EP1981333A2 - Modele animal pour une pathologie induite par le vih - Google Patents

Modele animal pour une pathologie induite par le vih

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Publication number
EP1981333A2
EP1981333A2 EP07762942A EP07762942A EP1981333A2 EP 1981333 A2 EP1981333 A2 EP 1981333A2 EP 07762942 A EP07762942 A EP 07762942A EP 07762942 A EP07762942 A EP 07762942A EP 1981333 A2 EP1981333 A2 EP 1981333A2
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Prior art keywords
hiv
proteins
animal
cellular
related proteins
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German (de)
English (en)
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EP1981333A4 (fr
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Nelson M. Karp
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Individual
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/05—Animals modified by non-integrating nucleic acids, e.g. antisense, RNAi, morpholino, episomal vector, for non-therapeutic purpose
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/10—Animals modified by protein administration, for non-therapeutic purpose
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/20—Animals treated with compounds which are neither proteins nor nucleic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0337—Animal models for infectious diseases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
    • C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to a composition and method for producing an animal model for HIV.
  • HIV is a viral infection. Therefore, by definition, HIV is an intra cellular parasite. The virus must assimilate a variety of host cellular proteins, lipids, carbohydrates and nucleic acids into its own structure and reproductive cycle. Attempts at inoculating animals with HIV have all failed. Animals such as mice lack one or more cellular proteins or other cellular derived molecules necessary for viral replication, immune evasion and immune suppression.
  • the purpose of this invention is to produce an animal that possesses the full complement of HIV immune mediated molecules in a manner that the animal can assimilate in trans the human derived proteins necessary for an HIV infection to proliferate. The animal will not recognize these foreign molecules as being foreign, and therefore, will not develop an immune response towards them. Furthermore, these human derived molecules will be directed towards Peyei ⁇ s patches, the very site of HIV replication. The animal will be susceptible to HIV disease.
  • a retroviral life cycle can be divided into an afferent and efferent limb.
  • the afferent limb starts with viral attachment and ends with viral DNA integration into the host genome.
  • the efferent limb commences with the production of viral messenger RNA and culminates with viral fission releasing immature virions.
  • the afferent lifecycle of the virus will be arbitrarily divided into the following steps: 1. Attachment to a target cell by its surface (SU) and transmembrane (TM) proteins. The surface protein binds to the CD4 receptor and to either the CCR5 or CXCR4 coreceptor.
  • Gag and Gag-Pol polyprotein cleaved by viral protease.
  • HIV as with all significant viral pathogens, is able to evade the host immune response. Furthermore, HIV down regulates or deregulates the host immunologic response.
  • proteins necessary for viral replication of the host immune response are human host derived proteins that are not found in animals. These include, but are not limited to, tRNA synthetase, tRNA lys , Tsg101 , TaI, Staufen, LEDGF/p75, Cyclin T, CDK9 and RNA polymerase II.
  • tRNA synthetase tRNA synthetase
  • tRNA lys Tsg101
  • TaI Staufen
  • LEDGF/p75 Cyclin T
  • CDK9 Cyclin T
  • RNA polymerase II RNA polymerase II
  • Viral evasion of the host's immune response requires the active participation of host derived cellular proteins such as the complement control proteins CD55, CD46 and Factor H. These proteins are necessary to prevent the host's immune cells from reacting to and destroying normal tissue. By incorporating these molecules into an intact HIV virion, the virus is able to fool the immune system in a "cloak-and-dagger" method that avoids virolysis.
  • Immune disregulation is accomplished by the virus skewing the host towards a Th2 immune response. This is accomplished by the virus hijacking the endosomal pathway by incorporating molecules such as Tsg101 , TaI and Ubiquitin.
  • the viral envelope incorporates MHC-II and CD86 molecules which are consistent with a Th2 response.
  • any given protein may exhibit different and at times divergent and conflicting functions, complicating the challenge to an animal model for HIV.
  • the present invention provides compositions and a method for producing an animal model for HIV induced disease.
  • the present invention is an animal adapted to simulate a human-like immune response to HIV, which is accomplished by activation and inactivation of complement of proteins within the animal. Accordingly, the present invention stages certain human proteins within an animal by way of its gut associated lymphoid tissue followed by infection of live HIV.
  • the present invention is directed to an animal model for HIV and the method of producing the same.
  • the present invention is a mouse adapted to simulate a human-like immune response to HIV, which is generated by appropriate protein behavior within the mouse.
  • the mouse genome has been published. 1 Extensive linkage conservation/synteny between mouse and human DNA has been established. 2 The present invention stages certain human proteins within a mouse by way of its gut associated lymphoid tissue (GALT).
  • GALT gut associated lymphoid tissue
  • a key to protein variability lies in the primary, secondary, tertiary and quaternary structure of the protein itself.
  • the protein may assume different secondary, tertiary and quaternary structures in various environmental conditions. Changes in ph, temperature, as well as the presence, absence, or concentration of cellular cofactors, such as calcium and magnesium, alter the structure and function of the protein.
  • proteins can be divided into basic building blocks or subunits known as motifs, each which possesses a specific function which is independent of the rest of the molecule. In some instances only a portion of the protein is directly involved in a certain metabolic process. The whole protein may or may not be needed to produce the desired effect.
  • the subunits not directly involved in the cellular activity may affect the overall structure, stability, intracellular location and often function as a scaffold.
  • a subunit of a protein that carries a significant function maintains that function when physically separated from the rest of the molecule.
  • Invariant amino acids in each protein are always noted. For example, the cystine residue occupying the position of amino acid 261 of Cyclin T is absolutely required for interaction with Tat. 3
  • All proteins administered to the animal model are encoded within the DNA.
  • Recombinant technology allows introduction of human DNA into bacteria, fungi, yeast or viruses. Utilizing commensal organisms, found normally in the gut of an animal such as a mouse, rat or rabbit for this recombination the proteins of human origin necessary for HIV replication and immune evasion and immune disregulation can be introduced into the animal without the animal rejecting the proteins as foreign.
  • the mechanisms of suppressor cells and regulatory cells found within the gut associated lymphoid tissue (GALT) prevent immunologic response to ingested food, commensal organisms and the products of the commensal organisms. Commensal organisms often produce vitamins necessary for the host to survive. Vitamins are protein based structures.
  • GALT constitutes nearly 80% of the total body's immune cell population. GALT is the most comprehensive lymphoid organ system in humans. The function of GALT is a paradox and at times is in conflict with the systemic immune system.
  • the systemic immune apparatus under normal conditions, functions in a sterile environment devoid of pathogens and pathogen associated toxins. Therefore, any foreign matter encountered by the systemic immune system is regarded as a potentially harmful invader and the appropriate immunologic response follows.
  • GALT 1 stands as a barrier between the human organism and an external environment replete with foreign tissue. The foreign matter includes a variety of commensal organisms, commensal derived products, pathogens, and pathogen derived products and ingested food.
  • GALT The entire Gl tract from the mouth to the anus is functionally external to the human body. Unlike the systemic immune system, which responds vigorously to any foreign matter, GALT must differentiate between commensal organisms and their products, as well as ingested food to which an immunologic response would have adverse consequences and invading pathogens potentially lethal to the host. 4
  • GALT is compartmentalized and, in contrast to the systemic and peripheral immune system (spleen & lymph nodes), is characterized by non-homogeneously distributed B and T cells.
  • GALT contains certain subsets of non-conventional lymphocytes such as ⁇ / ⁇ T cells. Overall GALT is characterized by afferent and efferent conduits not found in the systemic system. 5
  • GALT (armed with a variety of immunologic cells not found in the systemic circulation, and patterned or clustered into characteristic vehicles not found elsewhere in the body) is capable of immunologic suppression as well as classically based Th-1 and Th-2 immune responses.
  • Antigen uptake in GALT occurs through specialized epithelial cells known as "M" cells or “membranous” cells.
  • Antigen uptake in GALT can also occur directly by epithelial cells in close proximity to underlying T and B cells.
  • the uptake or assimilation of antigens through the "M" cells or epithelial cells may result in localized immune response, disseminated immune response and/or tolerance or immunosuppression.
  • the vast majority of antigens interacting with GALT results in specific suppression of immunity for that antigenic structure. This is necessary because the primary function of GALT is to prevent an immunologic reaction to innocuous, and at times beneficial, foreign material. 6
  • GALT The final determination in GALT of immunity versus tolerance rests on many variables. These include but are not limited to the chemical structure of the antigen, the dose of the antigen administered, and the cytokine environment. Whether this phenomenon is termed suppression, anergy, deletion, ignorance, and/or immunologic deviation is irrelevant. Importantly, immunologic tolerance within GALT depends on an intact epithelial barrier. 7
  • a plasmid is a genetic particle physically separate from the chromosomal DNA of the host cell that is stable and can function and replicate independently of the nucleus.
  • a bacteriophage is a virus with a specific affinity for bacteria and has been found in association with essentially all groups of bacteria. Like other viruses, they contain either RNA or DNA but never both. 11
  • Hybrid plasmid/phage vectors such as cosmids, phagemids or phasmids. 12
  • a promoter/regulatory region controlling the plasmid activity would need to be included.
  • the assimilation of the protein produced by the commensal into the animal may occur by passive (ATP independent) or active (ATP dependent) means.
  • the DNA encoding a cell penetrating peptide (CPP) may be fused with the DNA encoding the human protein(s) prior to the recombinant process incorporating the DNA into the bacteria.
  • CPP cell penetrating peptide
  • Many cell penetrating peptides have been defined in the literature and have been used to carry cargos (attached protein, carbohydrate or lipid molecules) into cells which would normally be impermeable to these attached structures. Cell penetrating peptides can pass through cell walls, nuclear membranes, as well as the membranes enclosing other intracellular organelles with ease. 15
  • the DNA encoding the below mentioned human proteins necessary for HIV viral replication, immune evasion and immune disregulation can be spliced into the DNA of an animal. Intuitively this may seem to be the most logical answer. For some proteins such as the CD4 receptor and the CCR5 and CXCR4 co- receptor, this would be workable and perhaps preferable, since the proteins would be a component of the host cell plasma membrane. Many potential problems arise using that conceptualized framework for all the proteins. Most difficult would be the targeting of the needed proteins to the sites of HIV replication (i.e., Peyer"s patches). Furthermore, encoding a protein into the DNA of an organism does not equate to transcription and translation of the DNA and protein production. 70% of the DNA in a mammal is not transcribed and has been termed "junk DNA". Production of a transgenic or chimeric animal does not equate to tissue targeting. External control of animals genetically modified at the level of embryonic cells is problematic.
  • the host proteins necessary for HIV to attach to a target cell, penetrate the target cell and replicate within the target cell include and are not limited to the following list.
  • the host derived proteins necessary for HIV to evade the immune response include but are not limited to the following, and preferably should be included in a workable animal model for HIV. (See Table in Appendix A for a complete list of "Host Proteins Incorporated into the Intact Virus and /or Pre-1 ntegration Complex (PIC)".
  • C4 binding protein C4b protein
  • Factor H Includes FHL-1 , FHR1 , FHR2, FHR3, FHR4, FHR5
  • the activity of Human Factor H in an animal can be limited by administration of soluble complement-receptor 1 (sCR1 ) by adding sCR1 exogenously or by splicing the genomic sequence for sCR1 into a commensal organism.
  • sCR1 soluble complement-receptor 1
  • This protein binds to C3b and C4b and facilitates the breakdown of these proteins by Factor I.
  • C3b By binding to C3b, sCR1 prevents complement activation by the C3 convertase.
  • the activity of Human Factor H in thwarting the complement cascade is mimicked by sCR1.
  • soluble CR1 is a controlled element or variable in the animal model.
  • sCR1 allows control of tissue levels of C3b thereby limiting the activity of the C3 and C5 convertases which mirrors the function of Factor H.
  • TRIM- ⁇ confers a potent post entry (i.e., meaning after entry into the cell) block to HIV-1 infection.
  • Cyclophilin A (CypA) binding to viral capsid proteins results in a similar response observed in vitro for certain human cell lines.
  • Cyclophilin A (CypA) binding to viral capsid proteins results in a similar response observed in vitro for certain human cell lines.
  • CypA Cyclophilin A
  • new world primates only owl monkeys exhibit post-entry restriction of HIV-1 replication. More specifically, monkey kidney cells of the Aotus trivirgatus owl restrict HIV infection, but are permissive for SIV infection. HIV restriction in these cells is completely abrogated when the interaction of the HIV-1 capsid and the cellular protein CypA Is disrupted.
  • the most effective weapon for immune perturbation within the HIV arsenal is the Tat protein.
  • the Tat protein is necessary for viral replication as well.
  • a multiplicity of immune down modulating effects of the Tat protein has been well documented in human studies.
  • An accurate model of HIV must include Tat mediated immune suppression. This will involve the Tat protein and the host cell receptors for the Tat protein.
  • CIITA class Il trans-activator
  • the Tat protein Inhibits CIITA function down regulating the expression of MHC Il genes.
  • Human cyclin T1 hCycTI
  • hCycTI Human cyclin T1
  • the Tat protein does not interact with the human counterpart of hCycTI , mouse cyclin T1 (mCycTI ).
  • mCycTI mouse cyclin T1
  • the Tat protein in mice does inhibit the activity of CIITA in a mechanism that is not dependent on mCycTI. The results are the same: the down regulation of the CIITA protein, decreased MHC Il production, and immunosuppression.
  • Murine cyclin T2 can bind HIV-1 Tat and facilitate TAR binding if a single residue, asparagine 260 is replaced with a cysteine residue.
  • Tat from HIV-2 does bind murine cyclin T1 and murine cyclin T2.
  • neither complex binds effectively the TAR residue.
  • With both HIV-1 and HIV-2 Tat effective binding and activity of Tat on HIV replication is rescued in murine cells by the above-mentioned mutation of Cyclin T2 at amino acid number 260. Therefore, if a murine model is anticipated, mutation of Cyclin T2 at residue 260 would equate to human Cyclin T1 supplied in trans.
  • a competent Cyclin T1 is necessary but not sufficient for HIV viral replication. This can be provided to a murine model by either one of the above-mentioned mutations in the mouse genome or by providing human Cyclin T1 in trans.
  • An effective block of HIV replication in a murine model is the inability of the virion to assimilate murine Factor H.
  • HIV directly activates the classical complement pathway in rabbit, mouse and guinea pig serum. This activation results in viral neutralization by lysis.
  • 19 Factor H is bound at multiple sites to gp120 and gp41 in the intact virus.
  • 20 Factor H is the main contributor to HIV evasion of complement mediated lysis.
  • 21 Murine and human Factor H is composed of twenty repetitive units and each unit is approximately sixty amino acids long. 22 Neither murine Factor H nor human Factor H is characterized by an alpha helix or a beta pleated sheet.
  • human and murine Factor H exists in two different conformational states ( ⁇ pi and q> 2 ) that can be separated by hydrophobic chromatography. Both have equal function. 23 Although murine Factor H possesses a high degree of homology to human Factor H, it does not bind to the HIV virus. Establishing an effective HIV infection, in a murine model would require the assimilation of human Factor H.
  • sialic acids characterized by a 9 carbon backbone
  • a glycan chain composed of mostly 5 and 6 carbon sugars
  • Mammals possess a variety of sialic acid recognizing proteins known as Siglecs.
  • Siglecs eleven functional Siglecs and one Siglecs like molecule (Siglec L1) have been characterized. Macrophages express Siglec 1 (sialoadhesin), B cells express Siglec 2 (CD22) and monocytes express Siglec 3 (CD33).
  • Cells involved in the innate immune response including natural killer cells and granulocytes are characterized by Siglecs 1 , 3, 5, 7 and 10.
  • the function of a protein and its potential immunogenicity are in part related to its surface glycan or sialic acid residues. Therefore, a potential rejection and function issue exists if proteins from animals expressing different surface sugar molecules coexist in the same animal.
  • the CMP-Neu5Ac synthetase genes that encode the enzymatic machinery necessary for sialic acids are found with one exception only in fruit flies, rainbow trout, mice and humans.
  • one bacteria Streptomyces coelicolor also expresses this genetic machinery. Lateral gene transfer between this bacterium and a eukaryotic host best explains this anomaly. 24 Therefore, a murine model obviates this overwhelming concern.
  • the mucosa of the murine Gl tract has been well described.
  • the surface of Peyer"s patches is covered by epithelium associated with a variety of lymphoid cells known as the follicle-associated epithelium (FAE).
  • the FAE is composed of a variety of cells including cells known as M cells. These cells exhibit slender cytoplasmic extensions around lymphoid cells.
  • the basolateral surface of the M cell is deeply invaginated forming a pocket that shortens the distance from the apical to the basolateral surface.
  • the pocket is rich in B cells, T cells, macrophages and dendritic cells.
  • M cells Antigen uptake by M cells does not result in intracellular degradation but rather delivery of the intact molecule to the underlying lymphoid tissue.
  • the apical surface of the M cell lacks the brush border of typical gut lining enterocytes.
  • the M cells are not coated with the thick glycocalyx found on enterocytes.
  • the distribution of actin-associated protein villin in M cells differs from enterocytes.
  • a variety of methods will target the M cells for absorption of defined proteins. These include, but are not limited to: (1 ) cholera toxin-B subunit, (2) carbohydrate lectins, (3) genetically engineered IgA or the secretory component of IgA. Splicing the genetic DNA sequence for a defined protein needed for HIV replication and linking that protein to 1 , 2 or 3, above, will target the protein to the M cells and ultimately to the underlying immune tissue. 26
  • Attenuated viruses particularly the mouse reovirus, attenuated Poliovirus type 1 and the attenuated Sabin strain selectively adhere to M cells. These viruses can be exploited for transporting a defined protein into Peyer"s patches.
  • Certain attenuated bacteria also target the M cell apical membrane. These include Vibrio Cholerae, Salmonella, Shigella, Yersinia and BCG. Attenuation of these organisms renders them non-virulent. They can be exploited in targeting recombinant proteins to the M cells and the underlying immune tissue. 28
  • the described proteins are administered to the animal by way of its GALT followed by infection of live HIV. Infection with live HIV will result in Tat protein transcription and translation with the resulting Tat mediated immune suppression.
  • Tat protein or the incorporation of the DNA encoding the Tat protein can be administered directly in combination with other proteins or incorporated into the commensal through recombinant technology described above.
  • proteins, composition of proteins and or compositions of incorporated DNA encoding the proteins can be administered as a pharmaceutical formulation or preparation, optionally with supplements or other compositions as described above. If protein carriers are used they must be "pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • protein carriers e.g., complement proteins
  • Administration may be made in a variety of routes, for example orally, transbucally, transmucosally, sublingually, nasally, rectally, vaginally, intraocularly, intramuscularly, intralymphatically, intravenously, subcutaneously, transdermal ⁇ , intradermally, intra tumor, topically, transpulmonarily, by inhalation, by injection, or by implantation, etc.
  • Various forms of the composition may include, without limitation, capsule, gel cap, tablet, enteric capsule, encapsulated particle, powder, suppository, injection, ointment, cream, implant, patch, liquid, inhalant, or spray, systemic, topical, or other oral media, solutions, suspensions, infusion, etc. Because some of the first targets for infection with HIV are epithelial cells and Langerhans cells in the skin and rectal mucosa, then a preferable embodiment of delivery is dermal combined with rectal suppositories.
  • aqueous solutions such as Ringer's solution or a saline buffer
  • Liposomes, emulsions, and solvents are other examples of delivery vehicles.
  • Oral administration would require carriers suitable for capsules, tablets, liquids, pills, etc, such as sucrose, cellulose, etc.
  • the preferred method of administration would be via commensal organisms genetically modified to express one or more human derived proteins needed for HIV replication.
  • the preferred area of administration would be the intestines targeting Peyei ⁇ s patches.
  • the delivery and deliberate infection of live HIV is well known in the art and includes intra vaginal, rectal and systemic portals.
  • the present invention provides compositions and a method for producing an animal model for HIV induced disease.
  • the present invention is an animal adapted to simulate a human-like immune response to HIV, which is accomplished by activation and inactivation of complement of proteins within the animal. Accordingly, the present invention stages certain human proteins within an animal by way of its GALT followed by infection of live HIV.
  • Prokaryotic organisms lack the post translational modification machinery found in eukaryotic organisms.
  • Yeast such as Saccharomyces cerevisiae are eukaryotes often found as commensal organisms in GALT. Yeast may therefore be preferable as recombinatorial vectors.
  • a blend of genetic manipulations may yield the optimal animal model.
  • a mouse with one or the other above-mentioned amino acid substitutions in the Cyclin T protein that renders it Tat and TAR processive would be a good starting point.
  • This murine model could then assimilate the CD4 receptor and the CCR5 and CXCR4 co- receptors by transgenic technology.
  • Other proteins the mouse is lacking to affect HIV replication, immune evasion and immune disregulation could be supplied in trans via recombinatorial GALT vectors.
  • Nicholl, Desmond S. T., An Introduction to Genetic Engineering, 2002, 2d ed., Ch. 5, pp. 57-85 11. Nicholl, Desmond S. T., An Introduction to Genetic Engineering, 2002, 2d ed., Ch. 5, pp. 57-85
  • HIV-1 Tat up regulates HLA-DR expression in monocyte-derived dendritic cells and T cells, thereby driving T cell-mediated immune responses and activation.
  • Associates with HIV-1 gp41. Enhances HIV-1 infectivity. Not affected by viral tropism which is determined by the V3 loop of gp120. Amino acids 708-750 of gp41 required for MHC-II incorporation into the HIV-1 envelope.
  • HLA Il DR is the predominant if not only subtype of HLA Il detected on the surface of most HIV-1 virions. Therefore, HLA Il DR is selectively incorporated into the viral envelope.
  • ICAM-1 A type 1 transmembrane Yes, envelope Increases HIV macrophages.
  • HIV-1 group N and group O Nef weakly down regulates CD4, CD28, and class I and Il MHC molecules and up regulates surface expression of the invariant chain (Ii) associated with immature major histocompatibility complex (MHC) class II.
  • Nef interrupts MHC- I trafficking to the plasma membrane and inhibits antigen presentation.
  • Nef interacts with the ⁇ 1 subunit of adaptor protein (AP) AP-1A, a cellular protein complex implicated in TGN linking endosome/lysosome pathways.
  • AP adaptor protein
  • HIV-1 Nef binds to the MHC-I (HLA-A2) hypo phosphorylated cytoplasmic tails in the endoplasmic reticulum; this Nef-MHC-I complex migrates into the Golgi apparatus then into the lysosomal compartments for degradation. Nef promotes a physical interaction between endogenous AP- 1 and MHC-I.
  • the Pro-X-X- Pro motif in HIV-1 Nef induces the accumulation of CCR5 (HIV-1 M-tropic coreceptor) in a perinuclear compartment where both molecules co- localize with MHC-1.
  • the Pro-X-X-Pro motif interacts with src homology region-3 domains of src-like kinases interfering with cell signaling pathways.
  • HIV-1 Nef selectively down regulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E 1 which allows HIV- infected cells to avoid NK cell-mediated lysis. Nef decreases the incorporation of MHC-1 molecules into virions. Furthermore, Nef down regulates MHC-1 expression on human dendritic cells. Therefore, HIV-1 Nef impairs antigen presentation to HIV- specific CD8+ T lymphocytes. HIV-1 Nef-induced down regulation of MHC-I expression and MHC-I targeting to the trans- Golgi network (TGN) require the binding of Nef to PACS-1 (phosphofurin acidic cluster sorting protein 1).
  • PACS-1 phosphofurin acidic cluster sorting protein 1
  • PACS-1 is a protein with a putative role in the localization of proteins to the trans- Golgi network (TGN) including furin which cleaves gp160.
  • HIV-1 Nef down regulates MHC-1 on lymphoid, monocytic and epithelial cells. Nef expression results in rapid internalization and accumulation of MHC-1 in endosomal vesicles which degrade MHC-1 molecules. Nef blocks transport of MHC-I molecules to the cell surface, leading to accumulation of MHC- 1 in intracellular organelles.
  • CD63 A type III Yes envelope The efferent arm of transmembrane protein viral replication occurs present on activated in the endosomes. platelets, monocytes, The CD63 marker is phosphatase facilitates dephosphorylation of phosphorylated Cdc25 protein by the protein phosphatase PP2A. Found on chromosome 19 location 19p13. Mediates GM-CSF production. Binds c-Fos through specific pS/T-P sites within the c-Fos TAD (carboxyl terminal transactivation domain) resulting in enhanced transcriptional response of c-Fos to polypeptide growth factors that stimulate ERK (extracellular regulated kinases).
  • CypA Immunophilin, peptidyl- Yes, virion Incorporated as a (Cyclophilin A) prolyl isomerase Found component of the Gag on chromosome 7 molecule at a 1/10 location 7p13. ratio. Also interacts Catalyzes the cis-trans with Vpr, Vif, MA, Nef isomerization of proline and gp120env. Binds imidic peptide bonds in to the central region of oligopeptides, the CA protein accelerates the folding of (residues 85 to 93). proteins. Catalyzes the cis/trans isomerization of the Gly-89-Pro-90 peptide bond.
  • the capsid sequence 87HiS-AIa- Gly-Pro-lle-Ala92 encompasses the primary cyclophilin A binding site. Inhibits ltk (lnterieukin-2 tyrosine kinase) catalytic activity, a cytoplasmic nonreceptor protein tyrosine kinase of the Tec (Molecular class: tyrosine kinase, Molecular Function: protein-tyrosine kinase activity, Biological Process: cell communication, signal transduction) family that participates in the intracellular signaling events leading to T cell activation.
  • ltk lnterieukin-2 tyrosine kinase
  • Tec Molecular class: tyrosine kinase, Molecular Function: protein-tyrosine kinase activity, Biological Process: cell communication, signal transduction
  • a proline-dependent conformational switch within the ltk SH2 domain regulates substrate recognition and mediates regulatory interactions with the active site of CypA. Regulates the cis/trans interconversion of the imidic bond within the conserved proline residues of Vpr in vivo. Implicated in capsid final assembly and defense of HIV-1 against innate host restriction factors specifically Ref-1. CypA/CD147 (Type l integral membrane glycoprotein found on hemopoietic, microglial, endothelial and peripheral blood cells) interaction follows CypA interaction with surface heparins. Facilitates viral/host cell binding prior to gp120/CD4 and gp120/CXCR4 or CCR5 co-receptor interaction. Increases probability of successful infection when a small amount of virus has been transmitted.
  • FKBP12 FK506 A peptidyl prolyl Yes, virion Growth of chronically binding proteins
  • UNG Uracil- Uracil-DNA glycosylase Yes, virion lntegrase is required
  • DNA removes DNA uracil for packaging of UNG glycosylase) residues. Excises the into virions. UNG2 uracil residues and binds the viral reverse introduces non transcriptase enzyme. Templated nucleotides Uracil repair pathway allowing for somatic is associated with HIV- hyper mutation. 1 viral particles. Increases immunoglobulin diversity. Essential for generation of strand breaks for class switch recombination. Both mitochondrial (UNG1 ) and nuclear (UNG2) isoforms have been described. UNG1 only uracil-DNA glycosylase isolated to date in mitochondria. Mitochondrial UNG1 is encoded by nuclear not mitochondrial DNA.
  • UNG2 predominant form in proliferating cells, UNG1 predominant form in non-proliferating cells. UNG2 levels high in S- phase and early G2 of the cell cycle. UNG2 primarily located at replication foci during S- phase.
  • a second uracil- DNA glycosylase, Single-strand-selective Monofunctional Uracil- DNA Glycosylase (SMUGI) has a preference for double- stranded DNA rather responsive element p300 for CDK9/P-TEFb binding protein]).
  • SMUGI Single-strand-selective Monofunctional Uracil- DNA Glycosylase
  • CBP can stimulate Tat binds to amino acid transcription through 1253-1790 of p300. activation of CREB. This interaction results in a structural change of p300/CBP.
  • Tat-p300 interaction increases the HAT activity of p300 on histone H4.
  • H4 is a component of nucleosomes. Histone H4 was acetylated on lysines 8, 12, and 16. Acetylation of H4 was inhibited by Lys- coenzyme A (CoA), a selective inhibitor of p300 acetyltransferase activity. Tat could auto acetylate itself, which was specific to lysine residues 41 and 71. Acetylated Tat is considered to be the transcriptionally active form intracellularly. p300 and PCAF directly acetylate Tat.
  • HLA-DR Antigen presentation Yes, envelope Interacts with CD4 MHC class Il directly glycoprotein on target presents peptide cells. Without antigens to CD4 T cells. associated antigen in Highly polymorphic. the peptide binding Heterodimer consisting cleft of HLA-DR and of an alpha (DRA) and a co-stimulating beta (DRB) chain, both molecular interactions, anchored in the CD4 cell will be membrane. Presents rendered anergic. peptides derived from HIV-1 Gag expression extracellular proteins by is able to induce HLA- antigen presenting ceils, DR cell-surface B cells, dendritic cells localization in H78- and macrophages. C10.0 cells.
  • HIV-1 6 location 6p21.3 Gag proteins co- localize with MHC Il (HLA-DR), CD63, and Lampi in MHC Il compartments.
  • HIV-1 Capsid (p24) inhibits interferon gamma induced increases in HLA-DR and cytochrome B heavy chain mRNA levels in the human monocyte- like cell line THP1.
  • HIV-1 Tat down regulates expression of MHC class Il genes in antigen-presenting cells (APC) by inhibiting the transactivator of MHC class Il genes, CIITA. HIV-1 Tat up regulates HLA-DR expression in monocyte-derived dendritic cells and T cells, thereby driving T cell-mediated immune responses and activation.
  • Associates with HIV-1 gp41. Enhances HIV-1 infectivity. Not affected by viral tropism which is determined by the V3 Ioop of gp120. Amino acids 708-750 of gp41 required for MHC-II incorporation into the HIV-1 envelope.
  • HLA-A HLA-A
  • HLA-B HLA-C 1 HLA-E
  • HLA-G MHC-1 binding groove
  • HLA-A 1 HLA-B and HLA- and co-stimulatory C function to present activity, anergy results.
  • antigens to CD8 T cells HIV-1 Nef down and to form ligands for regulates surface natural killer (NK) cell expression of CD4 and receptors.
  • NK surface natural killer
  • HLA-E and MHC-1 in resting CD4 + HLA-G also ligands for T lymphocytes. Nef NK-cell receptors.
  • HLA- up regulates cell A is found on surface levels of the chromosome 6 location MHC-2 invariant chain
  • CD74 Nef down regulates HLA class I expression and therefore suppresses the cytolytic activity of HI V-1 -specific cytotoxic T-lymphocyte (CTL) clones.
  • CTL cytotoxic T-lymphocyte
  • M- tropic Macrophage-tropic HIV-1 Nef down regulates expression of HLA-A2 on the surface of productively infected macrophages.
  • HIV-1 group N and group O Nef weakly down regulates CD4, CD28, and class I and Il MHC molecules and up regulates surface expression of the invariant chain (Ii) associated with immature major histocompatibility complex (MHC) class II. Nef interrupts MHC-I trafficking to the plasma membrane and inhibits antigen presentation.
  • Ii invariant chain
  • MHC major histocompatibility complex
  • Nef interacts with the ⁇ 1 subunit of adaptor protein (AP) AP-IA, a cellular protein complex implicated in TGN linking endosome/lysosome pathways.
  • HIV-1 Nef binds to the MHC-I (HLA-A2) hypo phosphorylated cytoplasmic tails in the endoplasmic reticulum; this Nef- MHC-I complex migrates into the Golgi apparatus then into the lysosomal compartments for degradation.
  • Nef promotes a physical interaction between endogenous AP- 1 and MHC-I.
  • the Pro-X-X- Pro motif in HIV-1 Nef induces the accumulation of CCR5 (HIV-1 M-tropic coreceptor) in a perinuclear compartment where both molecules co- localize with MHC-1.
  • the Pro-X-X-Pro motif interacts with src homology region-3 domains of src-like kinases interfering with cell signaling pathways.
  • HIV-1 Nef selectively down regulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E, which allows HIV- infected cells to avoid NK cell-mediated lysis.
  • Nef decreases the incorporation of MHC- 1 molecules into virions. Furthermore, Nef down regulates MHC-1 expression on human dendritic cells.
  • HIV-1 Nef impairs antigen presentation to HIV- specific CD8+ T lymphocytes.
  • HIV-1 Nef-induced down regulation of MHC-I expression and MHC-I targeting to the trans- Golgi network (TGN) require the binding of Nef to PACS-1 (phosphofurin acidic cluster sorting protein 1).
  • PACS-1 is a protein with a putative role in the localization of proteins to the trans-Golgi network (TGN) including furin which cleaves gp160.
  • HIV-1 Nef down regulates MHC-1 on lymphoid, monocytic and epithelial cells. Nef expression results in rapid internalization and accumulation of MHC-1 in endosomal vesicles which degrade MHC-1 molecules. Nef blocks transport of MHC-I molecules to the cell surface, leading to accumulation of MHC- 1 in intracellular organelles.
  • HSP70 Heat Chaperone intracellular Yes, virion May bind HIV-1 gag shock protein protein produced in polyprotein chain and 70) response to intracellular maintain proper stress. Found on tertiary confirmation chromosome 19 location during intracellular
  • UNG Uracil- Uracil-DNA glycosylase Yes, virion lntegrase is required
  • DNA removes DNA uracil for packaging of UNG glycosylase) residues. Excises the into virions. UNG2 uracil residues and binds the viral reverse introduces non transcriptase enzyme. templated nucleotides Uracil repair pathway allowing for somatic is associated with HIV- hyper mutation. 1 viral particles.
  • UNG1 mitochondrial
  • UNG2 nuclear
  • UNG1 only uracil-DNA glycosylase isolated to date in mitochondria.
  • Mitochondrial UNG1 is encoded by nuclear not mitochondrial DNA.
  • UNG2 predominant form in proliferating cells, UNG1 predominant form in non-proliferating cells.
  • UNG2 levels high in S- phase and early G2 of the cell cycle.
  • UNG2 primarily located at replication foci during S- phase.
  • a second uracil- DNA glycosylase Sing le-strand-selecti ve Monofunctional Uracil- DNA Glycosylase (SMUGI) has a preference for double- stranded DNA rather than single-stranded DNA as with UNG1 and UNG2.
  • SMUGI Monofunctional Uracil- DNA Glycosylase
  • RNA May be involved Transports mRNAs to in retroviral genome intracellular selection and compartments/organelle packaging into s. Found on assembling virions. chromosome 20 location Interaction with the 20q13.1. Binds tubulin. nucleocapsid domain Transports mRNA via of pr55(Gag) in vitro the microtubule network and in live cells to the RER. Five mediated by Staufen's transcript variants from dsRBD3 (RNA binding alternative splicing of domain 3), with a STAU gene encoding contribution from its C- three isoforms have terminal domain. been described. Preferentially binds with the 9-kb non- spliced viral RNA. Implicated in the generation of infectious virions. ⁇ -actinin 1 Required for Vpx- mediated nuclear import of the PIC.
  • LEDGF/p75 DNA-binding protein Yes PIC Central core domain (lens epithelium- implicated in cellular (preintegration and N-terminal zinc derived growth differentiation and complex) binding domain of factor/transcripti cellular response to integrase are involved on coactivator environmental stress. in the interaction with p75 [alternate Activates transcription of LEDGF/p75.
  • An names include stress related genes essential cofactor for PC( positive co- triggering a survival nuclear targeting of factor ⁇ and response.
  • a member of alternatively spliced journal articles the hepatoma-derived protein LEDGF/p52, differentiate p75 growth factor (HDGF). does not interact with from PC4 in
  • interaction protein 1 LEDGF/p75 links the (PSIP1 )) protein integrase protein to interactions with the host chromatin transcriptional during the G 2 phase of coactivators, general the cell cycle. May transcription factors, and target the HIV-1 splicing factors, proviral DNA to modulating pre-mRNA specific genomic sites splicing of class Il of actively transcribed genes.
  • the p75 protein genes to promote viral is not a transcriptional transcription. factor.
  • Heparin binds to Residues are the LEDGF/p75, facilitating integrase binding transport through the domain (IBD).
  • cytoplasm into the Dictates site(s) of HIV nucleus.
  • the N-terminal integration, most PWWP domain and its favored are areas beta-barrel substructure undergoing are needed for binding transcription, high G-C to metaphase (guanine-cytosine) chromatin. content, with active RNA polymerase subunits and transcription factors. Prevents proteasomal degradation of HIV-1 integrase.
  • the N- terminal zinc binding domain (amino acids 1-52) and the central core domain (amino acids 53-212) of HIV-1 integrase interact with LEDGF/p75.
  • tRNA synthetase Ligase charges or Yes
  • virion tRNA lys3 binds to the or aminoacyl aminoacylates key RNA primer binding site tRNA synthetase molecules linking the initiating reverse molecule to the transcription.
  • HIV-1 respective amino acid.
  • an RNA loop formed One synthetase for each by the tRNA lys3 amino acid found in anticodon and an mammalian cells.
  • ATP adenine rich RNA loop dependent. initiates reverse transcription.
  • tRNA lys Allows incorporation of Yes, virion Induces three lysine into proteins by associated dimensional structural the host translational attached to changes in the apparatus.
  • primer binding unspliced viral RNA to site (PBS) allow reverse transcription to proceed.
  • Glyceraldehyde enzymatically converts -3-phosphate Glyceraldehyde-3- dehydrogenase phosphate to 1 , 3- 6/sphosphoglycerate. Also involved in cell cycle regulation by modulating cyclin B- cdk1, apoptosis, membrane fusion, microtubule bundling, phosphotransferase activity, nuclear RNA export, programmed neuronal cell death, DNA replication, and DNA repair. Found on chromosome 12 location 12p13.
  • CD4 A type I transmembrane Yes, envelope Interacts with specific protein found on domains of gp120 helper/inducer T cells, facilitating viral fusion. monocytes, macrophages, and dendritic cells that is involved in T-cell recognition of antigens. Found on chromosome 12 location 12pter-p12.
  • CXCR4 Binds chemokine SDF-1 Yes, envelope Viral co-receptor (stromal cell derived determines viral factor 1 ). Found on tropism for CD4 T hematopoietic cells. precursors, mature white blood cells and plasma cells. Found on chromosome 2 location 2q21. Type fll transmembrane protein crossing the plasma membrane seven times.
  • CCR5 Found on Th1 cells, Yes, envelope Viral co-receptor dendritic cells, determines viral monocytes/macrophage tropism for s.
  • Type III macrophages transmembrane protein crossing the plasma membrane seven times.
  • Ligands include monocyte chemo attractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1 beta) and regulated on activation normal T expressed and secreted protein (RANTES). Found on chromosome 3 location 3p21.31
  • NFAT Cellular transcription Binding sites in the factor involved in the viral LTR necessary immune process. for viral transcription.

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Abstract

Le VIH ne cause pas de pathologie chez les espèces non humaines. Ainsi, il n'existe pas de système animal modèle permettant d'évaluer l'efficacité des stratégies ayant pour but de prévenir, traiter ou guérir une pathologie causée par ce virus. La présente invention concerne des compositions et un procédé visant à produire un modèle animal pour une pathologie induite par le VIH. La présente invention concerne un animal apte à simuler une réponse immunitaire au HIV semblable à celle de l'humain, qui est obtenue par activation et désactivation d'un complément protéinique au sein de l'animal. En conséquence, la présente invention concerne la classification de certaines protéines humaines au sein de l'animal par l'intermédiaire du tissu lymphoïde de ses intestins puis une infection par le virus vivant du VIH.
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