to magnetic field (M). Virus is dragged out of blood and plasma by GEM responding to magnetic field. This leads to elimination of virus by apheresis, leading to health recovery.

[0041] Provided herein are compositions of genomically engineered molecules (GEM) that have been rendered with superparamagnetic properties as well as their utility as a therapeutics facilitating rapid removal of HIV and other viremia-causing viruses from blood, lymph, or cerebrospinal fluid of the virus positive (+) patients. Also provided herein are genomically engineered molecules (GEM) compositions rendered with fluorescent properties as well as their utility as therapeutics facilitating rapid removal of HIV and other viremia- causing viruses from blood and, lymph, or cerebrospinal fluid of the virus positive (+) patients.

[0042] For a person skilled in art and science of biotechnology, genomic, immunology, and molecular and genomic medicine, this invention can be utilized for the treatment of patients with HIV viremia as well as other viremias upon the selection of the virus -specific genomically engineered molecule (GEM), as outlined herein.

[0043] As used herein, in some embodiments, a GEM comprises a VAM or binding fragment thereof fused within a VAM-AIM fusion protein or VAM linked to a SPM by means of a heterobifunctional linker. The linkage of VAM to SPM can be via an AIM domain or linker based system

[0044] As used herein, any amino acid based molecule that can be used to link a VAM to a SPM to render that VAM responsive to magnetic field is called Apheresis Initiating Molecule aka“AIM.”

[0045] As used herein, a “Superparamagnetic Particle Molecule (SPM)” denotes a molecule that is adequately magnetic such that its location can be biased via a magnetic field. This allows for the removal of the GEM complex that is complexed to the virus within or outside of the patients’ bodies.

[0046] In some embodiments, a genetically engineered molecule (GEM) composition comprising a soluble virus -attaching molecule (VAM), an apheresis initiating molecule (AIM), and a superparamagnetic (SPM) nanoparticle is provided. The virus- attaching molecule (VAM) is linked to (covalently) the apheresis initiating molecule (AIM). The apheresis initiating molecule (AIM) is linked to (covalently) the superparamagnetic (SPM) nanoparticle.

[0047] In some embodiments, a genetically engineered molecule (GEM) composition comprising a soluble virus -attaching molecule (VAM), an apheresis initiating molecule (AIM), and a superparamagnetic (SPM) nanoparticle is provided. The virus- attaching molecule (VAM) is fused to the apheresis initiating molecule (AIM) to create single fusion protein. The apheresis initiating molecule (AIM) is harboring (the superparamagnetic (SPM) nanoparticle.

[0048] In some embodiments, a genetically engineered molecule (GEM) composition comprising a virus-attaching molecule (VAM), an apheresis initiating molecule (AIM), and a fluorescent (F) molecule is provided. The virus -attaching molecule (VAM) is linked to (covalently) the apheresis initiating molecule (AIM). The apheresis initiating molecule (AIM) is linked to (covalently) the fluorescent (F) molecule.

[0049] In some embodiments, a genetically engineered molecule (GEM) composition comprising a virus-attaching molecule (VAM), an apheresis initiating molecule (AIM), and a fluorescent (F) molecule is provided. The virus -attaching molecule (VAM) is fused to the apheresis initiating molecule (AIM). The apheresis initiating molecule (AIM) is linked to (covalently) the fluorescent (F) molecule.

[0050] In some embodiments, linkage of the VAM to the AIM can be achieved by a covalent bond, as through an amino acid to amino acid bond in a peptide. In some embodiments, linkage of the AIM with the SPM may be a direct bond between thiol of AIM and shells of SPM, or can be between amine, carbonyl, or thiol groups of chemical linkers on VAM and amine, carbonyl or thiol groups of functionalized SPM.

[0051] In some embodiments, linkage of the VAM to the AIM can be achieved by a covalent bond, as through an amino acid to amino acid bond in a peptide or through chemical bifunctional linkers, including, but not limited to: 1 -Ethyl- 3- (3- dimethylaminopropyl)carbodiimide (EDC), PA -Pentynoic acid, TPA - thiol-polyethylene glycol-azide, PTAD - Poly-triethylene-acylhydrazide-dithiol, APTES also amino-propyl-tri- ethoxy- silane, SPDP N succinimidyl 3 (2-pyridyldithio)propionate, PEAD polyetheleglycoldithiolacylhydrazide , 3-Triethoxysilylpropylamine (APTES), Succinimidyl 4-(N-maleimidomethyl)cyclohexane-l-carboxylate (SMCC), N-succinimidyl-(2-pyridyl- dithiol-propionate) (SPDP).

[0052] In some embodiments, Genomically engineered molecules (GEM) offer unique simplicity of preparing therapeutics in the GMP regimens. Furthermore, they can significantly reduce the risk of immunogenicity in multiple administrations. These are fusion proteins manufactured in the sterile environment and come out from the production process ready to be saturated directly by click chemistry with sterile superparamagnetic particles (SPM) or fluorescent particles (FP aka FM).

[0053] Alternative process for manufacturing and testing molecules suitable for magnetic apheresis of viruses are provided as well. This can be achieved by transgenic expression of virus attaching molecules (VAM) (SEQ ID NO: 1-29) expressed from the plasmid (SEQ ID NO: 30) in their soluble, monomeric forms but with no modification of their DNA and AA sequences.

[0054] Thereafter, the VAM can be functionalized to bind SPM by reacting with the hetero-bi-functional linkers. SPM can also be functionalized. By reacting the two, VAM derived domain assured targeting the virus, while SPM rendered superparamagnetic properties. The exact for HIV, but as an exemplary for other viruses, detailed protocol follows.

[0055] Provided herein is another protocol for conjugating transgenically expressed CD4 (tgCD4) with SPM. The soluble, recombinant transgenically expressed CD4 (tgCD4) was dissolved from lyophilized from PBS powder. It dialyzed against phosphate buffer solution (PBS) pH 7.0 24 deg. C in lOkDa cutoff bags. The concentration was adjusted to 20 microM. An aliquot of 12 ml was sampled from that solution. Meanwhile, 1 ml of 100 mM stock solution of 4-pentynoic acid (PA) in 50 % of THF in PBS was prepared. While on the stirrer, 67 mirol of the PA stock solution was added to 12 ml of tgCD4 in PBS, while mixing at room temperature of around 24 deg C. Meanwhile, 1 ml of 50 mM stock solution of EDC in PBS at pH 7.0 at 24 deg C was prepared. While stirring of tgCD4 with PA solution continued for at least 15 min, we added quickly after dissolving 130 ml of EDC stock solution, while stirring continued. Subsequently, 1500 micol of THF and 1300 ml of PBS were simultaneously added to the ongoing mixture. This reacting process continued for 4 h under the fume hood at 24 deg C. The functionalized by alkynylation tgCD4 was then dialyzed in the lOkDa cutoff dialysis bags against PBS at room temperature of around 24 deg C at pH 7.0. At this point, we have already prepared the stock of the core-shell {(Fe304)Au| superparamagnetic particles (SPM) at 2.8 nM concentration in double distilled water. To 20 ml of the SPM stock, we added thiol-PEG-azide (TPA) up to 20 microM, while vigorously mixing. The reaction continued for 16 h at room temperature of around 24 deg C. The functionalized {(Fe304)Au| SPM was spun down at 15000 g for 30 min and resuspended in double distilled water three times to remove non-reacted reagents. Having functionalized VAM: CD4 and SPM: {(Fe304)Au|, we proceeded with conjugating them. The functionalized {(Fe304)Au| SPM were suspended in water at 13 nM concentration of 10 ml. The solution was placed on the stirrer 60 revolutions per min at room temp of 24 deg C. To that stirred solution the alkynylated tgCD4 was added to attain 130 nM concentration. Thereafter, 2.5 microl of 10 mM CuS04x5H20 with 50 microM ascorbic acid in water was added to the stirred solution. The reacting mix was transferred to 4 deg C. The reaction continued for 24 h at 4 deg C. The CD4-SPM conjugates were cleared from the non-reacted reagents by spinning down at l5,000g at 4 deg C and resuspending in PBS at least 5 times. Upon completion of this procedure the tgCD4-SPM conjugates were effectively binding HIV. We used the identical protocol for conjugating anti-gpl20, anti-gp4l, anti-p24 antibodies with core-shell superparamagnetic {(Fe304)Au| SPM. Alternatively, for well glycosylated molecules we have developed and proceeded an alternative protocol. Below, there is the detailed protocol for transgenic, soluble CD4. However, the same protocol works very well for other VAM. In 10 ml of 0.15 M NaCl, 0.01 M sodium phosphate solution, we dissolved tgCD4 up to 10 mg/ml concentration. We also prepared 0.088 M NaI04 solution in water in darkness at room temperature of 24 deg C. Having both solutions ready, we added 1 ml of NaI04 solution to the tgCD4 solution in the darkness at room temperature for 15 min. To stop the reaction, we added 1 ml of glycerol and running through the desalting column, while collecting the fractions determined on the spectrophotometer on the fraction collector at 280 nm. The fractions were pooled together and adjusted to 10 mg/ml and stored at 4 deg C. At this point, the core-shell superparamagnetic particles SPM {(Fe304)Si02}were functionalized by baking in 1 % solution of APTES for 1 h in oxygen free containers, flushed with nitrogen, at 60 deg C, for 1 h. The reaction was stopped by spinning the activated SPM at l5,000g for 30 min at room temperature of 24 deg C and re-suspending in water at least 5 times. Having both solutions ready, we proceeded with conjugating them. To 10 ml of tgCD4 solution, the functionalized {(Fe304)Si02| SPM were added at 13 nM concentration to attain 10 x molar concentration over tgCD4. The CD4-SPM conjugates were cleared from non-reacted reagents by spininning them at l5,000g for 30 min at 4 deg C for at least five cycles. At that point, we had them ready to be sterilized and used. We used the identical protocol for conjugating anti-gpl20, anti-gp4l, anti-p24 antibodies with core-shell superparamagnetic {(Fe304)Si04| SPM. We have developed yet another protocol for conjugating tgCD4 with SPM. In 10 ml of 0.15 M NaCl, 0.01 M sodium phosphate solution, we dissolved tgCD4 up to 10 mg/ml concentration. We also prepared 0.088 M NaI04 solution in water in darkness at room temperature of 24 deg C. Having both solutions ready, we added 1 ml of NaI04 solution to the tgCD4 solution in the darkness at room temperature for 15 min. To stop the reaction, we added 1 ml of glycerol and running through the desalting column, while collecting the fractions determined on the spectrophotometer on the fraction collector at 280 nm. The fractions were pooled together and adjusted to 10 mg/ml and stored at 4 deg C. We further proceeded with conjugation process by the preparing stock solution of 10 mM polyetheleglycoldithiolacylhydrazide (PEAD) or polytriethyleneglycol-acylhydrazide-dithiol (PTAD) in PBS. Having both solutions ready in darkness, we added 10 mM PTAD to the tgCD4 solution to attain equimolar concentration of tgCD4 and PTAD, while stirred at 4 deg C for 1 h. The reaction was completed by dialysis at 4 deg C against PBS in dialysis bags at 10 kDa cutoff for 1 h, while changing the soaking solution 5 times. At his point, we have already prepared the stock of the core-shell {(Fe304)Au| superparamagnetic particles (SPM) at 2.8 nM concentration in PBS. These SPM did not require any further activation. The PTAD activated tgSPM were added to the vigorously being stirred solution of SPM at 4 deg C for 4 h. The CD4-SPM conjugates were cleared from non-reacted reagents by spininning them at l5,000g for 30 min at 4 deg C for at least five cycles. At that point, we had them ready to be sterilized and used. We used the identical protocol for conjugating anti-gpl20, anti-gp4l, anti-p24 antibodies with core-shell superparamagnetic { (Fe304)Au| SPM.

[0056] In some embodiments, the superparamagnetic (SPM) nanoparticle of the genomically engineered molecule (GEM) composition comprises a solid homogeneous architecture or a core-shell architecture. In some embodiments, the core-shell architecture comprises a magnetic core and a biocompatible shell surrounding the magnetic core. In some embodiments, the shell can include a material to isolate the core material (the superparamagnetic material) from the host’s blood and comprises noble metal gold or silica.

[0057] In some embodiments, the fluorescent (F) molecule of the GEM composition is at least one of R-Phycoerythrin (RPE) or B-Phycoerythrin (BPE). In some embodiments, the fluorescent (F) molecule of the genomically engineered molecule (GEM) composition comprises Terbium (Tb) or Europium (Eu).

[0058] In some embodiments, the superparamagnetic (SPM) nanoparticle of the genomically engineered molecule (GEM) composition is selected from the group consisting of at least one of: {Fe₃0₄}Au and {Fe₃0₄} Si0_2.

[0059] In some embodiments, the genomically engineered molecule (GEM) composition further comprises (or in place of the AIM comprises) a chemical linker that serves to conjugate the virus -attaching molecule (YAM) to the superparamagnetic (SPM) nanoparticle. In some embodiments, the chemical linker is selected from the group comprising at least one of: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), PA -Pentynoic acid, TPA - thiol-polyethylene glycol-azide, PTAD - Poly-triethylene-acylhydrazide-dithiol, APTES also amino-propyl-tri-ethoxy-silane, SPDP N succinimidyl 3 (2- pyridyldithio)propionate, PE AD polyetheleglycoldithiolacylhydrazide , 3-

Triethoxysilylpropylamine (APTES), Succinimidyl 4-(N-maleimidomethyl)cyclohexane-l- carboxylate (SMCC), N-succinimidyl-(2-pyridyl-dithiol-propionate) (SPDP), or polyetheleglycoldithiolacylhydrazide (PE AD) .

[0060] In some embodiments, the genomically engineered molecule (GEM) composition further comprises a virus -attaching molecule (VAM) conjugated to a fluorescent (F) molecule via a chemical linker, wherein the chemical linker is selected form the group comprising at least one of: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), PA - Pentynoic acid, TPA - thiol-polyethylene glycol-azide, PTAD - Poly-triethylene- acylhydrazide-dithiol, APTES also amino-propyl-tri-ethoxy- silane, SPDP N succinimidyl 3 (2-pyridyldithio)propionate, PEAD polyetheleglycoldithiolacylhydrazide, 3- Triethoxysilylpropylamine (APTES), Succinimidyl 4-(N-maleimidomethyl)cyclohexane-l- carboxylate (SMCC), N-succinimidyl-(2-pyridyl-dithiol-propionate) (SPDP), or polyetheleglycoldithiolacylhydrazide (PEAD) .

[0061] In some embodiments, the functionalized VAM is selected from the group consisting of: dipeptidyl peptidase 4 (DPP4), heparin sulfate (HS), neurokinin 1 receptor (NK1R), T-cell immunoglobulin and mucin domain (TIM1), Hepatitis A virus cellular receptor 1 (HAVCR1), sodium-taurocholate co-transporting polypeptide (NTCP), C-type lectin domain family 4 (CLEC4M), complement receptor 1 (CR1/2), cluster of differentiation 4 (CD4), ephrin A2 receptor (EphA2R), cluster of differentiation 81 (CD81), integrin alpha-6 ( ITGA6), nectin (Nec), sialylated glycans (SG), cluster of differentiation 155 (CD155), integrin alpha- beta (a.2b 1 -ITGacctylcholinc receptor (AchR), and chondroitin sulfate (CS).

[0062] In some embodiments, the functionalized VAM or their fragments is selected from the group consisting of: the amino acid encoded by, or nucleic acid of, SEQ ID NO: 1, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 2, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 3, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 4, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 5, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 6, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 7, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 8, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 9-4, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 15, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 16-17, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 18-21, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 22, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 23, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 24-25, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 26, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 27-28, and the amino acid encoded by, or nucleic acid of, SEQ ID NO: 29. In some embodiments, the VAM comprises at least 50, 60, 70, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 99.9% of the protein identified above as a VAM. In some embodiments, the VAM is a binding portion of the protein noted above, such that enough of the protein is present to bind to the virus. Thus, in some embodiments, the VAM is a binding fragment of one or more of: DPP4, HS, NK1R, TIM1, HAVCR1, NTCP, CLEC4M, CR1/2, CD4, EphA2R, CD81, ITGA6, nectin, SG, CD155, a.2b 1 -ITO, AchR, and CS. In some embodiments, the functionalized VAM or their fragments is selected from the group consisting of: the amino acid encoded by, or nucleic acid of, SEQ ID NO: 1, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 2, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 3, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 4, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 5, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 6, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 7, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 8, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 9-4, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 15, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 16-17, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 18-21, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 22, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 23, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 24-25, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 26, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 27-28, and the amino acid encoded by, or nucleic acid of, SEQ ID NO: 29. The binding fragment of VAM will bind to the corresponding virus.

[0063] In some embodiments, the AIM is any one or more of the AIM molecules (DNA (SEQ ID NOs: 35-40) or amino acid SEQ ID NOs: 70, 72, 73, 74, 76, 78, 80) in the accompanying sequence listing. In some embodiments, the AIM is at least 80, 90, 95, 96, 97, 98, 99, or 99.9% identical to one or more of the AIM molecules (DNA or amino acid) in the accompanying sequence listing.

[0064] In some embodiments, the VAM is any one or more of the VAM molecules (DNA (SEQ ID NOs: 1-29) or amino acid (SEQ ID NOs: 82-108)) in the accompanying sequence listing. In some embodiments, the AIM is at least 80, 90, 95, 96, 97, 98, 99, or 99.9% identical to one or more of the AIM molecules (DNA or amino acid) in the accompanying sequence listing.

[0065] In some embodiments, the genomically engineered molecule (GEM) composition comprises a VAM that is DPP4 or a fragment thereof and AIM domains, and the SPM comprises {Fe₃0₄}Au.

[0066] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is HS/CLEC4M or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprise {Fe304}Au.

[0067] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is NK1R or a binding fragment thereof, the AIM domains, the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0068] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is TIM1 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0069] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is HAVCR1 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0070] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is NTCP or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0071] In some embodiments, the GEM comprises a VAM that is CLEC4M or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe304}Au. [0072] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CR1 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0073] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CD4 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0074] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is EphA2R or a binding fragment thereof, and the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0075] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CD81 or a binding fragment thereof, AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0076] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is ITGA6 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0077] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is nectin or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0078] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is SG or a binding fragment thereof and AIM domains, and the SPM comprises {Fe₃0₄}Au.

[0079] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CD155 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0080] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is a.2b 1 -ITO or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au.

[0081] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is AchR or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Au. [0082] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CS or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe304}Au.

[0083] In some embodiments, the genomically engineered molecule (GEM) composition comprises a VAM that is DPP4 or a fragment thereof and AIM domains, and the SPM comprises {Fe₃04}Si0₂.

[0084] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is HS/CLEC4M or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprise {Fe₃0₄}Si0₂.

[0085] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is NK1R or a binding fragment thereof, the AIM domains, the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0086] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is TIM1 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0087] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is HAVCR1 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0088] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is NTCP or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0089] In some embodiments, the GEM comprises a VAM that is CLEC4M or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0090] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CR1 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0091] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CD4 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂. [0092] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is EphA2R or a binding fragment thereof, and the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0093] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CD81 or a binding fragment thereof, AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0094] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is ITGA6 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0095] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is nectin or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0096] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is SG or a binding fragment thereof and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂.

[0097] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CD155 or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂..

[0098] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is a.2b 1 -ITO or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0099] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is AchR or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0100] In some embodiments, the genomically engineered molecule (GEM) comprises a VAM that is CS or a binding fragment thereof, the AIM domains, and the SPM, such that the SPM comprises {Fe₃0₄}Si0₂.

[0101] In some embodiments, the virus-attaching molecule (VAM) is fused with apheresis initiating molecule (AIM) domain, and AIM domain is conjugated to a SPM, so that the enabling process creates GEM-SPM, as a molecule responsive to magnetic field. The DNA coding sequence of VAM- AIM translated into AA sequences can be selected from any one of the following: the DNA coding sequences for the VAM-AIM fusion proteins with translated AA sequences specifically: SEQ ID NO: 41, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 42, DNA coding sequences for the VAM- AIM fusion proteins translated in AA sequences SEQ ID NO: 43, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 44, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 45, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 46, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 47, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 48, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 49, DNA coding sequences for the VAM- AIM fusion proteins translated in AA sequences SEQ ID NO: 50, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 51, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 52, DNA coding sequences for the VAM-AIM fusion proteins with translated AA sequences SEQ ID NO: 53, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 54, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 55, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 56, DNA coding sequences for the VAM- AIM fusion proteins translated in AA sequences SEQ ID NO: 57, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 58, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 59, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences, SEQ ID NO: 60, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences S EQ ID NO: 61, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 62, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 63, DNA coding sequences for the VAM- AIM fusion proteins translated in AA sequences SEQ ID NO: 64, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 65, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 66, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 67, DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 68, or DNA coding sequences for the VAM-AIM fusion proteins translated in AA sequences SEQ ID NO: 69. In some embodiments, the AIM sequence that is part of a GEM can be any one of the amino acid AIM sequences within the accompanying sequence listing and/or an amino acid sequence encoded by any one of the nucleic acid sequences for an AIM sequence within the accompanying sequence listing. In some embodiments, the AIM is any one or fragment thereof of an amino acid encoded by SEQ ID Nos: 35-40 or 71, 73, 75, 77, 79, and/or 81. In some embodiments, the AIM is any one or fragment thereof of the amino acid sequence within SEQ ID NO: 70, 72, 74, 76, 78, and/or 80. In some embodiments, the AIM can be taken from any one (or fragment thereof) of the AIM contained within the larger amino acid sequence encoded by one of SEQ ID Nos: 41-69. In some embodiments, the GEM can include an AIM of any one of those from SEQ ID NOs: 70- 81 (in protein form), and the AIM can be substituted for any one of the AIM sections in SEQ ID Nos: 41-69 (so the VAM can be the VAM section of any of the amino acids encoded by SEQ ID Nos: 41-69.

[0102] In some embodiments, a method of manufacturing the genomically engineered molecule (GEM) composition is described. The method comprises amplifying DNA sequences encoding the VAM and the AIM, synthesizing DNA sequences by extension overlap or by Gibson assembly with cloning overhangs, cloning DNA sequences coding VAM and AIM into pCMV-SV40 ds DNA vector, transfecting human myeloma cells, expressing in human Myeloma cells, and affinity isolation and/or purification.

[0103] In some embodiments, the virus attaching molecules VAM is transgenically expressed after being selected from one of the DNA coding sequences : SEQ ID No: 1, SEQ ID NO:2, SEQ ID NO: 3, SEQ ID NO:4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID No: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, or SEQ ID NO: 29, wherein the pCMV-INS-SV40 DNA vector comprises SEQ ID NO: 30. In some embodiments, cloning is achieved by synthesis and overlap extension of the DNA sequences comprising by extension overlap cloning overhangs of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, or SEQ ID NO: 34 to facilitate inserting into the plasmid pCMV-INS-SV40 SEQ ID NO: 30..

[0104] In some embodiments that the DNA coding sequence for AIM is DNA sequence or its fragment selected from SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, such that the p_CMV-INS-SV40 DNA vector comprises SEQ ID NO: 30. In some embodiments, the protein encoded by this DNA is employed in the GEM itself.

[0105] In some embodiments, the apheresis initiating molecule (AIM) domain comprises the amino acid sequence present within fusion VAM-AIM protein, while encoded by the DNA nucleic acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82.

[0106] In some embodiments, the method of manufacturing the GEM composition further comprises at least one of: making the SPM, making a functionalized SPM, making a functionalized VAM, and providing click chemistry between a functionalized SPM and a functionalized VAM through conjugation reactions of linker-enabled stable bonds. In some embodiments, the method further comprises sterilizing the composition in a sealed vial.

[0107] In some embodiments, the method further comprises reacting a Fe and

O containing compound to create a Fe₃04 superparamagnetic core; and reacting the superparamagnetic core with an Au containing compounds to create a core- shell superparamagnetic nanoparticle ({Fe₃0₄} Au), such that the {Fe₃0₄} core is covered with an Au shell.

[0108] In some embodiments, the method further comprises reacting a Fe and O containing compound to create a Fe₃04 as superparamagnetic core; and reacting the superparamagnetic core with a Si and O containing compound to create a core-shell superparamagnetic nanoparticles ({Fe₃0₄}Si0₂, such that the core {Fe₃0₄} is covered with a Si0₂ shell.

[0109] In some embodiments, the method further comprises reacting Ni, Co, Tb, Eu containing compounds to create solid superparamagnetic nanoparticles. [0110] In some embodiments, the method further comprises making a functionalized SPM by reacting SPM with a chemical linker selected from the group consisting of EDC, TPA, PTAD, PEAD, APTES, SPDP, SMCC. In some embodiments, the method further comprises making a functionalized VAM by reacting a VAM with a chemical linker selected from the group consisting of: EDC, TPA, PTAD, PEAD, APTES, SPDP, SMCC

[0111] In embodiments where the GEM composition comprises a VAM conjugated to a fluorescent (F) molecule, the method comprises making a functionalized fluorescent (F) molecules, making a functionalized VAM, and providing click chemistry between functionalized fluorescent (F) molecules and functionalized VAM through conjugation reaction of linker-enabled stable bonds.

[0112] In some embodiments, making a functionalized fluorescent (F) molecule comprises reacting the fluorescent (F) molecule with a chemical linker selected form the group consisting of: EDC, TPA, PTAD, PEAD, APTES, SPDP, SMCC. In some embodiments, making a functionalized VAM comprises reacting a VAM with chemical linker selected from the group consisting of: EDC, TPA, PTAD, PEAD, APTES, SPDP, SMCC. In some embodiments, the method further comprises reacting terbium (Tb) and Europium (Eu) to create nanoparticles having fluorescent properties.

[0113] In some embodiments, a method of treatment comprising administering the GEM composition, described herein, to a patient. In some embodiments, the method comprises intra-venous (i.v.) infusion, intra-lymphatic (i.l.) infusion, subcutaneous (s.c.) injection, intra muscular (i.m.) injection, or intra-cerebrospinal (i.c.s.) fluid injection.

[0114] In some embodiments, a use of the GEM composition described herein or produced by the method described herein for the treatment of a disease related to a virus occurring in a patient’s body, such that the virus causes viremia, is provided.

[0115] In some embodiments for the method of treatment or the use, the virus is selected from the group consisting of: Corona Virus (CoV), Chickenpox Virus aka Varicella Zoster Virus aka HHV3 (VZV), Dengue Virus (DENV), Ebola Virus (EBOV), Hepatitis A Virus (HAV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Herpes Virus 1/2 aka Herpes Simplex Virus aka HSV 1/2 (HHV1/2), Herpes Virus 4 aka EBV (HHV4), Herpes Virus 5 aka CMV (HHV5), Human G Virus aka HHV6 (HGV), Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Influenza Virus (IV), Roseolovirus aka RosV (HHV7), Kaposi Sarcoma Associated Virus aka KSAV (HHV8), Mumps Virus (MuV), Measles (MeV), Polio Virus (PV), Rotavirus (RoV), Rabies Syndrome Virus (RaV), Rubella Virus (RuV), Smallpox Virus aka Variola Virus (VARV), Yellow Fever Virus (YFV), and Zika Virus (ZiV).

[0116] In some embodiments, at least one of the following VAM can be used for one of the denoted viral infections, as described herein using the method of treatment or use as described herein: DPP4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 001), or a binding fragment thereof, for CoV, heparan sulfate (HS)/neurokinin receptor (NK1R) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 2-3), or a binding fragment thereof, for VZV, TIM- l(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for DENV, TIM- 1 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for EBOV, TIMl/HAVCRl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004-005), or a binding fragment thereof, for HAV, NTCP(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 006), or a binding fragment thereof, for HBV, TIMl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for HCV, heparan sulfate (HS)/CLEC4M (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 002/007), or a binding fragment thereof, for HHV4, CRl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 008), or a binding fragment thereof, for HHV5, CD4(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014), or a binding fragment thereof, for HHV7, EphA2R(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 0l5), or a binding fragment thereof, for HHV8, CD 81 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 016-017), or a binding fragment thereof, for HGV, CD4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014), or a binding fragment thereof, for HIV, ITGA6(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 018- 021), or a binding fragment thereof, for HPV, nectin (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 022), or a binding fragment thereof, for HSV 1/2, sialylated glycans (SG) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 023), or a binding fragment thereof, for IV, TIM-l(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for MuV, TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for MeaV, CD155 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 024-025), or a binding fragment thereof, for PV, a2b1- integrin (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 026), or a binding fragment thereof, for RoV, AchR(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 027-028), or a binding fragment thereof, for RaV, CD4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014), or a binding fragment thereof, for RuV HIV, chondroitin sulfate (CS) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 029), or a binding fragment thereof, for VARV, TIMl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for YFV, or TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for ZikV. It is noted that the above sequences recite nucleic acid sequences and that it is the amino acid sequence encoded by those sequences that are present in the final GEM. Thus, wherever a reference to a nucleic acid sequence is made herein, when referencing an amino acid sequence, it is to be understood that the amino acid sequence inherently encoded by the recited nucleic acid sequence is being used in the GEM composition, method, use, etc, unless DNA aspects are specifically called for.

[0117] In some embodiments, the virus-specific GEM is attained by genomic engineering of DNA sequences specific for selected GEM expressed and affinity purified, such that the virus -specific GEM is attained by biochemical affinity purification. In some embodiments, the use of the GEM further comprises infusion of a sterile composition and removing from the patient’s body by a GEM-aided apheresis pursued in a magnetic field generating instrument, wherein the composition is sterilized in sealed vials.

[0118] In some embodiments, the magnetic field generating instrument comprises at least one of: extra corporeal magnetic filters, intra-corporeal magnetic filters, personal external magnets, or personal internal magnets.

[0119] In some embodiments, a method of treating a subject is described. The method comprises providing a subject to be treated, and administering at least one of the GEM composition as described herein to the subject in an amount sufficient to allow binding of the GEM in the composition to a target protein in the subject, and removing the target protein and any associated biological material with the target protein, from the subject via a magnetic action on the SPM in the composition. In some embodiments, if the target material is removed ex vivo, the method comprises cleaning of subject’s blood or lymph of the SPM and material associated therewith. [0120] In some embodiments, the method can be used with a subject that is identified as having a virus selected form the group consisting of: Corona Virus (CoV), Chickenpox Virus aka Varicella Zoster Virus aka HHV3 (VZV), Dengue Virus (DENV), Ebola Virus (EBOV), Hepatitis A Virus (HAV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Herpes Virus 1/2 aka Herpes Simplex Virus aka HSV 1/2 (HHV1/2), Herpes Virus 4 aka EBV (HHV4), Herpes Virus 5 aka CMV (HHV5), Human G Virus aka HHV6 (HGV), Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Influenza Virus (IV), Roseolovirus aka RosV (HHV7), Kaposi Sarcoma Associated Virus aka KSAV (HHV8), Mumps Virus (MuV), Measles (MeV), Polio Virus (PV), Rotavirus (RoV), Rabies Syndrome Virus (RaV), Rubella Virus (RuV), Smallpox Virus aka Variola Virus (VARV), Yellow Fever Virus (YFV), and Zika Virus (ZiV).

[0121] In some embodiments, at least one VAM can be used for a viral infection as noted above. For example, DPP4 (encoded by SEQ ID NO: 1), or a binding fragment thereof, can be used for the treatment of CoV. In some embodiments, TIM-l(encoded by SEQ ID NO: 004), or a binding fragment thereof, can be used for the treatment of DENV. In some embodiments, TIM-l(encoded by SEQ ID NO: 004), or a binding fragment thereof, can be used for the treatment of EBOV. In some embodiments, TIMl/HAVCRl(encoded by SEQ ID NO: 004-005), or a binding fragment thereof, can be used for the treatment of HAV. In some embodiments, NTCP(encoded by SEQ ID NO: 006), or a binding fragment thereof, can be used for the treatment of HBV. In some embodiments, TIMl(encoded by SEQ ID NO: 004), or a binding fragment thereof, can be used for the treatment of HCV. In some embodiments, heparan sulfate (HS)/CLEC4M (encoded by SEQ ID NO: 002/007), or a binding fragment thereof, can be used for the treatment of HHV4. In some embodiments, CRl(encoded by SEQ ID NO: 008), or a binding fragment thereof, can be used for the treatment of HHV5. In some embodiments, CD4(encoded by SEQ ID NO: 009-014), or a binding fragment thereof, can be used for the treatment of HHV7. In some embodiments, EphA2R(encoded by SEQ ID NO: 015), or a binding fragment thereof, can be used for the treatment of HHV8. In some embodiments, CD81 (encoded by SEQ ID NO: 016-017), or a binding fragment thereof, can be used for the treatment of HGV. In some embodiments, CD4 (encoded by SEQ ID NO: 009- 014), or a binding fragment thereof, can be used for the treatment of HIV. In some embodiments, ITGA6(encoded by SEQ ID NO: 018-021), or a binding fragment thereof, can be used for the treatment of HPV. In some embodiments, nectin (encoded by SEQ ID NO: 022), or a binding fragment thereof, can be used for the treatment of HSV1/2. In some embodiments, sialylated glycans (SG) (encoded by SEQ ID NO: 023), or a binding fragment thereof, can be used for the treatment of IV. In some embodiments, TIM- 1 (encoded by SEQ ID NO: 004), or a binding fragment thereof, can be used for the treatment of MuV. In some embodiments, TIM-l (encoded by SEQ ID NO: 004), or a binding fragment thereof, can be used for the treatment of MeaV. In some embodiments, CD155 (encoded by SEQ ID NO: 024- 025), or a binding fragment thereof, can be used for the treatment of PV. In some embodiments, a.2p i -intcgnn (encoded by SEQ ID NO: 026), or a binding fragment thereof, can be used for the treatment of RoV. In some embodiments, AchR (encoded by SEQ ID NO: 027-028), or a binding fragment thereof, can be used for the treatment of RaV. In some embodiments, CD4 (encoded by SEQ ID NO: 009-014), or a binding fragment thereof, can be used for the treatment of RuV HIV. In some embodiments, chondroitin sulfate (CS) (encoded by SEQ ID NO: 029), or a binding fragment thereof, can be used for the treatment of VARV. In some embodiments, TIMl(encoded by SEQ ID NO: 004), or a binding fragment thereof, can be used for the treatment of YFV. In some embodiments, TIM-l (encoded by SEQ ID NO: 004), or a binding fragment thereof, can be used for the treatment of ZikV.

[0122] In some embodiments, a method of treating a subject is described. The method comprises infusion to the subject of any one of the GEM composition as described herein as a sterile composition, removing from the subject’s body a portion of the subject’s blood, conducting apheresis via a magnetic field on the portion of the subject’ s blood to provide a cleaned portion of the blood or lymph, and optionally returning the cleaned portion of the blood to the patient.

[0123] In some embodiments, a GEM composition is provided. The composition comprises a virus-attaching-molecule (VAM), wherein the VAM is soluble; a chemical linker; and a superparamagnetic (SPM) nanoparticle or a fluorescent molecule (F). The VAM is conjugated to the SPM or the fluorescent molecule via the chemical linker.

Superparamagnetic domains and molecules

[0124] In some embodiments, superparamagnetic molecules (SPM) are prepared to comprise solid homogenous or core-shell architecture. The solid superparamagnetic particles are used for in vitro diagnosis and research. The core-shell particles are manufactured for in vivo, in patients therapy. In some embodiments, their inner core provides superparamagnetic properties. In some embodiments, the outer layer - shells comprise biologically inert elements to protect the patients from potentially leaking, toxic magnetic material and to offer interfacing layer to link them with GEM.

[0125] In some embodiments, the solid, homogenous, magnetic nickel and iron metal binding domains / particles are synthesized according to classical protocols. [20, 37, 38] Therefore, the magnetic properties of genomically engineered molecules are gained either by incorporation of superparamagnetic entities into the structure of genomically engineered molecules or by attaching of superparamagnetic particles to the genomically engineered molecules. Chemical reactions involved in linking biomolecules and metalic entities are described herein. [35, 36, 39, 40]

[0126] The {Fe₃0₄}Au core-shell particles comprise Fe₃0₄ or Ni cores and Au or Si0₂ shells engineered according to classical protocols adopted in this project [37, 41]. Briefly, the cores are synthesized by mixing aqueous solutions of FeCl₃ x 6H₂0 / FeCl₂x4H₂0 in ½ molar ratio, followed by adding lm NaOH and stirring initially at room temperature, that was gradually increased to 90 deg. C for lh. The process is completed by multiple cycles of rinsing with water. The superparamagnetic particles are then retained by magnets and dispersed in water as ferrofluid.

[0127] An alternative protocol for iron oxide particles involved dextran capping. In this approach, 150 mM of FeCl₃ and FeCl₂ were dissolved in a 10 wt % T40 dextran solution. The solution was cooled at 4 deg C. At this point 25 vol % ammonia added to the ice cold solution. The temperature was raised to 75 deg C and kept for 1 h. That followed to cooling to room temperature. The form magnetic particles were separated from non-reacted reagents by placing in the 3T magnetic field and aspiration the solution from above the precipitate and re suspending after removal from the field at least 5x. Separation of particles with different diameter was done by centrifugation at various g, with the pellets formed at 25,000g used for further works. For forming dextran caps, the solution containing particles at 5 mg/mF iron concentration was spiked with ECH (5-20 vol%) while for 4 h. The particles then were sterile filtered to be stored at 4 deg C.

[0128] The gold shells for aforementioned SPM are prepared according to the modification of the classical Turkevich procedure. [41] The aliquots of the ferrofluid are mixed with HAuCU, that is immediately followed by adding 100 mM NH₂OH with constant stirring. The thickness of the shells was determined empirically monitoring time and changes in absorption at 400 nm indicative of depletion of Au.

[0129] The silica shells are prepared according to the modification of the classical Stober procedure [37]. We have developed a protocol which relied upon silane shells assembled over dextran caps. To 10 ml solution of the SPM capped with dextran at 5 mg/mL After functionalization of dextran, the solution sock solution a freshly prepared APTES was added up to 1 % vv. The reaction continued at room temperature in nitrogen atmosphere for lh. After removing the supernatant, the pellet was resuspended again in 10 ml of 10: 1 ethanol : ammonia mixture. To the solution of SPM, 3.5 ml of tetraethoxysilane (TEOS) was added under the fume hood in the nitrogen atmosphere. The sealing reaction continued for 24h under the fume hood at the nitrogen atmosphere. The reaction was stopped by spinning the solution at 4 deg C at 25,000g for 30 min and resuspending in ethanol ; ammonia mixture at least 5 times, while the last resuspension was with ethanol only without ammonia. This reaction sealed SPM cores within the solid silica shells: {Fe₃0₄}Si0₂.

[0130] Having the batch of {Fe₃0₄}Si0₂ ready, the tgCD4 was functionalized by adding 1 ml of NaI04 solution to 0.1 mg/ml tgCD4 solution of 0.15 M NaCl, 0.010 M phosphate buffer pH 7.0 in the darkness at room temperature for 15 min. To stop the reaction, we added 1 ml of glycerol and running through the desalting column, while collecting the fractions determined on the spectrophotometer on the fraction collector at 280 nm. The fractions were pooled together and adjusted to 10 mg/ml and stored at 4 deg C. At this point, the core-shell superparamagnetic particles SPM {(Fe₃0₄)Si0₂}were functionalized by reacting in 1 % solution of APTES for 1 h in oxygen free containers, flushed with nitrogen, at 60 deg C, for 1 h. The reaction was stopped by spinning the activated SPM at l5,000g for 30 min at room temperature of 24 deg C and re-suspending in water at least 5 times. Having both solutions ready, we proceeded with conjugating them. To 10 ml of tgCD4 solution, the functionalized {(Fe304)Si02| SPM were added at 13 nM concentration to attain 10 x molar concentration over tgCD4. The CD4-SPM conjugates were cleared from non-reacted reagents by spininning them at l5,000g for 30 min at 4 deg C for at least five cycles. The elemental map of the resulting GEM-SPM: {(Fe304)Si02| is shown in the FIG. 7. At that point, GEM- SPM were ready to be sterilized and used. Rapid removal of viruses with HIV Apheresis as an example

[0131] The GEM-SPM are utilized for virus apheresis in vitro or in vivo.

[0132] For in vitro apheresis, 100 ml of blood, lymph or 10 ml of cerebrospinal fluid (CSF) were acquired from the specific virus infected patients, who suffered viremia into the sterile vials in the sterile rooms by the aseptic procedure of the certified MD in the sterile environment of the surgical suite. The samples were prevented from coagulation by provision of EDTA anticoagulant. The vials were sealed with the sterile rubber plug containing caps. Then, 10 ml of the uniquely specific GEM-SPM was spiked into the blood, lymph, or CSF; for example, GEM-SPM being CD4-({Fe₃0₄}Au) was spiked into the blood, lymph, or CSF of the patient infected with HIV and suffering HIV viremia. The sealed vials closed into the sealed containers containing ice at 4 deg C. In these containers, blood, lymph, or CSF samples were transferred into 1 m proximity of the Clinical Magnetic Resonance Imagers (Signa, GE), which were on stand-by, thus not generating alternative field. They were operating at 1.5T or 3T. The samples were left for 1 hour on ice in that field. Presence in the magnetic field resulted in accumulation of the visual precipitate. While in the magnetic field, the sterile needle on a large sterile syringe was inserted through the rubber plug into the blood, lymph, or CSF containing vial, and aspiration of the virus free samples was aspirated. Both, the vials containing the GEM- SPM capturing the virus and the syringes with purified blood, lymph, or CSF were removed from the field. They were sampled for testing by polymerase chain reaction for presence of the virus count and by flow cytometry of the CD4+ cell count. The cycles of apheresis could be repeated depending on the outcome of the process determined by PCR and FCM as shown in the data provided herein.

[0133] The in vivo apheresis was imitated by 100 ml of blood acquired as above was filling the closed circulation system assembled from the tubing of the kidney dialysis system, that was propelled by the peristaltic pump (ABS) at the rate of 150 ml/min. The system was maintained at 37 deg C. The distal loop of the tubing, was connected through on line butterfly valves to the on-line buldge. The bulge was was located in the proximity of the magnet generating 7T stable magnetic field. The GEM-SPM as described above were very slowly injected into the circulation. After 1 h from the injection, the pump was topped, butterfly valves closed, and buldge removed from the circulating system. The samples from the circulating blood and GEM-SPM harboring the virus were studied by PCR and FCM to determine the HIB count and CD4+ cells population.

[0134] The outcomes were studied on two ways. First, to determine the HIV count, both, superparamagnetic (retained by the GEM-SPM held by magnetic fields) and diamagnetic (non-magnetic, thus not retained by magnetic field) materials, but separately, were processed through reverse transcription and polymerase chain reaction as outlined in details in the next section (RT-PCR). [30-34] Second, to determine CD4 expression and display as measures of HIV-infected populations, the samples were lysed for processing with RT and PCR aided by the primers, which sequences of the five known transcripts of CD4 were imported from the GenBank and synthesized. [35,36] Alternatively, the cells were labeled with superparamagnetic antibodies against CD4 to be quantified by NMR as or with fluorescent antibodies to be quantified by FCM as outlined in details in the next sections (FCM, FACS, NMR, MACS). [21, 26, 27]

[0135] FIG. 7 is an EDXS spectrum illustrating the elemental composition of some embodiments of a genomically designed superparamagnetic molecule (GEM-SPM) specifically CD4 (Fe304@Si02). It was determined with EDXS through revealing the energy edge peaks for iron (Fe), oxygen (O), silica (Si), carbon (C), chlorine (Cl).

[0136] FIG. 8 is a p-CMV-INS-SV4 map that supplements the sequence of cloning vector sequence (SEQ ID NO: 30). FIG. 8 illustrates the location of the CMV promoter, MCS and STOP. With pointing restriction sites, it also illustrates positioning of the overhangs for Nhel and MamHI, which are used for cloning and expression (SEQ ID NO: 31-34).

[0137] FIG. 9. is an EDXS spectrum illustrating the elemental composition of some embodiments of a genomically designed superparamagnetic molecule (GEM-SPM) specifically CD4-(Fe304@Au). It was determined with EDXS through revealing the energy edge peaks for iron (Fe), oxygen (O), gold (Au), carbon (C), chlorine (Cl).

[0138] Progression of virus-caused diseases can only occur through continuous infections by viruses of preferred cells and hijack their metabolism for the virus self replication. Viral infections are the primary cause of debilitating diseases and deaths World wide. While currently approved vaccines (e.g., HBV Vaccine) prevent some of them, new viruses (e.g., HIV) or new viruses’ strains, which are evading vaccination acquired immunity or therapy emerge (e.g., influenza), that make vaccines ineffective. Moreover, currently approved therapies, while suppressing replication mechanisms, cause serious adverse effects. Nevertheless, none of the currently approved approaches removes the viruses infected cells from the infected patients’ bodies. Herein, we disclose and claim designs, manufacturing processes, and utility of not reported before, not obvious, genomically engineered molecules (GEMs), which facilitate removing of the virus -infected cells from the patients’ bodies by GEMs-aided apheresis.

[0139] In some embodiments, a Genomically engineered antibodies (GEA) can be employed, which is distinct from a VAM, as the antibody is not a molecule that the virus attaches to (instead, it is the antibody that binds to the virus, and thus, is a different and distinct concept). In some embodiments, a genomically engineered receptors (GERs) aka virus entry molecules (VEM, e.g., gpl20) can be employed. In the case of HIV, the CD4 is the primary HIV entry molecule. In some embodiments, an antibody can be linked to a SPM. In some embodiments, a VAM is employed, to which a virus binds.

[0140] In some embodiments, the methods provided herein can be used for treatment of deadly diseases that progress through viremia and kill while no treatment available (e.g., Ebola) or not recommended (e.g., Zika in pregancy). In some embodiments, the treatment has no adverse effects.

[0141] Treatment denotes the lessoning of symptoms and/or the slowing of the onset of disease or the extension of symptom free or life duration for the subject. It does not require the full removal of any disease bearing tissue or cell or viral particle from the patient.

[0142] In some embodiments, at least 50% of the viral particles and/or cells are removed from the subject, e.g., at least 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.9, 99.99, or greater percent has been removed from the subject after therapy.

Superparamagnetic domains and molecules

[0143] Superparamagnetic molecules (SPM) were prepared to comprise solid homogenous or core-shell architecture. The choice of the supermagnets can be driven by the particular application. The solid superparamagnetic particles are used for in vitro diagnosis and research. The core-shell particles are manufactured for in vivo, in patients therapy. Their inner core provides superparamagnetic properties. The outer layer - shells comprise biologically inert elements to protect the patients from potentially leaking, toxic magnetic material and to offer interfacing layer to link them with GEMs.

[0144] The solid, homogenous, magnetic nickel and iron metal binding domains / particles are synthesized according to classical protocols adopted in this project. [20, 37, 38] Therefore, the magnetic properties of genomically engineered molecules are gained either by incorporation of superparamagnetic entities into the structure of genomically engineered molecules or by attaching of superparamagnetic particles to the genomically engineered molecules. Chemical reactions involved in linking biomolecules and metalic entities are described in the details. [35, 36, 39, 40]

[0145] The core-shell particles comprise Fe₃0₄ or Ni cores and Au or Si0₂ shells engineered according to classical protocols adopted in this project. [37, 41] Briefly, the cores are synthesized by mixing aquous solutions of FeCh x6H₂0 / FeCl₂x4H₂0 in ½ molar ratio, followed by adding lm NaOH and stirring initially at room temprerature, that was gradually increased to 90 deg. C for lh. The process is completed by multiple cycles of rinsing with water. The superparamagnetic particles are then retained by magnets and dispersed in water as ferrofluid. The gold shells are prepared according to the modification of the classical Turkevich procedure. [41] The aliquots of the ferrofluid are mixed with 01.% HAuQ4, that is followed by adding 100 mM NH20H. The thickness of the shells was determine empirically monitoring time and changes in absorption at 400 nm indicative of depletion of Au. The sillica shells are prepared according to the modification of the classical Stober procedure. [37] The solution is added to the aliquots of the ferrofluid and multiple cycles of incubation for lh at 90 deg. C, that are followed by multiple rinses with water.

[0146] In some embodiments, a method of treating a subject having a virus -induced disease is provided. The method comprises removing one or more virus-infected cells and/or an infecting virus from a subject by magnetic apheresis. Apheresis is performed using a genomically engineered molecule (GEM), wherein the GEM comprises any one of the GEMs from claims 1-8, and wherein the SPM within the GEM allows for the use of a magnetic field to achieve apheresis to remove the virus-infected cells and/or virus from the subject.

[0147] In some embodiments the GEM for the above method comprises an antibody against an envelope or capsid molecule of a virus in the subject, the virus is selected from the group consisting of: California Encephalitis Virus, Chickengunya Virus, Coronavirus, Dengue Virus, Ebola Virus, Hanta Virus, Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus, Hepatitis D Virus, Human Herpes Virus 1, Human Herpes Virus 2, Human Herpes Virus 3 - Chickenpox - Varicella, Human Herpes Virus 4 - EBV., Human Herpes Virus 5 - CMV, Human Herpes Virus 6, Human Herpes Virus , Human Herpes Virus 8, Human Parainflunza Virus type 1, Human Parainflunza Virus type 2, Human Parainflunza Virus type 3, Human Parainflunza Virus type 4, Human Respiratory Syncytial Virus - HRSV, Influenza A Virus, Influenza B Virus, Influenza C Virus, Lymphocytic Choriomeningitis Virus, Marburg Virus, Mumps Virus, Measles Virus, Rabies Virus, Rubella Virus, Smallpox Virus, West Nile Virus, Yellow Fever Virus, and Zika Virus.

[0148] In some embodiments, of the method, the GEM comprises a virus attachment and entry molecule as a VAM that binds to one or more of the following viruses: California Encephalitis Virus, Chickengunya Virus, Coronavirus, Dengue Virus, Ebola Virus, Hanta Virus, Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus, Hepatitis D Virus, Human Herpes Virus 1, Human Herpes Virus 2, Human Herpes Virus 3 - Chickenpox - Varicella, Human Herpes Virus 4 - EBV, Human Herpes Virus 5 - CMV, Human Herpes Virus 6, Human Herpes Virus 7, Human Herpes Virus 8, Human Parainflunza Virus type 1, Human Parainflunza Virus type 2, Human Parainflunza Virus type 3, Human Parainflunza Virus type 4, Human Respiratory Syncytial Virus - HRSV, Influenza A Virus, Influenza B Virus, Influenza C Virus, Lymphocytic Choriomeningitis Virus, Marburg Virus, Mumps Virus, Measles Virus, Rabies Virus, Rubella Virus, Smallpox Virus, West Nile Virus, Yellow Fever Virus, and Zika Virus.

[0149] In some embodiments, the SPM comprises at least one of: Ni, Co, Fe, Eu, and/or Gd.

[0150] In some embodiments, the SPM comprises a core and a shell and wherein the shell comprises at least one of: Au, Pd, Ag, Pt, Si, Apatite, or Carbide.

[0151] In some embodiments, the SPM comprises at least one of: DTPA, EDTA, DOTA, His, Glu, Asp, Lys, or Cys.

[0152] In some embodiments, the GEM is administered by: intravenous infusion, subcutaneous injection, intramuscular injection, intra-lymphatic system infusion, and/or injection into fluids in apheresis machines. [0153] In some embodiments, apheresis employs at least one of: blood or lymph extra-vessel magnetic filters, blood or lymph intra-vessel magnetic filters, personal external magnets, personal internal magnets, magnetic over-flown surfaces in apheresis machines, magnetic needles, and/or magnetic filters in apheresis machines.

EXAMPLE I

Healthy Donors and HIV+ Patients

[0154] Per the Institutional Review Board approval and in compliance with the Declaration of Helsinki, all healthy donors and patients were presented with the Patient Bill of Rights and provided Patient Informed Consent with their identities entirely concealed, while all the procedures involving them were pursued by the licensed physicians.

[0155] Six healthy volunteers (three women, three men) had no past or present diseases in their medical records, so they were not taking any medications. Results of their routine laboratory tests of blood, with emphasis on ESR and immunoglobulin profiles, and of urine, with emphasis on potential presence of cells and proteins, were within laboratory norms.

[0156] Three oncology patients (all males) were diagnosed with Kaposi sarcomas. Their blood routine laboratory tests revealed low counts of CD4+ lymphocytes, but increased ESR. These results prompted us to test for Human Immunodeficiency Virus (HIV), Herpes Simplex Virus (HSV), Cytomegalo-virus (CMV). The HIV test came out positive, but the HSV and CMV tests came out negative. These patients had not received any therapy yet.

[0157] Five oncology patients (three women, two men) were diagnosed Multiple myelomas. Their blood routine laboratory tests revealed high ESR. These results prompted us to test for protein profiles, which revealed high immunoglobulin. Their urine routine laboratory tests revealed protein presence, identified as Bence-Jones protein. These patients were treated by aspiration of pleural and peritoneal effusion as the first therapeutic steps. EXAMPLE2

Blood, lymph, plasma, effusion, virus

[0158] Processing, storage, and culture of blood, erythrocyte-free blood, peritoneal or pleural effusions, lymph, and plasma were pursued according to the original, detailed protocols published earlier and only briefly outlined here. [20-27] Blood was drawn according to the standard clinical procedure by venipuncture into citric acid / dextran receiving buffer. It was stored at 4 deg. C until further processing. For virus binding assays, the blood was depleted of fibrinogen and calcium (later re-adjusted to physiological levels). Erythrocyte-free blood was prepared by magnetophoresis aided by antibodies conjugated with magnetic beads. Plasma was prepared by simple sedimentation and collecting supernatant or alternatively sampled during plasmapheresis. T cell fractions were prepared by activated sheep erythrocyte resetting. B cells were removed by complement receptor activated lysis. Desired cell fractions were enriched by FACS after labeling with fluorescent antibodies followed or by MACS after labeling with superparamagnetic antibodies. Plasma and B cells were isolated from erythrocyte-free blood by MACS after labeling with anti-CD 19 and anti-CD20 magnetic antibodies. [21, 26, 27]. Lymph was acquired according to the standard clinical procedure during surgeries on open abdomens. The viruses and cells from lymph were prepared according to the protocols for erythrocyte-free blood. All the samples were processed in two ways: secured for long term storing or immediately upon being drawn. For storing, the samples were prepared by cryo-biobanking. The samples were equilibrated with 10% DMSO in the patients’ serum at 4 deg C. They were frozen according to the gradual lowering temperature down to - 35 deg C, -70deg C, -196 deg C per 24 h on each step. (These samples were stored indefinitely without compromised quality. When needed, these samples were thawed according to the reverse-to-freezing protocol for processing. Alternatively, the total RNA was prepared and either stored as such or converted into cDNA for storing and / or shipping [27, 29]. For immediate processing, the HIV+ patients’ viremia in blood, lymph, or plasma were tested by reverse transcription and polymerase chain amplification of the sequences nested by the primers designed upon the published HIV-l sequences in PubMed / GenBank from the samples generated by isolation of total RNA [22, 23, 24, 27, 29, 30, 31, Sequence Listing]. Healthy donors’ blood, lymph, and plasma served as the controls and processed in parallel to those of the HIV+ patients. For research, the samples acquired from the HIV+ patients, whose HIV count were adjusted to the experimental levels were spiked with GEMs as indicated in the Results. The infected samples in vials were incubated at the desired time at 37 deg. C and 5 % C02 while on the gyroscopic tables. Depending on the plans for further tests, lysis of the cells was pursued in two buffers: NP40 and RIPA, as outlined in the forthcoming section (IP and IL). In NP40, they were prepared for immunoprecipitation. In RIPA, they were prepared for immunoblotting .

[0159] HIV was aspirated from the peritoneal or pleural effusions of the HIV+ oncology patients, who were diagnosed with Kaposi sarcoma. Of these sterile effusions, 100 microliters containing the HIV copy number determined by RT-PCR, was injected into in the H9 culture (ATCC) and propagated strictly according to the published protocols [24, 25].

Rapid removal of HIV - HIV Apheresis

[0160] Removal of HIV aka HIV Apheresis was also as it is already outlined above, pursued three ways.

[0161] First, the GEM treated samples in metal-free vials were exposed to the uniform, steady magnetic field from 0.5 T - 7.0 T. The superparamagnetic content of the samples was retained by magnetic field through GEMs. The diamagnetic content of these samples was aspirated.

[0162] Second, the samples were filtered through the polystyrene-coated magnetism-inducible gauze inserted into the steady magnetic field from 0.5 T - 7.0 T. The GEM labeled material was retained by the magnetic field, but non-magnetic flow-through was collected. Thereafter, the GEM tagged material was immediately released, to separate from flow-through vials, upon removal from the influence of magnetic field.

[0163] Third, the GEM treated blood or lymph was flown over large magnetic surface that was retaining GEM tagged virus on the flow.

[0164] The outcomes were studied on two ways. First, to determine the HIV count, both, superparamagnetic (retained by the GEM (including SPM) held by magnetic fields) and diamagnetic (non-magnetic, thus not retained by magnetic field) materials, but separately, were processed through reverse transcription and polymerase chain reaction as outlined in details in the next section (RT-PCR). [30-34] Second, to determine CD4 expression and display as measures of HIV-infected populations, the samples were lysed for processing with RT and PCR aided by the primers, which sequences of the five known transcripts of CD4 were imported from the GenBank and synthesized. [35,36] Alternatively, the cells were labeled with superparamagnetic antibodies against CD4 to be quantified by NMR as or with fluorescent antibodies to be quantified by FCM as outlined in details in the next sections (FCM, FACS, NMR, MACS). [21, 26, 27]

Genomically Engineered Molecule (GEM) for HIV attaching molecule GEM (CD4)

[0165] Human CD4, which is virus attaching molecule (VAM) displayed by

CD4+ cells to harbor HIV, was manufactured on three ways: cell lysis - immunoprecipitation - immunoblotting and genomic isolation -amplification - recombination, and DNA fragments synthesis with overlap extension with overhangs for restriction sites for Nhel and BamHI with the sequences provided (SEQ ID NO: 31-24) so that they were easily inserted into the universal plasmid p_CMV-ins-sv40 after it was linearized at the unique single cuts by restricition enzymes Nhel and BamHI with the sequences provided (SEQ ID NO: 30) and the map included (FIG. 8). T lymphocytes from healthy volunteers were initially selected by sheep erythrocyte resetting precipitation followed by B cell complement lysis. Later, these fractions were enriched by CD4+ selection with our anti-CD4 superparamagnetic antibodies on MACS or our anti-CD4 fluorescent antibodies by FACS. As controls, we used OKT4 antibodies secreted by ATCC hybridomas (ATCC) and render them superparamagnetic or fluorescent. [21, 26, 27, For immunoprecipitation, the enriched fractions of the CD4+ cells were lysed with 1% NP40 in 0.010 HEPES pH 6.9 at 4 deg C. The soup was mixed with the anti-CD4, superparamagnetic, genomically engineered antibodies (GEA), incubated for 1 h at 4 deg. C, and inserted into magnetic field at room temperature for 15 minutes. Diamagnetic content was rinsed off, while in the field. The fraction retained by anti-CD4 GEAs was released after the magnetic field ceased. Aliquots of this fraction were electrophoresed on PAGE and transferred onto the PVDF membranes (Amersham) as outlined below. The immunoblots were tested by the standard OKT4 antibody produced by the cell line were initially grown in the recommended cell culture conditions, which we modified so the cells were grown in sera- free media (ATCC). For immunoblotting, the enriched fractions of the CD4+ cells were lysed with RIPA. The lysates were electrophoresed by PAGE and validated as immune-precipitated ones.

[0166] Alternatively, primarily for future expression of the CD4 selected domains, total mRNA was isolated from these cells and stored exactly according to the original Chomczynski protocol. [26, 27] After importing the CD4 mRNA main transcripts’ sequences from GenBank, the primers flanking the CD4 coding sequence were designed with the aid of 5Prime software [NIH] and synthesized. [26, 27, 35, 36, SEQ ID NO: 009-014] These primers served to create cDNA templates, which were cloned into the p_CMV-INS-SV40 as described.

[26] [SEQ ID NO: 30] The choice of the coding cloning vector was contingent upon the future superparamagnetic molecule to be used with. Propagated plasmids were electroporated into the human myelomas, which were established from the oncology patients diagnose with Multiple myelomas, to express the recombinant CD4. [21, 26, 27] The cells were conditioned to grow in the serum-free RPMI media in roller bottles at 37 deg. C and 5% C02 following exactly the protocols as described. [29, 35, 36] Therefore, supernatant could be easily used to test secreted recombinant receptors expressed from all the transcript variant versions by NMR and FCM. [35, 36].

Genomically engineered molecules conjugated with superparamagnetic particles (GEM)

[0167] The GEM molecules are directly absorbed onto surfaces of the aforementioned superparamagnetic particles (SPM) thanks to the cysteine groups incorporated into them as fusion protein expressed from the pertienent DNA sequences coding them (SEQ ID NO: 31-39 If the VAM were to attain superparamgentic capabilities, they had to be linked to bifunctional linkers which were capble of developing covalent bonds with either Au shells or Si02 shells. Those linkers were reacted with transgenically expressed VAM through bifunctional linkers to the -SH, -COOH, or -NH2 groups present on surfaces of the superparamagnetic molecules to form genomically engineered and transgenically expressed VAM as described in the detailed protocols provided (GEM (including SPM)). [20, 39, 40] [FIG. 1] Human Immunodeficiency Virus gpl60, gpl20, gp41, p24

[0168] HIV glycoproteins gpl60, as well as it proteolytic fragments gpl20, gp4l, as well as p24, were prepared from the effusions of the HIV+ oncology patients admitted primarily for treatment of Kaposi sarcomas. Templates were generated by two ways. Total mRNA was isolated from HIV+ producing CD4+ lymphocytes of the HIV+ patients as described. [21, 26, 27,) The gpl60, as well as it fragments for gpl20 and gp4l mRNA was converted from total mRNA into ds cDNA by reverse transcription and polymerase chain reaction aided by the primers for gpl60, gpl20, and gp4l having sequences imported from GenBank and synthesized. [30, 31, 32, 33, 34] The yielded amplicons were inserted into plasmids comprising CMV promoters and metal binding coding sequences or bifunctional linker binding domains as in the details described elsewhere. [21] These plasmids were propagated in Escherichia coli grown in Luria-Bartani media on shakers at 37 deg. C. After isolation of plasmids on Maxipreps (Qiagen), the restriction sites were tested and plasmids cut opened to accept the inserts coding for gpl60, gpl20, gp4l.

[0169] The new plasmids (pCMV-gpl60, pCMV-gpl20, and pCMV-gp4l) were created by inserting the gpl60, gpl20, gp4l, p24 coding sequences synthesized with Nhel and BamHI overhangs by overlap extension into the p_CMV-INS-SV40 after it was linearized with Nhel and BamHI to create the specific overhangs. The plasmid DNA constructs were electroporated into the myeloma cells in cultures established from effusions of the oncology patients diagnosed with Multiple myelomas. The culture media were based upon RPMI1640 (ATCC) supplemented with effusion fluids rather than bovine sera. Alternatively, the HIV was isolated and propagated directly from the patients’ samples. [22, 23, 24]

Anti-CD4, anti-gpl20, anti-gpl60, anti-p24 genomically engineered antibodies (GEAs)

[0170] All HIV+ patients manifested anti-HIV antibodies, which were detected in their blood and lymph with the clinical diagnostic tests. [7] One of these patients manifested also anti-CD4 antibodies.

[0171] Taking advantage of these laboratory results, coding sequences were adopted from the plasma and B cells of these patients, while using them for biomolecular engineering of genomically engineered antibodies (GEAs), which in the process were also rendered magnetic and / or fluorescent. All the procedures of manufacturing of antibodies was pursued as previously described and briefly outlined here. [20, 21, 26, 27]

[0172] The plasma and B cells were selected from blood of HIV+ patients by

MACS and FACS using anti-CDl9 and anti-CD20 magnetic antibodies. Total mRNA was isolated and stored. [22] After importing the human HC and LC sequences [Kabat], the primers were designed with the aid of 5Prime software [NIH] for heavy and light variable chains and synthesized. After reverse transcription, these primers primers served to create cDNA templates, which were cloned into the plasmid containing CMV promoter and SV40 terminal.

[20] [SEQ ID NO: 30] Plasmids were propagated in Escherichia coli grown in the Luria- Bartani media in cultures maintained on the shakers at 37 deg. C. After purification on MaxiPreps [Qiagen], the plasmids were electroporated into the cells in cultures of myelomas, which were established from the effusions of the oncology patients, who were diagnosed with Multiple myelomas. The cells were cultured in RPMI1640 media, but modified on such a way that they were supplemented with the supernatants of the patients’ effusions, but not bovine sera. Later, the cells were conditioned to grow in serum-free media in roller bottles at 37 deg C and 5% C02. [29, 30] Therefore, supernatant could be easily used to test specificity of secreted antibodies. Metal binding domains (MBD) facilitated rendering them superparamagnetic and / or fluorescent, if MBD were saturated with Eu or Tb. The metal binding domains were chosen to provide strong direct binding to activated shells of core-shell superparamagnetic molecules as outlined herein.

EXAMPLE 3— Nuclear magnetic resonance spectroscopy (NMR)

Magnetic, activated cell sorting (MACS)

Magnetic apheresis

[0173] The cells were labeled with the superparamagnetic antibodies as described in details elsewhere.

[0174] The cells were labeled with the superparamagnetic antibodies as described in details elsewhere . [20, 21, 26, 27]. Briefly, the antibodies were dissolved and all washing steps carried in phenol-free, Ca-i- / Mg+- free, PIPES buffered saline solution, supplemented with 20 mM glucose, 10% human serum. The aliquots were dispensed into the magnetism-free NMR tubes (Shigemi). The relaxation times Tl and T2 were measured in resonance to the applied pulse sequences on the NMR spectrometers: DMX 400 WB or AVANCE II NMR (Bruker, Billerica, MA) or the Signa clinical scanners (General Electric).

[0175] The GEM (including-SPMs) and Abs-SPMs were used to isolate the labeled molecules and/or cells from the solution. The labeled cells rendered superparamagnetic properties, which facilitated their isolation on the magnetic, activated cell sorter (MACS) operated at 0.5 T - 1.5 T and / or clinical MRI instruments operating at 0.5 T - 3 T and / or NMR scanners operating at 0.5 T- 7 T (Bruker).

[0176] Apheresis of the GEMs tagged Human Immunodeficiency Virus was conducted on three ways: external field, magnetic filters, and magnetic traps.

Flow cytometry (FCM)

Fluorescent, activated cell sorting (FACS)

Multiphoton spectroscopy

[0177] The cells were labeled with the fluorescent antibodies as described in details elsewhere [20, 21, 26, 27]. They were sorted on the Calibur, Vantage SE, or Aria (Becton- Dickinson). The antibodies were dissolved and all washing steps carried in phenol-free, Ca-i- / Mg+- free, PIPES buffered saline solution, supplemented with 20 mM glucose, 10% human serum. Sorting was performed on Aria, Calibur, Vantage SE (Becton-Dickinson) with the sheath pressure set at 20 pounds per square inch pressure and low count rate. The sorted batches were analyzed on Calibur or Aria using FACSDiva software or on the FC500 (Beckman- Coulter). For the measurement of the fluorescently labeled cells, these settings were tuned at the maximum emission for the Eu chelated antibody at 500V with references to isotype antibodies and non-labeled cells. This assured the comparisons between populations of cells labeled with multiple antibodies without changing the settings on PMTs.

[0178] The fluorescently labeled cells or tissues were imaged with the Axiovert (Zeiss) equipped with the Enterprise argon ion (457 nm, 488 nm, 529 nm lines) and ultraviolet (ETV) (364 nm line) lasers; Odyssey XL digital high- sensitivity with instant deconvolution confocal laser scanning imaging system operated up to 240 frames/s (Noran), and the Diaphot (Nikon) equipped with the diode-pumped Nd:YLF solid state laser (1048 nm line) (Microlase). Energy dispersive X-ray spectroscopy (EDXS)

Electron energy loss spectroscopy (EELS)

X-ray reflection fluorescence spectroscopy (XRFS)

[0179] Elemental analyses were pursued by EDXS, EELS, and XRFS as described earlier [20, 21, 26, 27]. The field emission, scanning transmission, electron microscope FESTEM HB501 (Vacuum Generators) was equipped with the energy dispersive x-ray spectrometer (EDXS) (Noran) and post-column electron energy loss spectrometer (EELS) (Gatan). The cryo-energy filtering transmission electron microscope 912 Omega was equipped with the in-column, electron energy loss spectrometer (EELS) and the energy dispersive x-ray spectrometer (EDXS) (Zeiss). The cryo-energy filtering transmission electron microscopes 410 and 430 Phillips were equipped with the post-column, electron energy loss spectrometers (EELS) and the energy dispersive x-ray spectrometer (EDXS) (Noran). The field emission, scanning electron microscope SEM1530 (Zeiss) was equipped with the energy dispersive x- ray spectrometer (EDXS) (Noran). The field emission, scanning electron microscope 3400 was equipped with the energy dispersive x-ray spectrometer (EDXS) (Hitachi). The S2 Picofox XRFS spectrometer was equipped with a molybdenum (Mo) X-ray target and the Peltier cooled Xflash Silicon Drift Detector (Bruker AXS). Scan times ranged up to 1000 seconds. The ICP standard of 1000 mg/l of mono-element Gallium or Gadolinium (CPI International) was added to 500 microL of each sample to the final concentration of 10 mg/l. Instrument control, data collection, and analysis were under the SPECTRA 7 software (Bruker AXS).

Statistical analysis

[0180] All the measurements were run in triplicates for each sample from six patients. The numbers were analyzed and displayed using statistical analysis software (GraphPad). Data were presented as mean of standard error of the mean (SEM). Statistical significance was calculated by t-test for two groups.

Rapid reduction of the HIV viremia in blood of the HIV+ patients

[0181] Rapid reduction of the HIV viremia in blood of the HIV+ patients thanks to administration of genomically engineered molecules engineered with superparamagnetic molecules (GEMs) is presented in FIG. 2. The GEM portions of the GEMs comprise recombinant CD4. Therefore, they are uniquely and reliably specialized in docking the HIV through its gpl20. The SPM portions of the GEMs comprise superparamagnets. Therefore, they efficiently aid retention of HIV, anchored through its gpl20 docked into CD4 of GEM, by magnetic field. GEM are effective in all heights of the HIV viremia. Equivalent results were acquired for treatment of lymph with GEMs. Although, the antibodies linked to form GEAs (including SPM) were not as effective as CD4. However, the efficacy of the HIV rapid removal is primarily contingent upon the dose and regimen. [43, 44]

[0182] FIG. 2 is a diagram illustrating the rapid reduction of the various heights of HIV viremia in blood of the HIV+ patients by means of GEM aided apheresis. GEM indicates genomically engineered molecule comprising VAM that attaches to the virus and AIM domains and that harbours SPM. The y-axis of the diagram illustrates HIV viremia in the unit copies/ml while the x-axis of the diagram illustrates GEM concentration in the unit pictogram (pg). The HIV copy number was determined in blood by polymerase chain reaction (PCR) with the HIV specific primers. As the GEM concentration increased, the HIV viremia decreased for all three patients - one with 5,000,000 copies/ml of HIV viremia, one with 50,000 copies/ml of HIV viremia, and one with 500 copies/ml of HIV viremia.

Rapid reduction of the viral count

[0183] Rapid reduction of the viral count has long term consequence for the height of the HIV viremia in time; thus spend of progression of the disease towards AIDS as shown in FIG. 3. The presented results compare how viremia, in blood from the HIV+ patients, progresses in absence of administration of GEMs and how it is repressed thanks to the daily administration GEMs and apheresis. Without administration of GEM, viremia may reach hundred thousand copies in a milliliter of blood or lymph in a month. With administration of GEMs the HIV viremia is repressed down to only a few hundred copies of HIV or undetectable by PCR levels contingent upon the concentration and number of cycles of the administered GEM.

[0184] FIG. 3 is a diagram illustrating that the reduction of HIV viremia in blood of the HIV+ patients was maintained over time by means of GEM apheresis. The HIV copy number was determined in blood by polymerase chain reaction (PCR) with the HIV specific primers. The y-axis of the diagram illustrates HIV viremia in the unit copies/ml while the x- axis of the diagram illustrates the number of weeks. The patient who received no treatment, as illustrated the circle, at week one, had HIV viremia increase from about 10² copies/ml at week one to roughly 10⁷ copies/ml at week six. The patient who received GEM apheresis treatment, as illustrated by the square, at week one, had HIV viremia increase from about 10² copies/ml at week one to roughly 2xl0² copies/ml at week six.

Preventive effects onto the progress of the HIV infection

[0185] GEMs have also preventive effects onto the progress of the HIV infection as shown in FIG. 4. These effects were revealed, when the human lymphocytes in cultures with or without GEMs were spiked with 100 copies of HIV adjusted in 100 microliter of blood or lymph from the HIV+ patients. In a week, the HIV copy number in culture without GEM increased to a few thousand copies. During the same time, the HIV copy number in the culture containing GEM prior to infection and treated by magnetic apheresis was retained at very low, down to undetectable by PCR, levels, if the concentration of the preventive GEMs was sufficiently high.

[0186] FIG. 4 is a diagram illustrating the preventive administration of GEM prior to the HIV infection. The preventive administration of GEM prior to HIV infection resulted in significant reduction of the HIV viremia upon infection. The HIV copy number was determined in blood by polymerase chain reaction (PCR) with the HIV specific primers. The y-axis of the diagram illustrates HIV viremia in the unit copies/ml. The x-axis of the diagram illustrates GEM does in pictogram (pg). As shown by the circles, HIV viremia decreased as the dose of GEM increased. When the patient has about 300 copies/ml of HIV viremia in the blood, the HIV viremia in copies/ml decreased as the GEM dose increased. The HIV viremia is roughly 50 copies/ml when the GEM dose is about 1000 pg.

Rapid reducing the HIV viremia

[0187] Reducing the HIV viremia thanks to administration of GEMs resulted in the dramatic reduction of the newly infected CD4+ lymphocytes as shown in FIG. 5. The graph shows, that the number of CD4+ of newly infected, in the samples in which GEMs were applied, was significantly lower than in the samples in which its administration was absent. Therefore, GEM were very effective decoys protecting CD4+ cells against being infected by HIV.

[0188] FIG. 5 is a diagram illustrating the reduction of HIV infection CD4+ cells with the continued administration of GEM. This diagram shows significantly reduced number of CD4+ lymphocytes, which became newly infected with HIV, if infection occurred after the administration of GEM. The CD4+ lymphocyte count was conducted by flow cytometry after labelling with anti-CD4 antibodies rendered fluorescent with phycoerythrin. The y-axis of the diagram illustrates HIV infected CD4+ cells in the unit number of infected cells/mΐ. The x-axis of the diagram illustrates the GEM concentration in picogram (pg). The number of HIV infected CD4+ cells decrease to close to zero when the GEM concentration is roughly 1000

Pg·

Dramatic improvement of the CD4+ cells’ population

[0189] Progression of the HIV infection into AIDS is primarily driven by the cytopathic effects upon CD4+ cells. Administration of GEM caused the dramatic improvement of the CD4+ cells’ population as demonstrated in the FIG. 6. The CD4+ cell counts in blood and lymph cultures were quickly depleted upon the HIV infection with 100 microliters of the blood or lymph from the HIV+ patients. However, when the parallel samples were treated with GEMs followed by daily session of apheresis and replenishing of fresh batches of GEMs, populations of the CD4+ cells were retained near borders of the low norm levels; thus in clinical practice giving the time for the infected patient immune system to assemble immune response.

[0190] FIG. 6 illustrates the reduction of CD4+ lymphocyte count after HIV infection when no treatment was administered versus retaining solid levels of healthy CD4+ cell counts, when GEM-aided apheresis treatment was administered of no treatment . CD4+ lymphocyte population is protected by the administration of GEM, which is repressed in the viral count, therefore is reducing CD4+ lymphocyte cytopathic depletion. The CD4+ lymphocyte count was conducted by flow cytometry after labelling with anti-CD4 antibodies rendered fluorescent with phycoerthrin. The y-axis of the diagram illustrates the CD4+ lymphocyte count in the unit number of lymphocyte per millilitre and the x-axis of the diagram illustrates the number of weeks. If there is no treatment, the number of CD4+ lymphocyte count decreased from roughly 1100 count per ml at week 0 to roughly 500 count per ml at week 6. When there is treatment by GEM apheresis, the CD4+ lymphocyte count decreased from about 1100 count per ml at week 0 to roughly about 1000 count per ml at week 6.

Specificity of GEMs to engage HIV infected cells

[0191] Specificity of GEMs to engage HIV-infected cells was tested by immunoprecipitation. The recombinant GEM (Fe3O4@SiO2@anti-gpl20 and Fe3O4@Au@anti-gpl20) were immuno-precipitated with GEMs, followed by lysis of blood and lymph with lysates being electrophoresed, transferred on PVDF fllowed by immunoblotting with the anti-CD4 international standard OKT3 antibodies produced by the ATCC cell line. All of the samples were labeling one and only molecule: CD4, i.e., only CD4+ cells infected with HIV and budding complete viruses were selected from the patients’ samples.

Elemental composition of GEM

[0192] Elemental composition of GEM in the Fe304-Si02-CD4 architecture was tested by EDXS as shown in FIG. 7. Energy peaks for Fe, C, O, Si are shown. Therefore, these EDXS spectra validate the elemental composition of GEMs: Fe304-Si02-CD4.

EXAMPLE 4

Healthy Donors and Patients

[0193] Per the Institutional Review Board approval and in compliance with the Declaration of Helsinki, all healthy donors and patients were presented with the Patient Bill of Rights and provided Patient Informed Consent with their identities entirely concealed, while all the procedures involving them were pursued by the licensed physicians.

[0194] Six healthy volunteers (three women, three men) had no past or present diseases in their medical records, so they were not taking any medications. Results of their routine laboratory tests of blood, with emphasis on ESR and immunoglobulin profiles, and of urine, with emphasis on potential presence of cells and proteins, were within laboratory norms. [0195] Three oncology patients (all males) were diagnosed with Kaposi sarcomas. Their blood routine laboratory tests revealed low counts of CD4+ lymphocytes, but increased ESR. These results prompted us to test for Human Immunodeficiency Virus (HIV), Herpes Simplex Virus (HSV), Cytomegalo-virus (CMV). The HIV test came out positive, but the HSV and CMV tests came out negative. These patients had not received any therapy yet.

[0196] Five oncology patients (three women, two men) were diagnosed Multiple myelomas. Their blood routine laboratory tests revealed high ESR. These results prompted a test for protein profiles, which revealed high immunoglobulin. Their urine routine laboratory tests revealed protein presence, identified as Bence-Jones protein. These patients were treated by aspiration of pleural and peritoneal effusion as the first therapeutic steps.

Blood, lymph, plasma, effusion, virus

[0197] Processing, storage, and culture of blood, erythrocyte-free blood, peritoneal or pleural effusions, lymph, and plasma were pursued according to the original, detailed protocols published earlier and only briefly outlined here. [20-27]

[0198] Blood was drawn according to the standard clinical procedure by venipuncture into citric acid / dextran receiving buffer. It was stored at 4 deg. C until further processing. For virus binding assays, the blood was depleted of fibrinogen and calcium (later re-adjusted to physiological levels). Erythrocyte-free blood was prepared by magnetic apheresis aided by antibodies conjugated with magnetic beads. Plasma was prepared by simple sedimentation and collecting supernatant or alternatively sampled during plasmapheresis. T cell fractions were prepared by activated sheep erythrocyte resetting. B cells were removed by complement receptor activated lysis. Desired cell fractions were enriched by FACS after labeling with fluorescent antibodies followed or by MACS after labeling with superparamagnetic antibodies. Plasma and B cells were isolated from erythrocyte-free blood by MACS after labeling with anti-CD 19 and anti-CD20 magnetic antibodies. [21, 26, 27].

[0199] Lymph was acquired according to the standard clinical procedure during surgeries on open abdomens. The viruses and cells from lymph were prepared according to the protocols for erythrocyte-free blood.

[0200] All the samples were processed on two ways: secured for long term storing or immediately upon being drawn. [0201] For storing, the samples were prepared by cryo-biobanking. The samples were equilibrated with 10% DMSO in the patients’ serum at 4 deg C. They were frozen according to the gradual lowering temperature down to -35 deg C, -70deg C, -196 deg C per 24 h on each step (to MM). These samples were stored indefinitely without compromised quality. When needed, these samples were thawed according to the reverse-to-freezing protocol for processing. Alternatively, the total RNA was prepared and either stored as such or converted into cDNA for storing and / or shipping. [27, 29]

[0202] For immediate processing, the HIV+ patients’ viremia in blood, lymph, or plasma were tested by reverse transcription and polymerase chain amplification of the sequences nested by the primers designed upon the published HIV-l sequences in PubMed / GenBank from the samples generated by isolation of total RNA. [22, 23, 24, 27, 29, 30, 31, Sequence Listing] The healthy donors’ blood, lymph, and plasma served as the controls and processed in parallel to those of the HIV+ patients.

[0203] For research, the samples samples acquired from the HIV+ patients, whose HIV count were adjusted to the experimental levels were spiked with GEM (including SPM)s as indicated in the Results. The infected samples in vials were incubated at the desired time at 37 deg. C and 5 % C02 while on the gyroscopic tables.

[0204] Depending on the plans for further tests, lysis of the cells was pursued in two buffers: NP40 and RIPA, as outlined in the forthcoming section (IP and IL). In NP40, they were prepared for immunoprecipitation. In RIPA, they were prepared for immunoblotting.

[0205] HIV was aspirated from the peritoneal or pleural effusions of the HIV+ oncology patients, who were diagnosed with Kaposi sarcoma. Of these sterile effusions, 100 microliters containing the HIV copy number determined by RT-PCR, was injected into in the H9 culture (ATCC) and propagated strictly according to the published protocols. [24, 25]

Human Immunodeficiency Virus gpl60, gpl20, gp41, p24

[0206] HIV glycoproteins gpl60, as well as its proteolytic fragments gpl20, gp4l, as well as p24, were prepared from the effusions of the HIV+ oncology patients admitted primarily for treatment of Kaposi sarcomas. Templates were generated by two ways. Total mRNA was isolated from HIV+ producing CD4+ lymphocytes of the HIV+ patients as described. [21, 26, 27,] The gpl60, as well as it fragments for gpl20 and gp4l mRNA was converted from total mRNA into ds cDNA by reverse transcription and polymerase chain reaction aided by the primers for gpl60, gpl20, and gp4l having sequences imported from GenBank (NCBI), primers designed on 5Prime (NIH), and synthesized on oligonucleotide synthesizers (Applied Biosystems). [30, 31, 32, 33, 34, Sequence listing] The yielded amplicons were inserted into plasmids comprising CMV promoters and metal binding coding sequences or bifunctional linker binding domains as in the details described elsewhere. [21] These plasmids were propagated in Escherichia coli grown in Luria-Bartani media on shakers at 37 deg. C. After isolation of plasmids on Maxipreps (Qiagen), the restriction sites were tested and plasmids cut opened to accept the inserts coding for gpl60, gpl20, gp4l, and p24. The new plasmids (pCMV-MBS-gpl60, pCMV-MBS-gpl20, pCMV-MBS-gp4l. pCMV- MBS-p24) were electroporated into the myeloma cells in cultures established from effusions of the oncology patients diagnosed with Multiple myelomas. The culture media were based upon RPMI1640 supplemented with effusion fluids rather than bovine sera. Alternatively, the HIV was isolated and propagated directly from the patients’ samples as previously described.

[22, 23, 24]

Anti-gpl20, anti-gpl60, anti-gp41, anti-p24 genomically engineered antibodies (GEAs)

[0207] All the HIV+ patients manifested anti-HIV antibodies, which were detected in their blood and lymph with the clinical diagnostic tests. [7] One of these patients manifested also anti-CD4 antibodies.

[0208] Taking advantage of these laboratory results and access to the human cells, adopted coding sequences were obtained from the plasma and B cells of these patients, while using them for biomolecular engineering of genomically engineered antibodies (GEAs), which in the process were also rendered magnetic and / or fluorescent. All the procedures of manufacturing of antibodies was pursued as previously described and briefly outlined here.

[20, 21, 26, 27,

[0209] The plasma and B cells were selected from blood of HIV+ patients by MACS and FACS using anti-CDl9 and anti-CD20 magnetic antibodies. Total mRNA was isolated and stored. [22] After importing the human HC and LC sequences [Kabat], the primers were designed with the aid of 5Prime software [NIH] for heavy and light variable chains and synthesized. [Sequence Listing] After reverse transcription, these primers primers served to create cDNA templates, which were cloned into the plasmid containing CMV promoter and metal binding domains. [20, Sequence listing] Plasmids were propagated in Escherichia coli grown in the Luria-Bartani media in cultures maintained on the shakers at 37 deg. C. After purification on MaxiPreps [Qiagen], the plasmids were electroporated into the cells in cultures of myelomas, which were established from the effusions of the oncology patients, who were diagnosed with Multiple myelomas. The cells were cultured in RPMI1640 media, but modified on such a way that they were supplemented with the supernatants of the patients’ effusions, but not bovine sera. Later, the cells were conditioned to grow in serum-free media in roller bottles at 37 deg C and 5% C02. Therefore, supernatant could be easily used to test specificity of secreted antibodies. Metal binding domains (MBS) facilitated rendering them superparamagnetic and / or fluorescent, if MBS were saturated with Eu or Tb. The metal binding domains were chosen to provide strong direct binding to Ni, Co, Fe, Au, Si02, as well as activated shells of core-shell superparamagnetic molecules as outlined herein.

Human CD4 - Genomically Engineered Receptor (GER)

[0210] Human CD4 was manufactured on two ways: cell lysis immunoprecipitation - immunoblotting and genomic isolation - amplification - expression. T lymphocytes from healthy volunteers were initially selected by sheep erythrocyte resetting precipitation followed by B cell complement lysis. Later, these fractions were enriched by CD4+ selection with our anti-CD4 superparamagnetic antibodies, raised from the plasma and B cells of the anti-CD4+ patient, on MACS or our anti-CD4 fluorescent antibodies by FACS.

[21, 26, 27, Sequence Listing (SEQ ID NO: 54- SEQ ID NO:58)]

[0211] For immunoprecipitation, the enriched fractions of the CD4+ cells were lysed with NP40. The soup was mixed with the anti-CD4, superparamagnetic, genomically engineered anti-CD4 antibodies (GEA-(including SPM)), incubated for 1 h at 4 deg. C, and inserted into magnetic field at room temperature for 15 minutes. Diamagnetic content was rinsed off, while in the field. The fraction retained by anti-CD4 GEAs was released after the magnetic field ceased. Aliquots of this fraction were electrophoresed on PAGE and transferred onto the PVDF membranes (Amersham). The immunoblots were tested by the standard OKT4 antibody produced by the hybridoma cell line (ATCC), which was initially grown in the recommended cell culture conditions (ATCC)., but which we modified so the cells were grown in sera- free media as described. [21]

[0212] For immunoblotting, the enriched fractions of the CD4+ cells were lysed with RIPA. The lysates were electrophoresed by PAGE and validated as immune-precipitated ones.

[0213] Alternatively, primarily for future expression of the full CD4 and its selected domains - in particular AA 1-108, total mRNA was isolated from these cells and stored. [26, 27] After importing the CD4 mRNA main transcripts’ sequences from GenBank (NCBI), the primers flanking the CD4 coding sequence were designed with the aid of 5Prime software (NIH) and synthesized (Applied Biosystems). [26, 27, 35, 36, Sequence listing SEQ. ID. NO.: 54 - 58] These primers served to create cDNA templates, which were cloned into the plasmids comprising CMV promoter and metal binding domains, and hetero-bifunctional linker domains linking chelates. [20, 26] The choice of the coding cloning vector was contingent upon the future superparamagnetic molecule to be used with. Propagated plasmids were electroporated into the human myelomas, which were established from the oncology patients diagnose with Multiple myelomas, to express the recombinant CD4. [21, 26, 27] The cells were conditioned to grow in the serum-free RPMI media in roller bottles at 37 deg. C and 5% C02. Therefore, supernatant could be easily used to test secreted recombinant receptors expressed from all the transcript variant versions by NMR and FCM. [35, 36]

Separation of the HIV-infected cells from HIV

[0214] GEM (with SPMs) tag not only HIV-infected cells through the HIV envelope molecules of budding viruses, but also the viruses themselves. Separation of HIV- infected cells from the viruses was performed by spinning the GEM (including SPMs’) labelled samples at 1000 rpm at room temperature. The supernatant contained the HIV tagged with GEM (including SPMs), while the HIV-infected cells, but not healthy cells, were collected in the pellet.

Immunoprecipitation

[0215] For immunoprecipitation, the enriched fractions of the CD4+ cells were lysed with NP40. The soup was mixed with our anti-CD4, superparamagnetic, genomically engineered antibodies (GEA), incubated for 1 h at 4 deg. C, and inserted into magnetic field at room temperature for 15 minutes. Diamagnetic content was rinsed off, while in the field. The fraction retained by anti-CD4 GEAs was released after the magnetic field ceased. Aliquots of this fraction were electrophoresed on PAGE and transferred onto the PVDF membranes (Amersham). The immunoblots were tested by the standard OKT4 antibody produced by the cell line were initially grown in the recommended cell culture conditions, which we modified so the cells were grown in sera-free media (ATCC).

Immunoblotting

[0216] For immunoblotting, the enriched fractions of the CD4+ cells were lysed with RIPA. The lysates were electrophoresed by PAGE and validated as immune-precipitated ones.

[0217] Alternatively, primarily for future expression of the CD4 selected domains, total mRNA was isolated from these cells and stored. [26, 27] After importing the CD4 mRNA main transcripts’ sequences from GenBank, the primers flanking the CD4 coding sequence were designed with the aid of 5Prime software [NIH] and synthesized. [26, 27, 35, 36, Sequence listing] These primers served to create cDNA templates, which were cloned into the plasmids comprising CMV promoter and metal binding domains, hetero-bifunctional linker domains linking chelates. [26] The choice of the coding cloning vector was contingent upon the future superparamagnetic molecule to be used with. Propagated plasmids were electroporated into the human myelomas, which were established from the oncology patients diagnose with Multiple myelomas, to express the recombinant CD4. [21, 26, 27, Sequence listing: SEQ. ID. NO.: 54-58] The cells were conditioned to grow in the serum-free RPMI media in roller bottles at 37 deg. C and 5% C02. Therefore, supernatant could be easily used to test secreted recombinant receptors expressed from all the transcript variant versions by NMR and FCM. [35, 36]

Genomically engineered molecules with superparamagnetic domains ( GEM ( including SPM))

[0218] GEMs employed included two kinds: genomically engineered antibodies (GEA) and genomically engineered receptors (GERs) aka virus entry molecules (VEM). In the case of HIV, the CD4 is the primary HIV entry molecule. All known in GenBank (NCBI) variants were expressed from genomics data transcripts, but as recombinant, soluble molecules. They were transgenically expressed from the constructs generated from reverse transcription of the total mRNA isolated from the patients’ CD4+ cells. They were transgenically expressed from the constructs, which contained superparamagnetic metal binding or functional group domains’ coding sequences. These soluble molecules are directly absorbed onto surfaces of the aforementioned superparamagnetic molecules or reacted through bifunctional linkers to the -SH, -COOH, or -NH2 groups present on surfaces of the aforementioned superparamagnetic molecules to form genomically engineered molecule rendered superparamagnetic properties (GEM (including the SPM). [20, 39, 40]

[0219] In the case of HIV, the primary virus targeting molecule is gpl20, which is docking HIV into CD4. In response to infection, the patients generate antibodies against this and other HIV antigens, including gpl20, gp4l, gpl60, p24, etc depending at which stage of the cell take-over by HIV these antigens were presented by APCs. Based upon the universal primers, which we have designed, we have generated multiple anti-HIV molecules’ coding sequences, which after cloning within aforementioned above vectors containing superparamagnetic binding or bifunctional linkers domains, have been expressed in human myelomas. [20, 39, 40, Sequence listing: SEQ. ID. NO.: 1-53]

[0220] As such aforementioned said GEM (including SPMs) comprise anti-HIV antibodies and / or comprise virus recombinant, soluble virus entry molecules, while also comprise superparamagnetic domains that facilitate responsiveness to magnetic fields.

Nuclear magnetic resonance spectroscopy (NMR)

Magnetic, activated cell sorting (MACS)

Magnetic apheresis

[0221] The cells were labeled with the superparamagnetic genomically engineered antibodies (GEA (including SPMs) as described in details elsewhere. [20, 21, 26, 27] Briefly, the GEA (including SPMs) were dissolved and all washing steps carried in phenol-free, Ca-i- / Mg+- free, PIPES buffered saline solution, supplemented with 20 mM glucose, 10% human serum. The aliquots were dispensed into the magnetism-free NMR tubes (Shigemi). The relaxation times Tl and T2 were measured in resonance to the applied pulse sequences on the NMR spectrometers: DMX 400 WB or AVANCE II NMR (Bruker, Billerica, MAJ or the Signa clinical scanners (General Electric).

[0222] The GEA -SPMs were used to isolate the labeled molecules and/or cells from the solution. The labeled cells rendered superparamagnetic properties, which facilitated their isolation on the magnetic, activated cell sorter (MACS) operated at 0.5 T - 1.5 T and / or clinical MRI instruments operating at 0.5 T - 3 T and / or NMR scanners operating at 0.5 T- 7 T (Bruker).

[0223] The infected cells were tagged with the GEA (including SPMs) by docking onto the virus envelope molecules, which were displayed on surfaces of the virus-infected cells by the budding viruses.

[0224] Apheresis of the GEA (including SPMs) tagged Human Immunodeficiency Virus -infected cells was conducted on three ways: external field, magnetic filters, magnetic baits, magnetic needles, and / or magnetic traps.

Flow cytometry (FCM)

Fluorescent, activated cell sorting (FACS)

Multiphoton spectroscopy

[0225] The cells were labeled with the fluorescent antibodies as described in details elsewhere. [20, 21, 26, 27] They were sorted on the Calibur, Vantage SE, or Aria (Becton- Dickinson). The antibodies were dissolved and all washing steps carried in phenol-free, Ca-i- / Mg+- free, PIPES buffered saline solution, supplemented with 20 mM glucose, 10% human serum. Sorting was performed on Aria, Calibur, Vantage SE (Becton-Dickinson) with the sheath pressure set at 20 pounds per square inch pressure and low count rate. The sorted batches were analyzed on Calibur or Aria using FACSDiva software or on the FC500 (Beckman- Coulter). For the measurement of the fluorescently labeled cells, these settings were tuned at the maximum emission for the Eu chelated antibody at 500V with references to isotype antibodies and non-labeled cells. This assured the comparisons between populations of cells labeled with multiple antibodies without changing the settings on PMTs. [0226] The fluorescently labeled cells or tissues were imaged with the Axiovert (Zeiss) equipped with the Enterprise argon ion (457 nm, 488 nm, 529 nm lines) and ultraviolet (UV) (364 nm line) lasers; Odyssey XL digital high- sensitivity with instant deconvolution confocal laser scanning imaging system operated up to 240 frames/s (Noran), and the Diaphot (Nikon) equipped with the diode-pumped Nd:YLF solid state laser (1048 nm line) (Microlase).

Energy dispersive X-ray spectroscopy (EDXS)

Electron energy loss spectroscopy (EELS)

X-ray reflection fluorescence spectroscopy (XRFS)

[0227] Elemental analyses were pursued by EDXS, EELS, and XRFS as described earlier. [20, 21, 26, 27] The field emission, scanning transmission, electron microscope FESTEM HB501 (Vacuum Generators) was equipped with the energy dispersive x-ray spectrometer (EDXS) (Noran) and post-column electron energy loss spectrometer (EELS) (Gatan). The cryo-energy filtering transmission electron microscope 912 Omega was equipped with the in-column, electron energy loss spectrometer (EELS) and the energy dispersive x-ray spectrometer (EDXS) (Zeiss). The cryo-energy filtering transmission electron microscopes 410 and 430 Phillips were equipped with the post-column, electron energy loss spectrometers (EELS) and the energy dispersive x-ray spectrometer (EDXS) (Noran). The field emission, scanning electron microscope SEM1530 (Zeiss) was equipped with the energy dispersive x- ray spectrometer (EDXS) (Noran). The field emission, scanning electron microscope 3400 was equipped with the energy dispersive x-ray spectrometer (EDXS) (Hitachi). The S2 Picofox XRFS spectrometer was equipped with a molybdenum (Mo) X-ray target and the Peltier cooled Xflash Silicon Drift Detector (Bruker AXS). Scan times ranged up to 1000 seconds. The ICP standard of 1000 mg/l of mono-element Gallium or Gadolinium (CPI International) was added to 500 microL of each sample to the final concentration of 10 mg/l. Instrument control, data collection, and analysis were under the SPECTRA 7 software (Bruker AXS). Statistical analysis

[0228] All the measurements were run in triplicates for each sample from all healthy volunteers and patients. The numbers were analyzed and displayed using statistical analysis software (GraphPad). Data were presented as mean of standard error of the mean (SEM). Statistical significance was calculated by t-test for two groups.

Rapid reduction of the HIV-infected cells’ counts

[0229] Progression of the HIV infection into AIDS is primarily driven by the cytopathic, lytic effects upon CD4+ cells, which practically wipes out their population. This disables patients’ immune system and leads to Acquired Immunodeficiency Syndrome (AIDS). The triggering factor for the progression of the HIV infection into AIDS is rapidly increasing number of HIV-infected cells - being de facto HIV factories. Administration of our GEMs (including SPM) to the blood and / or lymph containing HIV-infected cells very effectively eliminated most of them as shown in FIG. 9.

Rapid improvement of not-infected to HIV-infected CD4+ cells ratio

[0230] As the HIV infection progresses into AIDS, the ratio between non-inf ected and HIV-infected cells quickly changes in favor of the latter. Therefore, repression of the rapid increase of the HIV-infected cells, in particular at the earliest stages post infection, is the key element of preventing the disease progression. At all stages of the HIV-induced disease, administration of GEM (including SPM) caused the rapid depletion of the HIV infected cells, and immediate improvement of the healthy, non-infected T helper cells to HIV-infected cells ratio as shown in FIG. 10.

Great long-term improvement of the total CD4+ cells’ counts after administration of GEMs ( including SPM).

[0231] Within weeks from the HIV infection, the CD4+ cells’ counts rapidly fall down. The CD4+ cell counts in blood and lymph cultures were quickly depleted upon the HIV infection with 100 microliters of the blood or lymph from the HIV+ patients. However, when the parallel samples were treated with GEM (including a SPM) followed by daily session of apheresis and replenishing of fresh batches of GEM (including a SPM), populations of the CD4+ cells were retained near borders of the low norm levels; thus in clinical practice giving the time for the infected patient immune system to assemble immune response as documented in FIG. 11. It is worth noticing, that administered GEMs (including a SPM), engineered to comprise anti-gpl20 of budding virus and CD4 the HIV docking receptor, not only depleted HIV-infected cells, but also effectively removed the HIV.

Specificity of GEMs ( including SPM) to tag only HIV-infected cells

[0232] Efficacy of GEM (including SPMs), engineered around antibodies against HIV envelope, to tag HIV-infected cells followed by their magnetic apheresis, relied upon the specificity of antibodies against HIV envelope molecules of the viruses, which were budding from the cells - primarily anti-gpl20. Specificity of GEM (including a SPM) engineered around anti-gpl20 to engage HIV-infected cells was tested by immune-pull-off of selected fraction from the entire cell sample as shown in FIG. 12. The cells exposed to the identical treatment, but drawn from the HIV- patients served as the negative control. The cells exposed to the identical treatment, but drawn from the HIV- and HIV+ patients followed by immune- pull-off with anti-p24-SPM served as the positive control.

[0233] Similarly, efficacy of GEM (including a SPM), engineered around the recombinant, soluble virus entry molecules relied upon their specificity towards budding molecules - primarily towards 108 AA residues of amino terminus of CD4. This specificity was tested by immune-pull-off of the HIV-infected cells as illustrated in the FIG. 12. The cells exposed to the identical treatment, but drawn from the HIV- patients served as the negative control. The cells exposed to the identical treatment, but drawn from the HIV- and HIV+ patients followed by immune-pull-off with anti-CD4-SPM served as the positive control.

[0234] In both cases of cells’ pulled-off by GEM (including a SPM), lysates of blood and lymph were electrophoresed followed by immunoblotting with the anti-CD4 OKT3 antibodies - to validate the cell type and processed by RT-PCR for HIV - to validate these cells as HIV-infected. All of the samples were labeling one and only molecule: CD4, while no healthy cells were ever immuno-pulled-off by the HIV-targeting GEM(including a SPM). [0235] FIG. 13 is an image of a gel depicting the specificity of GEM (including a CD4-SPM) in pulling out the HIV-infected and HIV-producing cells. This was assessed by Western blotting with anti-p24. Lanes: 1 - healthy volunteer’s blood; GEM (including a CD4- mutant-SPM); 3 - ; 4-5 - HIV+ patients’ lst-2nd blood; 6-7 - HIV+ patients’ lst-2nd lymph; 8 - reference p24; 9 - HIV+ patient I^st blood after 3 cycles of GEM (including CD4-aided) apheresis (no actively HIV-producing cells detected).

[0236] The spectra of the GEM- (including SPM), {Fe304} Au, are shown in FIGs.

14 and 15.

Example 5

[0237] The soluble, recombinant transgenically expressed CD4 (tgCD4) was dissolved from lyophilized from PBS powder. It dialyzed against phosphate buffer solution (PBS) pH 7.0 24 deg. C in lOkDa cutoff bags. The concentration was adjusted to 20 microM. An aliquot of 12 ml was sampled from that solution. Meanwhile, 1 ml of 100 mM stock solution of 4-pentynoic acid (PA) in 50 % of THF in PBS was prepared. While on the stirrer, 67 mirol of the PA stock solution was added to 12 ml of tgCD4 in PBS, while mixing at room temperature of around 24 deg C. Meanwhile, 1 ml of 50 mM stock solution of EDC in PBS at pH 7.0 at 24 deg C was prepared. While stirring of tgCD4 with PA solution continued for at least 15 min, we added quickly after dissolving 130 ml of EDC stock solution, while stirring continued. Subsequently, 1500 micol of THF and 1300 ml of PBS were simultaneously added to the ongoing mixture. This reacting process continued for 4 h under the fume hood at 24 deg C. The functionalized by alkynylation tgCD4 was then dialyzed in the lOkDa cutoff dialysis bags against PBS at room temperature of around 24 deg C at pH 7.0.

[0238] At his point, we have already prepared the stock of the core- shell {(Fe₃0₄)Au] superparamagnetic particles (SPM) at 2.8 nM concentration in double distilled water. To 20 ml of the SPM stock, we added thiol-PEG-azide (TPA) up to 20 microM, while vigorously mixing. The reaction continued for 16 h at room temperature of around 24 deg C. The functionalized ](Fe304)Au] SPM was spun down at 15000 g for 30 min and resuspended in double distilled water three times to remove non-reacted reagents. [0239] Having functionalized VAM: CD4 and SPM: {(Fe₃0₄)Au}, we proceeded with conjugating them. The functionalized {(Fe₃0₄)Au} SPM were suspended in water at 13 nM concentration of 10 ml. The solution was placed on the stirrer 60 revolutions per min at room temp of 24 deg C. To that stirred solution the alkynylated tgCD4 was added to attain 130 nM concentration. Thereafter, 2.5 microl of 10 mM CuS0₄x5H₂0 with 50 microM ascorbic acid in water was added to the stirred solution. The reacting mix was transferred to 4 deg C. The reaction continued for 24 h at 4 deg C. The CD4-SPM conjugates were cleared from the non-reacted reagents by spinning down at l5,000g at 4 deg C and resuspending in PBS at least 5 times. Upon completion of this procedure the tgCD4-SPM conjugates were effectively binding HIV.

[0240] We used the identical protocol for conjugating anti-gpl20, anti-gp4l, anti- p24 antibodies with core-shell superparamagnetic {(Fe₃0₄)Au| or {(Fe₃0₄)Si0₂] SPM.

Additional Embodiments

[0241] Alternatively, for well glycosylated molecules another option can be used. Below, there is the detailed protocol for transgenic, soluble CD4. However, the same protocol works very well for other YAM.

EXAMPLE 6

[0242] In 10 ml of 0.15 M NaCl, 0.01 M sodium phosphate solution, we dissolved tgCD4 up to 10 mg/ml concentration. We also prepared 0.088 M NaI04 solution in water in darkness at room temperature of 24 deg C. Having both solutions ready, we added 1 ml of NaI04 solution to the tgCD4 solution in the darkness at room temperature for 15 min. To stop the reaction, we added 1 ml of glycerol and running through the desalting column, while collecting the fractions determined on the spectrophotometer on the fraction collector at 280 nm. The fractions were pooled together and adjusted to 10 mg/ml and stored at 4 deg C. At this point, the core-shell superparamagnetic particles SPM {(Fe304)Si02}were functionalized by baking in 1 % solution of APTES for 1 h in oxygen free containers, flushed with nitrogen, at 60 deg C, for 1 h. The reaction was stopped by spinning the activated SPM at l5,000g for 30 min at room temperature of 24 deg C and re-suspending in water at least 5 times. Having both solutions ready, we proceeded with conjugating them. To 10 ml of tgCD4 solution, the functionalized {(Fe₃0₄)Si0₂} SPM were added at 13 nM concentration to attain 10 x molar concentration over tgCD4. The CD4-SPM conjugates were cleared from non-reacted reagents by spininning them at l5,000g for 30 min at 4 deg C for at least five cycles. At that point, we had them ready to be sterilized and used.

[0243] We used the identical protocol for conjugating anti-gpl20, anti-gp4l, anti- p24 antibodies with core-shell superparamagnetic |(Fe304)Si04} SPM.

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Claims

1. A GEM composition comprising: a virus-attaching-molecule (VAM), wherein the VAM is soluble; and an apheresis initiating molecule (AIM); and a superparamagnetic (SPM) nanoparticle or a fluorescent molecule (F), wherein the VAM is fused to the AIM, and wherein the AIM is conjugated to the superparamagnetic (SPM) nanoparticle or the fluorescent (F) molecule.

2. The GEM composition of Claim 1, wherein the superparamagnetic (SPM) nanoparticle comprises: a) a solid homogenous architecture; or b) a core-shell architecture.

3. The GEM composition of Claim 1 or 2, wherein the core-shell architecture comprises: a) a magnetic core and b) a biocompatible shell surrounding the magnetic core.

4. The GEM composition of Claims 1-3, wherein the fluorescent (F) molecule is at least one of R-Phycoerythrin (RPE) or B-Phycoerythrin (BPE).

5. The GEM composition of Claims 1-4, wherein the superparamagnetic (SPM) nanoparticle is selected from the group consisting of at least one of: {Fe₃0₄}Au and

{Fe₃0₄} Si0_2.

6. The GEM composition of Claims 1-5, wherein the composition further comprises a chemical linker that serves to conjugate the VAM to the SPM, wherein the chemical linker is selected from the group comprising at least one of: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Pentynoic acid (PA), thiol-polyethylene-glycol-azide (TPA), Poly-triethylene - acylhydrazide-dithiol (PTAD), Poly-ethylene-acylhydrazide-dithiol (PEAD), amino-propyl-tri-ethoxy- silane (APTES), N-succinimidyl-(2- pyridyl-dithiol-propionate) (SPDP), succinimidyl 4-(N- maleimidomethyl)cyclohexane-l-carboxylate) (SMCC)

7. The GEM composition of Claims 1-6, wherein the composition comprises a VAM conjugated to a fluorescent (F) molecule via a chemical linker, wherein the chemical linker is selected from the group comprising at least one of: l-Ethyl-3-(3- dimcthylaminopropyljcarhodiimidc (EDC), Pentynoic acid (PA), thiol-polyethylene- glycol-azide (TPA), Poly-triethylene-acylhydrazide-dithiol (PTAD), Poly-ethylene - acylhydrazide-dithiol (PEAD), amino-propyl-tri-ethoxy-silane (APTES), SPDP N succinimidyl 3 (2-pyridyldithio)propionate, N-succinimidyl-(2-pyridyl-dithiol-propionate) (SPDP), (EDC, TPA, PTAD, PEAD, APTES, SPDP, succinimidyl 4-(N- maleimidomethyl)cyclohexane-l-carboxylate) (SMCC)

8. The GEM composition of Claim 1, wherein,

A the GEM comprises DPP4 or a binding fragment thereof and AIM domains, and the SPM comprises {Fe₃0₄}Au,

B the GEM comprises HS/CLEC4M or a binding fragment thereof, and AIM domains, and the SPM comprise {Fe304}Au,

C the GEM comprises NK1R or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

D the GEM comprises TIM1 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

E the GEM comprises HAVCR1 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

F the GEM comprises NTCP or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

G the GEM comprises CLEC4M or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe304}Au,

H the GEM comprises CR1 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

I the GEM comprises CD4 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au, J the GEM comprises EphA2R or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

K the GEM comprises CD81 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

L the GEM comprises ITGA6 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

M the GEM comprises nectin or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

N the GEM comprises SG or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

O the GEM comprises CD 155 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

P the GEM comprises a.2b1 -ITO or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au,

Q the GEM comprises AchR or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Au, or

R the GEM comprises CS or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe304}Au.

9. The GEM composition of Claim 1, wherein,

A the GEM comprises DPP4 or a binding fragment thereof and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

B the GEM comprises HS/CLEC4M or a binding fragment thereof, and AIM domains, and the SPM comprise {Fe₃0₄}Si0₂,

C the GEM comprises NK1R or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

D the GEM comprises TIM1 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

E the GEM comprises HAVCR1 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂, F the GEM comprises NTCP or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

G the GEM comprises CLEC4M or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

H the GEM comprises CR1 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

I the GEM comprises CD4 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

J the GEM comprises EphA2R or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

K the GEM comprises CD81 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

L the GEM comprises ITGA6 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

M the GEM comprises nectin or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

N the GEM comprises SG or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

O the GEM comprises CD 155 or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

P the GEM comprises a.2b1 -ITO or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

Q the GEM comprises AchR or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂,

R the GEM comprises CS or a binding fragment thereof, and AIM domains, and the SPM comprises {Fe₃0₄}Si0₂.

10. A method of manufacturing a GEM composition of any one of Claims 1-8, the method comprising: amplifying DNA sequences encoding the VAM and AIM; synthesizing DNA sequences by extension overlap with cloning overhangs; cloning DNA sequences coding VAM and AIM into pCMV-SV40 DNA vector; transfecting human myeloma cells; expressing in human myeloma cells; and applying biochemical affinity isolation and/or purification.

11. The method of claim 9, wherein the VAM is selected from one of SEQ ID Nos:

1-29, wherein the p_CMV-INS-SV40 DNA vector comprises SEQ ID NO: 30.

12. The method of claim 10, wherein cloning is achieved by synthesis by extension overlap cloning overhangs of SEQ ID Nos: 31-34.

13. The method of claim 9, wherein the DNA coding sequence for AIM is DNA sequence or its fragment selected from SEQ ID Nos: 35-40, and 70-82 wherein the p_CMV-INS-SV40 DNA vector comprises SEQ ID NO: 30.

14. The method of any one of Claims 9-12, further comprising at least one of: making the SPM; making a functionalized SPM; making a functionalized VAM; providing click chemistry between a functionalized SPM and a functionalized VAM through conjugation reactions of linker-enabled stable bonds.

15. The method of any one of Claims 9-13, further comprising sterilizing the composition in a sealed vial.

16. The method of any one of claims 9-14, wherein the functionalized VAM or their fragments is selected from the group consisting of: A DPP4,

B HS,

C NK1R,

D TIM1,

E HAVCR1,

F NTCP,

G CLEC4M,

H CR1/2,

I CD4,

J EphA2R,

K CD81,

L ITGA6,

M nectin,

N SG,

O CD155,

P a2b1-PΌ,

Q AchR, and

R CS.

17. The method of any one of claims 9-14, wherein the functionalized VAM is selected from the group consisting of:

A dipeptidyl peptidase 4 (DPP4),

B heparin sulfate (HS),

C neurokinin 1 receptor (NK1R),

D T-cell immunoglobulin and mucin domain (TIM1),

E Hepatitis A virus cellular receptor 1 (HAVCR1),

F sodium-taurocholate co-transporting polypeptide (NTCP),

G C-type lectin domain family 4 (CLEC4M),

H complement receptor 1 (CR1),

I cluster of differentiation 4 (CD4), J ephrin A2 receptor (EphA2R),

K cluster of differentiation 81 (CD81),

L integrin alpha-6 ( ITGA6),

M nectin (Nec),

N sialylated glycans (SG),

O cluster of differentiation 155 (CD155),

P integrin alpha-beta (a2b1-ITΰ),

Q acetylcholine receptor (AchR), and

R chondroitin sulfate (CS).

18. The method of any one of Claims 9-16, further comprising: reacting a Fe and O containing compound to create a Fe₃0₄ superparamagnetic core; and reacting the superparamagnetic core with an Au containing compounds to create a core-shell superparamagnetic nanoparticle ({Fe₃0₄} Au), wherein the {Fe₃0₄} core is covered with an Au shell.

19. The method of any one of Claims 9-16, further comprising: reacting a Fe and O containing compound to create a Fe₃0₄ as superparamagnetic core; and reacting the superparamagnetic core with a Si and O containing compounds to create a core-shell superparamagnetic nanoparticles ({Fe₃0₄}Si0₂), wherein the core {Fe₃0₄} is covered with a Si0₂ shell.

20. The method of any one of Claims 9-16, further comprising: reacting Ni, Co, Tb, Eu containing compounds to create solid superparamagnetic nanoparticles.

21. The method of any one of Claims 9-16, further comprising making a functionalized SPM, which comprises reacting SPM with a chemical linker selected from the group consisting l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), Pentynoic acid (PA), thiol- polyethylene-glycol-azide (TPA), Poly-triethylene-acylhydrazide-dithiol (PTAD), Poly-ethylene-acylhydrazide-dithiol (PEAD), amino-propyl-tri- ethoxy-silane (APTES), SPDP N succinimidyl 3 (2- pyridyldithio)propionate, N-succinimidyl-(2-pyridyl-dithiol-propionate) (SPDP), (EDC, TPA, PTAD, PEAD, APTES, SPDP, succinimidyl 4-(N- maleimidomethyl)cyclohexane-l-carboxylate) (SMCC)

22. The method of any one of claims 9-16, wherein making a functionalized VAM comprises reacting a VAM with a chemical linker selected from the group consisting of: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Pentynoic acid (PA), thiol- polyethylene-glycol-azide (TPA), Poly-triethylene-acylhydrazide-dithiol (PTAD), Poly- ethylene-acylhydrazide-dithiol (PEAD), amino-propyl-tri-ethoxy-silane (APTES), SPDP N succinimidyl 3 (2-pyridyldithio)propionate, N-succinimidyl-(2-pyridyl-dithiol- propionate) (SPDP), (EDC, TPA, PTAD, PEAD, APTES, SPDP, succinimidyl 4-(N- maleimidomethyl)cyclohexane-l-carboxylate) (SMCC)The method of any one of Claims 9-16, wherein the composition comprises a VAM conjugated to a fluorescent (F) molecule, wherein the method further comprises: making a functionalized fluorescent (F) molecules; making a functionalized VAM; and providing click chemistry between functionalized fluorescent (F) molecules and functionalized VAM through conjugation reactions of linker-enabled stable bonds.

23. The method of Claim 22, wherein making a functionalized fluorescent (F) molecule comprises reacting the fluorescent (F) molecule with a chemical linker selected from the group consisting of: l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), Pentynoic acid (PA), thiol- polyethylene-glycol-azide (TPA), Poly-triethylene-acylhydrazide-dithiol (PTAD), Poly-ethylene-acylhydrazide-dithiol (PEAD), amino-propyl-tri- ethoxy-silane (APTES), SPDP N succinimidyl 3 (2- pyridyldithio)propionate, N-succinimidyl-(2-pyridyl-dithiol-propionate) (SPDP), (EDC, TPA, PTAD, PEAD, APTES, SPDP, succinimidyl 4-(N- maleimidomethyl)cyclohexane-l-carboxylate) (SMCC)

24. The method of Claim 22, wherein making a functionalized VAM comprises reacting a VAM with chemical linker selected from the group consisting of: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Pentynoic acid (PA), thiol-polyethylene-glycol-azide (TPA), Poly-triethylene- acylhydrazide-dithiol (PTAD), Poly-ethylene-acylhydrazide-dithiol (PEAD), amino-propyl-tri-ethoxy-silane (APTES), SPDP N succinimidyl 3 (2-pyridyldithio)propionate, N-succinimidyl-(2-pyridyl-dithiol-propionate) (SPDP), (EDC, TPA, PTAD, PEAD, APTES, SPDP, succinimidyl 4-(N- maleimidomethyl)cyclohexane-l-carboxylate) (SMCC)The method of any one of Claims 22-24, further comprising: reacting Tb or Eu to create a nanoparticles having fluorescent properties.

25. A method of treatment, the method comprising, administering the composition of any one of Claims 1-8 to a patient, the method comprising:

A. intra-venous (i.v.) infusion;

B intra-lymphatic (i.l.) infusion;

C sub-cutaneous (s.c.) injection;

D intra-muscular (i.m.) injection; or

E intra-cerebrospinal (i.c.s.) fluid injection.

26. A use of the composition of any one of Claims 1-8, or produced by the method of any one of claims 9-22, for the treatment of a disease related to a virus occurring in a patient’s body, wherein the virus causes viremia, wherein the virus is selected from the group consisting of: Corona Virus (CoV), Chickenpox Virus aka Varicella Zoster Virus aka HHV3 (VZV), Dengue Virus (DENV), Ebola Virus (EBOV), Hepatitis A Virus (HAV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Herpes Virus 1/2 aka Herpes Simplex Virus aka HSV 1/2 (HHV1/2), Herpes Virus 4 aka EBV (HHV4), Herpes Virus 5 aka CMV (HHV5), Human G Virus aka HHV6 (HGV), Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Influenza Virus (IV), Roseolovirus aka RosV (HHV7), Kaposi Sarcoma Associated Virus aka KSAV (HHV8), Mumps Virus (MuV), Measles (MeV), Polio Virus (PV), Rotavirus (RoV), Rabies Syndrome Virus (RaV), Rubella Virus (RuV), Smallpox Virus aka Variola Virus (VARV), Yellow Fever Virus (YFV), and Zika Virus (ZiV).

27. The use of Claim 27, wherein the use includes at least one of the following pairings:

DPP4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 001) for CoV, heparan sulfate (HS)/neurokinin receptor (NK1R) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 2-3) for VZV,

TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004) for DENV, TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004) for EBOV, TIM1/HAVCR1 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004-005 for HAV,

NTCP (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 006) for HBV, TIM1 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004) for HCV, heparan sulfate (HS)/CLEC4M (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 002/007) for HHV4,

CR1 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 008) for HHV5, CD4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014) for HHV7, EphA2R (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 015) for HHV8, CD81 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 016-017) for HGV, CD4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014) for HIV, ITGA6 the amino acid encoded by, or nucleic acid of, SEQ ID NO: 018-021) for HPV, nectin (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 022) for HSV1/2, sialylated glycans (SG) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 023) for IV,

TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004) for MuV, TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004) for MeaV, CD155 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 024-025) for PV, a.2p i -intcgrin (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 026) for RoV,

AchR (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 027-028) for RaV, CD4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014) for RuV HIV,

chondroitin sulfate (CS) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 029) for VARV,

TIM1 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004) for YFV, or TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004) for ZikV.

28. The use of one of claims 22-25, wherein the virus-specific GEM is attained by genomic engineering of DNA sequences specific for selected GEM expressed and affinity purified, wherein the virus specific GEM is attained by biochemical affinity purification.

29. The use of one of claims 22-26, wherein the use comprises infusion of a sterile composition and removing from the patient’s body the viruses by a GEM-aided apheresis pursued in a magnetic field generating instrument, wherein the composition is sterilized in sealed vials.

30. The use of one of Claims 22-27, wherein the magnetic field generating instrument comprises at least one of:

A extra-corporeal magnetic filters;

B intra-corporeal magnetic filters;

C personal external magnets; or

D personal internal magnets.

31. A method of treating a subject, the method comprising:

providing a subject to be treated; and administering at least one of the compositions of claim 1-8 to the subject in an amount sufficient to allow binding of the GEM in the composition to a target protein in the subject; and

removing the target protein and any associated biological material with the target protein, from the subject via a magnetic action on the SPM in the composition.

32. The method of claim 29, wherein the target material is removed ex vivo, via cleaning of subject’s blood or lymph of the SPM and material associated therewith.

33. The method of any one of claims 29 or 30, wherein the subject is identified as having a virus, wherein the virus is selected from the group consisting of: Corona Virus (CoV), Chickenpox Virus aka Varicella Zoster Virus aka HHV3 (VZV), Dengue Virus (DENV), Ebola Virus (EBOV), Hepatitis A Virus (HAV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Herpes Virus 1/2 aka Herpes Simplex Virus aka HSV 1/2 (HHV1/2), Herpes Virus 4 aka EBV (HHV4), Herpes Virus 5 aka CMV (HHV5), Human G Virus aka HHV6 (HGV), Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Influenza Virus (IV), Roseolovirus aka RosV (HHV7), Kaposi Sarcoma Associated Virus aka KSAV (HHV8), Mumps Virus (MuV), Measles (MeV), Polio Virus (PV), Rotavirus (RoV), Rabies Syndrome Virus (RaV), Rubella Virus (RuV), Smallpox Virus aka Variola Virus (VARV), Yellow Fever Virus (YFV), and Zika Virus (ZiV).

34. The method of any one of claims 29-31, wherein at least one of the following VAM is used for one of the denoted viral infections:

DPP4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 001), or a binding fragment thereof, for CoV,

heparan sulfate (HS)/neurokinin receptor (NK1R) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 2-3), or a binding fragment thereof, for VZV,

TIM-l(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for DENV, TIM-l(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for EBOV,

TIMl/HAVCRl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004-005), or a binding fragment thereof, for HAV,

NTCP(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 006), or a binding fragment thereof, for HBV,

TIMl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for HCV,

heparan sulfate (HS)/CLEC4M (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 002/007), or a binding fragment thereof, for HHV4,

CRl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 008), or a binding fragment thereof, for HHV5,

CD4(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014), or a binding fragment thereof, for HHV7,

EphA2R(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 015), or a binding fragment thereof, for HHV8,

CD81 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 016-017), or a binding fragment thereof, for HGV,

CD4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014), or a binding fragment thereof, for HIV,

ITGA6(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 018-021), or a binding fragment thereof, for HPV,

nectin (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 022), or a binding fragment thereof, for HS V 1/2,

sialylated glycans (SG) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 023), or a binding fragment thereof, for IV,

TIM-l(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for MuV,

TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for MeaV, CD155 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 024-025), or a binding fragment thereof, for PV,

a.2p i-intcgrin (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 026), or a binding fragment thereof, for RoV,

AchR (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 027-028), or a binding fragment thereof, for RaV,

CD4 (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 009-014), or a binding fragment thereof, for RuV HIV,

chondroitin sulfate (CS) (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 029), or a binding fragment thereof, for VARV,

TIMl(the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for YFV, or

TIM-l (the amino acid encoded by, or nucleic acid of, SEQ ID NO: 004), or a binding fragment thereof, for ZikV.

35. The method of one of claims 29-32, wherein the method comprises:

infusion to the subject of any one of the GEM compositions of claims 1-8 as a sterile composition;

removing from the subject’s body a portion of the subject’s blood;

conducting apheresis via a magnetic field on the portion of the subject’s blood to provide a cleaned portion of blood or lymph; and

optionally returning the cleaned portion of blood to the patient.

36. The composition of any one of claims 1-8, wherein the AIM comprises the sequence of the amino acid encoded by, or nucleic acid of, SEQ ID NO: 35, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 36, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 37, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 38, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 39, the amino acid encoded by, or nucleic acid of, SEQ ID NO: 40. SEQ ID NO: 70 - SEQ ID No: 82.

37. The composition of any one of Claims 1-8, wherein the VAM is fused with AIM, and AIM is conjugated to a SPM, wherein the GEM is selected from any one of the following: the amino acid encoded by, or nucleic acid of, SEQ ID NO: 41 - the amino acid encoded by, or nucleic acid of, SEQ ID NO: 69.

38. A GEM composition comprising: a virus-attaching-molecule (VAM), wherein the VAM is soluble; and a chemical linker; and a superparamagnetic (SPM) nanoparticle or a fluorescent molecule (F), wherein the VAM is conjugated to the SPM or the fluorescent molecule via the chemical linker.

40. A method of treating a subject having a virus-induced diseases, the method comprising: removing virus-infected cells and an infecting virus from a subject, by magnetic apheresis, wherein apheresis is performed using a genomically engineered molecule (GEM), wherein the GEM comprises any one of the GEMs from claims 1-8, and wherein the SPM within the GEM allows for the use of a magnetic field to achieve apheresis to remove the virus-infected cells and/or virus from the subject.

41. The method of claim 40, wherein the GEM comprises an antibody against an envelope or capsid molecule of a virus in the subject, the virus is selected from the group consisting of:

1. California Encephalitis Virus,

2. Chickengunya Virus,

3. Coronavirus,

4. Dengue Virus,

5. Ebola Virus,

6. Hanta Virus,

7. Hepatitis A Virus,

8. Hepatitis B Virus,

9. Hepatitis C Virus,

10. Hepatitis D Virus,

11. Human Herpes Virus 1,

12. Human Herpes Virus 2,

13. Human Herpes Virus 3 - Chickenpox - Varicella,

14. Human Herpes Virus 4 - EBV,

15. Human Herpes Virus 5 - CMV,

16. Human Herpes Virus 6,

17. Human Herpes Virus 7,

18. Human Herpes Virus 8,

19. Human Immunodeficiency Virus

20. Human Parainflunza Virus type 1,

21. Human Parainflunza Virus type 2,

22. Human Parainflunza Virus type 3,

23. Human Parainflunza Virus type 4,

24. Human Respiratory Syncytial Virus - HRSV,

25. Influenza A Virus,

26. Influenza B Virus,

27. Influenza C Virus,

28. Lymphocytic Choriomeningitis Virus,

29. Marburg Virus,

30. Mumps Virus,

31. Measles Virus,

32. Rabies Virus,

33. Rubella Virus,

34. Smallpox Virus,

35. West Nile Virus,

36. Yellow Fever Virus, and

37. Zika Virus.

42. The method of claim 41, wherein the GEM comprises a virus entry molecule as a VAM that binds to one or more of the following viruses:

1. California Encephalitis Virus,

2. Chickengunya Virus,

3. Coronavirus,

4. Dengue Virus,

5. Ebola Virus,

6. Hanta Virus,

7. Hepatitis A Virus,

8. Hepatitis B Virus,

9. Hepatitis C Virus,

10. Hepatitis D Virus,

11. Human Herpes Virus 1,

12. Human Herpes Virus 2,

13. Human Herpes Virus 3 - Chickenpox - Varicella,

14. Human Herpes Virus 4 - EBV,

15. Human Herpes Virus 5 - CMV,

16. Human Herpes Virus 6,

17. Human Herpes Virus 7,

18. Human Herpes Virus 8,

19. Human Immunodeficiency Virus

20. Human Parainflunza Virus type 1,

21. Human Parainflunza Virus type 2,

22. Human Parainflunza Virus type 3,

23. Human Parainflunza Virus type 4,

24. Human Respiratory Syncytial Virus - HRSV,

25. Influenza A Virus,

26. Influenza B Virus,

27. Influenza C Virus,

28. Lymphocytic Choriomeningitis Virus,

29. Marburg Virus,

30. Mumps Virus,

31. Measles Virus,

32. Rabies Virus,

33. Rubella Virus,

34. Smallpox Virus,

35. West Nile Virus,

36. Yellow Fever Virus, or

37. Zika Virus.

43. The method of one of claims 41-43, wherein the SPM comprises:

1. Ni,

2. Co,

3. Fe,

4. Eu, and/or,

5. Gd.

44. The method of one of claims 41-43, wherein the SPM comprises a core and a shell and wherein the shell comprises at least one of:

1. Au,

2. Pd,

3. Ag,

4. Pt,

5. Si,

6. Apatite, or

7. Carbide.

45. The method of any one of claims 41-44, wherein the SPM comprises at least one of:

1. DTPA,

2. EDTA,

3. DOTA,

4. His,

5. Glu,

6. Asp,

7. Lys, or

8. Cys.

46. The method of any one of claims 41-45, wherein the GEM is administered by:

1. intravenous infusion,

2. subcutaneous injection,

3. intramuscular injection,

4. intra-lymphatic system infusion, and/or

5. injection into fluids in apheresis machines.

47. The method of any one of claims 41-46, wherein apheresis employs at elast one of:

1. blood or lymph extra- vessel magnetic filters,

2. blood or lymph intra-vessel magnetic filters,

3. personal external magnets,

4. personal internal magnets,

5. magnetic over- flown surfaces in apheresis machines,

6. magnetic needles, and/or

7. magnetic filters in apheresis machines.