WO2016063251A1 - Réactifs et procédés de réactivation du vih latent - Google Patents

Réactifs et procédés de réactivation du vih latent Download PDF

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WO2016063251A1
WO2016063251A1 PCT/IB2015/058168 IB2015058168W WO2016063251A1 WO 2016063251 A1 WO2016063251 A1 WO 2016063251A1 IB 2015058168 W IB2015058168 W IB 2015058168W WO 2016063251 A1 WO2016063251 A1 WO 2016063251A1
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hiv
cells
hdaci
patient
memory
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Giuseppe Pantaleo
Matthieu PERREAU
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Centre Hospitalier Universitaire Vaudois
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/505—Cells of the immune system involving T-cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus, feline leukaemia virus, human T-cell leukaemia-lymphoma virus
    • G01N2333/155—Lentiviridae, e.g. visna-maedi virus, equine infectious virus, FIV, SIV
    • G01N2333/16—HIV-1, HIV-2
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70514—CD4

Definitions

  • This disclosure relates to reagents and methods for reactivating latent human immunodeficiency virus (HIV) using at least one inhibitor of histone deacetylases (HDACi).
  • HDACi histone deacetylases
  • HDACis histone deacetylases
  • HDACis are potent inducers of replication competent and infectious HIV-1 in resting memory CD4 T cells of long-term ART treated patients using a modified VOA and identified givinostat and belinostat as the most potent latency-reversing agents (LRAs).
  • HDACis including vorinostat, romidepsin, belinostat, panobinostat and givinostat were shown to be able to re-activate HIV replication in in vitro models of HIV latency using either genetically transduced cell-lines or CCL19-treated resting memory CD4 T cells from ART treated HIV-1 infected patients.
  • the recent study by Bullen et al. has however underscored the difficulty to reactivate HIV-1 latency in primary resting memory CD4 T cells isolated from aviremic long-term treated HIV-1 infected individuals using a modified enhanced VOA.
  • HDACis may have limited potency in the re-activation of replication competent HIV in primary resting memory CD4 T cells thus questioning their use to induce HIV re-activation in vivo in aviremic long-term ART treated patients.
  • HDACis may require longer incubation time to reactivate efficiently HIV-1 replication in vitro.
  • a number of clinical studies have shown promising results on the ability of HDACis such as vorinostat, romidepsin and panobinostat to increase cell associated RNA and more importantly detection of transient blips in viremia following administration to aviremic ART treated subjects.
  • FIG. 1 A. Acetyl Histone H3 MFI.
  • FIG. 1 HDACi efficiently reactivate HIV-1 replication from latenly infected resting memory CD4 T cells isolated from long-term treated HIV-1 infected subjects.
  • A Schematic representation of the modified VOA.
  • B Proportion of responders to HDACis treatment based on the detection of HIV-1 RNA.
  • C Proportion of responders to HDACis treatment based on the detection of p24.
  • D Proportion of HIV-1 RNA positive wells induced following HDACis treatment.
  • E Proportion of p24 positive wells induced following HDACis treatment.
  • F Levels of HIV-1 RNA copies/mL induced following HDACis treatment.
  • G Levels of p24 (ECL units) induced following HDACis treatment.
  • H ECL units
  • FIG. 3 Infectivity of HIV-1 re-activated by HDACis treatment.
  • A Proportion of p24- positive wells at day 5 and day 14 after in vitro HIV-1 inoculation of CD8-depleted resting memory CD4 T cells from healthy HIV negative subjects with the modified VOA culture supernatants (obtained from p24 positive supernatants at day 14).
  • B P24 values at day 5 and day 14 in vitro HIV-1 infection.
  • Statistical significance (P values) was either obtained using Chi-square analysis for comparison of positive proportions (A) or using Wilcoxon Matched-pairs Signed Rank test (B) or using Spearman's rank correlations (C).
  • Figure 4 Lack of synergistic effect between HDACi treatment and TCR stimulation on the reactivation of HIV-1 replication.
  • D Levels of p24 (ECL units) induced following givinostat treatment and/or anti-CD3/CD28 mAbs. Red bars correspond to mean ⁇ SEM.
  • this disclosure relates to methods for inducing human immunodeficiency virus (HIV) re-activation in vitro in resting primary memory CD4 + cells of an aviremic antiretrovial therapy (ART)-treated patient by exposing the cells to one or more inhibitors of histone deacetylases (HDACis) for greater than about 18 hours.
  • HBV human immunodeficiency virus
  • ART aviremic antiretrovial therapy
  • this disclosure relates to virus outgrowth assays comprising: co-culturing purified viable resting latent human immunodeficiency virus positive (HIV + ) memory T cells being cell surface positive for CD4 and cell surface negative for CD25, CD69' and HLA-DR of an HIV + aviremic long-term antiretrovial therapy (ART)-treated patient with allogenic primary CD8- depleted blood mononuclear cells from HIV uninfected subjects in the continuous presence of at least one histone deacetylase inhibitor (HDACi) for greater than 18 hours; isolating the supernatant of the co-culture; and, assaying the culture supernatant for the presence of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles therein; wherein the presence of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles in the culture supernatant indicates HIV replication has been reactivated in the memory CD4 + T cells.
  • HDACi histone deacety
  • this disclosure relates to methods for inducing human immunodeficiency virus (HIV) re-activation in vivo in resting memory CD4 + cells of an aviremic long-term antiretrovial therapy (ART)-treated patient, the method comprising administering to the patient one or more inhibitors of histone deacetylases (HDACi) such that the resting memory CD4 + cells in the patient are continuously exposed to the one or more HDACi for greater than about 18 hours.
  • HDACi histone deacetylases
  • This disclosure relates to reagents including pharmacological molecules (e.g., drugs) and methods for diagnosing and / or treating and / or preventing and / or ameliorating infection and / or symptoms of human immunodeficiency virus (HIV) infection.
  • pharmacological molecules e.g., drugs
  • HIV human immunodeficiency virus
  • this disclosure relates to methods for inducing human immunodeficiency virus (HIV) re-activation in vitro in resting primary memory CD4 + cells of an aviremic antiretrovial therapy (ART)-treated patient by exposing the cells to one or more inhibitors of histone deacetylases (HDACis) for greater than about 18 hours.
  • HBV human immunodeficiency virus
  • ART aviremic antiretrovial therapy
  • this disclosure relates to virus outgrowth assays comprising: co-culturing purified viable resting latent human immunodeficiency virus positive (HIV + ) memory T cells being cell surface positive for CD4 and cell surface negative for CD25, CD69' and HLA-DR of an HIV + aviremic long-term antiretrovial therapy (ART)-treated patient with allogenic primary CD8- depleted blood mononuclear cells from HIV uninfected subjects in the continuous presence of at least one histone deacetylase inhibitor (HDACi) for greater than 18 hours; isolating the supernatant of the co-culture; and, assaying the culture supernatant for the presence of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles therein; wherein the presence of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles in the culture supernatant indicates HIV replication has been reactivated in the memory CD4 + T cells.
  • HDACi histone deacety
  • this disclosure relates to methods for inducing human immunodeficiency virus (HIV) re-activation in vivo in resting memory CD4 + cells of an aviremic long-term antiretrovial therapy (ART)-treated patient, the method comprising administering to the patient one or more inhibitors of histone deacetylases (HDACi) such that the resting memory CD4 + cells in the patient are continuously exposed to the one or more HDACi for greater than about 18 hours.
  • HDACi histone deacetylases
  • the one or more HDACi is selected from the group consisting of vorinostat, romidepsin, belinostat, panobinostat and / or givinostat (Table 1 ), and / or any other HDACi that may be available to those of ordinary skill in the art.
  • the HDACi is belinostat or givinostat and, in particular, givinostat.
  • HIV-1 is known to comprise at least ten subtypes (A1 , A2, A3, A4, B, C, D, E, F1 , F2, G, H, J and K) (Taylor et al, NEJM, 359(18): 1965-1966 (2008)).
  • HIV-2 is known to include at least five subtypes (A, B, C, D, and E). Subtype B has been associated with the HIV epidemic in homosexual men and intravenous drug users worldwide.
  • HIV-1 immunogens laboratory adapted isolates, reagents and mapped epitopes belong to subtype B.
  • subtype B In sub-Saharan Africa, India and China, areas where the incidence of new HIV infections is high, HIV-1 subtype B accounts for only a small minority of infections, and subtype HIV-1 C appears to be the most common infecting subtype. Any of these types of isolates may be addressed using the reagents and methods described herein.
  • One or more of the reagents described herein may also be administered with or used in conjunction with, or the methods described herein may incorporate and be used in conjunction with, one or more agents used to prevent, treat and / or ameliorate HIV such as for example, a protease inhibitor, an HIV entry inhibitor, a reverse transcriptase inhibitor, and / or an anti- retroviral nucleoside analog.
  • agents used to prevent, treat and / or ameliorate HIV such as for example, a protease inhibitor, an HIV entry inhibitor, a reverse transcriptase inhibitor, and / or an anti- retroviral nucleoside analog.
  • Suitable compounds include, for example, Agenerase (amprenavir), Combivir (Retrovir / Epivir), Crixivan (indinavir), Emtriva (emtricitabine), Epivir (3tc / lamivudine), Epzicom, Fortovase / Invirase (saquinavir), Fuzeon (enfuvirtide), Hivid (ddc / zalcitabine), Kaletra (lopinavir), Lexiva (Fosamprenavir), Norvir (ritonavir), Rescriptor (delavirdine), Retrovir / AZT (zidovudine), Reyatax (atazanavir, BMS-232632), Sustiva (efavirenz), Trizivir (abacavir / zidovudine / lamivudine), Truvada (Emtricitabine / Tenofovir DF), Videx (ddl / didanosine), Videx EC (
  • This disclosure also provide a viral outgrowth assay ("VOA") modified to accurately and efficiently ascertain the ability of drugs such as HDACis to induce and / or reactive HIV replication in cells.
  • VOA viral outgrowth assay
  • VOA2 modified VOA
  • HDACis modified VOA
  • VOA2 modified VOA
  • differrent cell concentrations (as exemplified, five-fold limiting dilutions of 5x10 5 , 10 5 , 2x10 4 and 4x10 3 cells) of sorted viable resting memory CD4 + T cells (about >95% CD4 + CD25 " CD69 " HLADR " ) may be cultured with allogenic fresh CD8-depleted blood mononuclear cells (as exemplified, 10 6 cells/mL) from HIV uninfected subjects in the presence or in the absence (negative control) of one or more HDACis (e.g., as in the Examples, one of vorinostat (400 nM), romidepsin (5 nM), panobinostat (15 nM), givinostat (400 nM) or belinostat (400 nM) in complete RPMI).
  • HDACis e.g., as in the Examples, one of vorinostat (400 nM), romidepsin (5 nM), pan
  • a positive control in which cells are stimulated for three days on anti-CD3/anti-CD28 imAb coated plates may also be included.
  • Cells may be cultured in an appropriate cell culture media such as complete RPMI supplemented with IL-2 (50 units/mL) and IL-7 (10 ng/mL) during culture (e.g., 14 days as in the Examples). Medium may then be replaced at appropriate times such as day 5, and then re-supplemented with the one or more HDACis and other cell culture components (e.g., IL-2 and IL-7 as in the Examples).
  • Supernatants may be collected at appropriate times for assaying for the presence of HIV (e.g., days 5, 14 and 21 as in the Examples).
  • the presence of HIV in culture supernatants may be measured by any available technique including the many different protein detection and polymerase chain reaction (PCR) assays available to one of ordinary skill in the art (see, e.g., Eriksson, et al. Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies. PLOS Pathogens, vol. 9, no. 2 (2013)).
  • PCR polymerase chain reaction
  • the presence of p24 antigen may be assessed by a technique using enhanced chemiluminescence (ECL).
  • ECL enhanced chemiluminescence
  • HIV-1 RNA may be assessed by any available technique such as the COBAS® AmpliPrep/TaqMan® HIV-1 Test (Roche; Switzerland) following 1/10 medium dilution in basement matrix buffer (RUWAG bottles AG) as in the Examples.
  • RNA per million resting memory CD4+ T cells (RUPM) and infectious units per million (IUPM) induced by anti-CD3/anti- CD28 imAbs coated plates may be calculated by conventional limiting dilution methods using Extreme Limiting Dilution analysis (http://bioinf.wehi.edu.au/software/elda/).
  • the Examples provide non-limiting exemplary conditions and one of ordinary skill in the art could readily modify those conditions as desired by the user. For instance, while a purified (>95%) population of viable resting memory CD4 + T cells, lesser purified populations may also be suitable (e.g., about any of 50%, 60%, 70%, 80%, or 90% viable resting memory CD4 + T cells).
  • the ratio of viable resting memory CD4 + T cells to allogenic fresh CD8-depleted blood mononuclear cells may also be modified as desired by the user as long as the effect provided by those cells upon the viable resting memory CD4 + T cells is maintained.
  • the ratio of resting memory CD4 + T cells to allogenic fresh CD8-depleted blood mononuclear cells may be about any of 1 :20, 1 :15, 1 : 10, 1 :5, 1 :4, 1 :3, 1 :2, or 1 : 1 .
  • the type and amounts of cytokines may also be modified as may be determined by one of ordinary skill in the art. Different mediums may also be used, and replacement thereof may take place at different timepoints.
  • An important aspect of the VOA2 system that must be maintained is that exposure of the resting primary memory CD4 + T cells to the one or more HDACis is continuous (or at least substantially continuous) throughout the culture period and that the cells are co-cultured with freshly isolated CD8-depleted allogenic mononuclear cells from HIV negative healtly donors.
  • continuous is meant that the cells are exposed to HDACis for at least about 90%, 95%, 99% or more of the culture period. For instance, if the culture period is about 14 days (or about 336 hours), cells are considered continuously exposed to the one or more HDACis if the exposure is for at least about 300 hours (90% of the time).
  • the reagents and / or methods described herein may be also be used to determine the presence of a disease state in a patient, to predict prognosis, or to determine the effectiveness of a chemotherapeutic or other treatment regimen.
  • Expression profile assays may be used to determine the presence of HIV in a cell or tissue.
  • the modified VOA VOA2
  • VOA2 may be used to activate HIV replication in a test cell or tissue that may be subsequently assayed to detect HIV.
  • expression of HIV RNA, p24, and / or the production of infective HIV particles may be measured using standard techniques.
  • the level of expression and / or HIV particle production may then be correlated with base (e.g., control) levels to determine whether a particular disease is present within the patient, the patient's prognosis, or whether a particular treatment regimen is effective. For example, if the patient is being treated with a particular anti- infective regimen, an increased or decreased level of expression of HIV RNA, p24 and / or the production of infectious HIV particles in or from the patient's tissues such as CD4 + T cells isolated from the patient may indicate the regimen is worsening or improving the HIV load in that host. The increase or decrease in expression may indicate the regimen is having or not having the desired effect and another therapeutic modality may therefore be selected.
  • base e.g., control
  • reagents and / or methods described herein in drug screening assays to test, for example, new drug candidates.
  • the reagents may be used to ascertain the effect of a drug candidate on the expression of HIV expression products such as RNA and / or p24 antigen and / or production of infectious HIV particles.
  • the expression profiling technique may be combined with high throughput screening techniques to allow rapid identification of useful compounds and monitor the effectiveness of treatment with a drug candidate (see, for example, Zlokarnik, et al., Science 279, 84-8 (1998)).
  • Drug candidates may be chemical compounds, nucleic acids, proteins, antibodies, or derivatives therefrom, whether naturally occurring or synthetically derived. Drug candidates thus identified may be utilized, among other uses, as pharmaceutical compositions for administration to patients or for use in further screening assays.
  • a pharmaceutically acceptable carrier is a material that is not biologically or otherwise undesirable, e.g., the material may be administered to a subject, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. Suitable pharmaceutical carriers and their formulations are described in, for example, Remington's: The Science and Practice of Pharmacy, 21 st Edition, David B. Troy, ed., Lippicott Williams & Wilkins (2005).
  • an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic.
  • the pharmaceutically-acceptable carriers include, but are not limited to, sterile water, saline, buffered solutions like Ringer's solution, and dextrose solution. The pH of the solution is generally from about 5 to about 8 or from about 7 to about 7.5.
  • Other carriers include sustained-release preparations such as semipermeable matrices of solid hydrophobic polymers containing polypeptides or fragments thereof. Matrices may be in the form of shaped articles, e.g., films, liposomes or microparticles.
  • Carriers are those suitable for administration of polypeptides and / or fragments thereof to humans or other subjects.
  • Pharmaceutical compositions may also include carriers, thickeners, diluents, buffers, preservatives, surface active agents, adjuvants, immunostimulants, in addition to the immunogenic polypeptide.
  • Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents and anesthetics.
  • the pharmaceutical composition may be administered orally, parentally, by inhalation spray, rectally, intranodally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • pharmaceutically acceptable carrier or “physiologically acceptable carrier” as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of a nucleic acid, polypeptide, or peptide as a pharmaceutical composition.
  • a “pharmaceutical composition” is a composition comprising a therapeutically effective amount of a nucleic acid or polypeptide.
  • effective amount and “therapeutically effective amount” each refer to the amount of a pharmacological molecule / agent (e.g., drug) or the like used to observe the desired therapeutic effect.
  • compositions may be used in the methods described herein.
  • the reagents and methods described herein may be used to treat HIV infection in a mammalian host by administering to the mammal at least one or more effective doses of one or more HDACis described herein or as may be otherwise available.
  • the HDACi is vorinostat, romidepsin, belinostat, panobinostat and / or givinostat.
  • the one or more HDACis may be used ex vivo and / or in vitro at clinically relevant concentrations such as, for instance, about 1 to about 1500 nm, such as about any of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1 100, 1 125, 1 150, 1 175, 1200, 1225, 1250, 1275, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, or 1500 nm (in, e.g., cell culture media such as RP
  • vorinostat may be used at about 400 nM, romidepsin at about 5 nM, panobinostat at about 7.5 to about 32 nm such as about 15 nM, givinostat at about 250 to about 500 nm such as about 400 nM, and belinostat at about 250 to about 500 nm such as about 400 nM.
  • the HDACis may reach a peak plasma level of up to or about any of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 1200, 1300, 1400, 1500 nm such as about 100 nm.
  • the HDACis may also be administered in vivo using, for instance, a tablet comprising an effective amount of the one ore more HDACi such as about any of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 125, 150, 175 or 200 mg, or more.
  • the effective amount may also be measured as mg/m 2 such as, for instance, any of about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/m 2 .
  • the one or more HDACis may be administered in a dosage amount of about 1 to about 50 mg / kg, about 1 to about 30 mg / kg, or about 5 to about 30 mg / kg (e.g., about any of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, or 40 mg / kg). Doses may be administered multiple times per day or per week, and may be interrupted by rest periods during which a dose is not administered. However, in some preferred embodiments, continuous exposure of cells to the one or more HDACis is required and, in such embodiments, dosing may be adjusted accordingly as could be determined by one of ordinary skill in the art.
  • the one or more HDACis may be administered to the mammal (e.g., intradermally, intravenously, orally, rectally) one or more times.
  • the doses may comprise about the same or different amount of pharmacological agent (i.e., one or more HDACis) in each dose.
  • the doses may also be separated in time from one another by the same or different intervals.
  • the doses may be separated by about any of 6, 12, 24, 36, 48, 60, 72, 84, or 96 hours, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 1 1 months, 12 months, 1.5 years, 2 years, 3 years, 4 years, 5 years, or any time period before, after, and / or between any of these time periods.
  • the one or more HDACis are administered such that CD4 + T cells of a mammalian host are continuously exposed to the same during the treatment period which is typically at least more than 18 hours.
  • the one or more HDACis may be administered in conjunction with other agents such as another anti-HIV agent as described above. Such other agents may be administered about simultaneously with the one or more HDACis, or at a different time and / or frequency. Other embodiments of such methods may also be appropriate as could be readily determined by one of ordinary skill in the art.
  • kits described herein may also be provided in kit format which may also include instructions for carrying out the methods described herein.
  • a kit including one or more HDACis and optionally other components necessary for using the same to reactivate HIV replication in cells is provided.
  • the kit may also include reagents necessary to perform positive and / or negative control reactions such as cell lines (such HIV + and / or HIV " CD4 + T cells and / or CD8 + cells for co-cultures), one or more activating reagents such as anti-CD3 mAbs and / or anti-CD28 mAbs and / or anti-CD3 and / or anti-CD28 imAb coated plates.
  • the reagents of the kit may be provided in any suitable form, including frozen, lyophilized, and / or in a pharmaceutically acceptable buffer such as TBS or PBS.
  • the kit may also include reagents required to isolate and / or analyze certain cell types such as CD4+ T cells (e.g., components corresponding to or being found within the Aqua LIVE/DEAD stain kit, anti-CD4, anti-CD45RA, anti-HLA-DR, anti-CD25, and / or anti-CD69 labeled antibodies).
  • the kit may also include other reagents required for utilization of the reagents in vitro or in vivo such as buffers (e.g., TBS, PBS), blocking agents (solutions including nonfat dry milk, normal sera, Tween-20 Detergent, BSA, or casein), and / or detection reagents (e.g., goat anti-mouse IgG biotin, streptavidin-HRP conjugates, allophycocyanin, B-phycoerythrin, R-phycoerythrin, peroxidase, detectable labels, and other labels and / or staining kits (e.g., ABC Staining Kit, Pierce)).
  • buffers e.g., TBS, PBS
  • blocking agents solutions including nonfat dry milk, normal sera, Tween-20 Detergent, BSA, or casein
  • detection reagents e.g., goat anti-mouse IgG biotin, streptavidin-HRP conjugates, allo
  • kits may also include other reagents and / or instructions for using the antibodies in commonly utilized assays described above such as, for example, flow cytometric analysis, ELISA, immunoblotting (e.g., western blot), in situ detection, immunocytochemistry, immunhistochemistry.
  • the kit may also comprise the components required to measure integrated HIV DNA, expressed HIV RNA, expressed HIV p24 expression, and / or detect infectious HIV particles.
  • reagents may be a lysis buffer (10 mM Tris-HCI, pH 8.0, 50 nM KCI, 400 ⁇ g/ml proteinase K; Invitrogen) and the tools required to carry out integrated HIV DNA and CD3 gene copy number determinations (e.g., using a cross-clade ultrasensitive nested Alu PCR Buffers).
  • the kit may also include reagents for determining the presence of HIV-1 RNA such as may be obtained using commercially available tests such as the COBAS® AmpliPrep/TaqMan® HIV-1 Test (Roche; Switzerland). Reagent necessary for detecting the p24 antigen by standard assays such as ECL may also be included.
  • the kit may also include cell populations for detecting infectious HIV particles such as CD8-depleted blood mononuclear cells. These reagents and the like required for use in such systems are well-known in the art and / or may be prepared by the end-user or provided as a component of the kit.
  • the kit may also include a solid support containing positive- and negative-control protein and / or tissue samples.
  • kits for performing spotting or western blot-type assays may include control cell or tissue lysates for use in SDS-PAGE or nylon or other membranes containing pre-fixed control samples with additional space for experimental samples.
  • Kits for visualization of HIV in and / or on cells on slides may include pre-formatted slides containing control cell or tissue samples with additional space for experimental samples.
  • kits are also contemplated herein as would be understood by those of ordinary skill in the art.
  • this disclosure provides methods for inducing human immunodeficiency virus (HIV) re-activation in vitro in resting primary memory CD4 + cells of an aviremic antiretrovial therapy (ART)-treated patient by exposing the cells to one or more inhibitors of histone deacetylases (HDACis) for greater than about 18 hours.
  • the cells are continuously or substantially continuous exposure to the one or more HDACis for about 18, 24 or 48 hours, or for about one to about two weeks.
  • the patient was treated by ART for about two to about eight years.
  • reactivation of HIV may be determined by detecting the production of HIV-1 RNA, p24 by and / or infectious HIV particles from primary resting memory CD4 + cells of the patient.
  • the methods may include determining the difference in HIV-1 RNA, p24 and / or infectious HIV particle production between the primary resting memory CD4 + cells of the patient and those of the an aviremic long-term antiretrovial thereapy (ART)-treated patient that were not exposed to the one or more HDACi for the same length of time is determined.
  • the difference in HIV-1 RNA, p24 production and / or infectious HIV particle production before and after, or with and without, exposure to the one or more HDACis may be significant.
  • the one or more HDACi is selected from the group consisting of vorinostat, romidepsin, belinostat, panobinostat and / or givinostat, and / or any other HDACi that may be available to those of ordinary skill in the art.
  • the HDACi is belinostat or givinostat and, in particular, givinostat.
  • the one or more HDACis are the sole active pharmaceutical agents to which the cells are exposed.
  • this disclosure provides a virus outgrowth assay (“VOA2”) comprising co-culturing purified viable resting latent human immunodeficiency virus positive (HIV + ) memory T cells being cell surface positive for CD4 and cell surface negative for CD25, CD69' and HLA-DR of an HIV + aviremic long-term antiretrovial therapy (ART)-treated patient with allogenic primary CD8-depleted blood mononuclear cells from HIV uninfected subjects in the continuous presence of at least one histone deacetylase inhibitor (HDACi) for greater than 18 hours; isolating the supernatant of the co-culture; and, assaying the culture supernatant for the presence of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles therein wherein the presence of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles in the culture supernatant indicates HIV replication has been reactivated in the memory CD4 + T cells.
  • VOA2 virus outgrowth as
  • VOA2 further comprises the step of comparing the amount of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles in the culture supernatant of a) with that of a second culture supernatant of memory T cells being cell surface positive for CD4 and cell surface negative for CD25, CD69' and HLA-DR of an HIV uninfected subject co- cultured with allogenic primary CD8-depleted blood mononuclear cells from HIV uninfected subjects in the absence of at least one histone HDACi, wherein a difference in the amount of HIV p24 antigen and / or HIV RNA and / or infectious HIV particles between the culture supernatant of the exposed cells and the second culture supernatant indicates HIV replication was reactivated in the memory T cells of the HIV + aviremic long-term antiretrovial therapy (ART)-treated patient.
  • ART antiretrovial therapy
  • the memory T cells of the HIV + aviremic long- term antiretrovial therapy (ART)-treated patient with allogenic primary CD8-depleted blood mononuclear cells from HIV uninfected subjects are cultured in the continuous presence of at least one histone deacetylase inhibitor (HDACi) for one to fourteen days.
  • HDACi histone deacetylase inhibitor
  • the difference in HIV-1 RNA, p24 production and / or infectious HIV particle production before and after, or with and without, exposure to the one or more HDACis may be significant.
  • the one or more HDACi is selected from the group consisting of vorinostat, romidepsin, belinostat, panobinostat and / or givinostat, and / or any other HDACi that may be available to those of ordinary skill in the art.
  • the HDACi is belinostat or givinostat and, in particular, givinostat.
  • the one or more HDACis are the sole active pharmaceutical agents to which the cells are exposed.
  • This disclosure also provides methods for inducing human immunodeficiency virus (HIV) re-activation in vivo in resting memory CD4 + cells of an aviremic long-term antiretrovial therapy (ART)-treated patient, the method comprising administering to the patient one or more inhibitors of histone deacetylases (HDACi) such that the resting memory CD4 + cells in the patient are continuously or substantially continuously exposed to the one or more HDACi for greater than about 18 hours such as, for example, about 48 hours.
  • the ART treatment was for about two to about eight years.
  • the reactivation of HIV may be determined by detecting the production of HIV-1 RNA, p24 and / or infectious HIV particles from primary resting memory CD4 + cells of the patient.
  • the difference in HIV-1 RNA, p24 and / or infectious HIV particle production between the resting memory CD4 + cells of the patient following exposure to the one or more HDACis and those of the or an aviremic long-term antiretrovial thereapy (ART)-treated patient not exposed to the one or more HDACis for greater than about 18 hours is significant.
  • the one or more HDACi is selected from the group consisting of vorinostat, romidepsin, belinostat, panobinostat and / or givinostat, and / or any other HDACi that may be available to those of ordinary skill in the art.
  • the HDACi is belinostat or givinostat and, in particular, givinostat.
  • the one or more HDACis are the sole active pharmaceutical agents to which the cells are exposed.
  • the patient may be immunized with a vaccine comprising at least one HIV antigen following the continuous exposure of the resting memory CD4 + cells in the patient to the one or more HDACi for greater than about 18 hours.
  • a subject or a host is meant to be an individual.
  • the subject can include domesticated animals, such as cats and dogs, livestock (e.g., cattle, horses, pigs, sheep, and goats), laboratory animals (e.g., mice, rabbits, rats, guinea pigs) and birds.
  • livestock e.g., cattle, horses, pigs, sheep, and goats
  • laboratory animals e.g., mice, rabbits, rats, guinea pigs
  • the subject is a mammal such as a primate or a human.
  • Optional or optionally means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
  • the phrase optionally the composition can comprise a combination means that the composition may comprise a combination of different molecules or may not include a combination such that the description includes both the combination and the absence of the combination (i.e., individual members of the combination).
  • Ranges may be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent about or approximately, it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. Ranges (e.g., 90-100%) are meant to include the range per se as well as each independent value within the range as if each value was individually listed.
  • combined or “in combination” or “in conjunction” may refer to a physical combination of agents that are administered together or the use of two or more agents in a regimen (e.g., administered separately, physically and / or in time) for treating, preventing and / or ameliorating a particular disease.
  • treat, prevent, and / or ameliorate or derivatives thereof are used herein in connection with a given treatment for a given condition (e.g., preventing cancer infection by HIV), it is meant to convey that the treated patient either does not develop a clinically observable level of the condition at all, or develops it more slowly and/or to a lesser degree than he/she would have absent the treatment.
  • a given treatment for a given condition e.g., preventing cancer infection by HIV
  • a treatment will be said to have prevented the condition if it is given during exposure of a patient to a stimulus that would have been expected to produce a given manifestation of the condition, and results in the patient's experiencing fewer and/or milder symptoms of the condition than otherwise expected.
  • a treatment can "prevent" infection by resulting in the patient's displaying only mild overt symptoms of the infection; it does not imply that there must have been no penetration of any cell by the infecting microorganism.
  • reduce, reducing, and reduction as used herein in connection with prevention, treatment and / or amelioration of a given condition by a particular treatment typically refers to a subject developing an infection more slowly or to a lesser degree as compared to a control or basal level of developing an infection in the absence of a treatment.
  • a reduction in the risk of infection may result in the patient's displaying only mild overt symptoms of the infection or delayed symptoms of infection; it does not imply that there must have been no penetration of any cell by the infecting microorganism.
  • Vorinostat Merk Research Laboratory; USA
  • romidepsin Cellgene; USA
  • panobinostat Novartis; Switzerland
  • givinostat Italfarmaco; Italy
  • belinostat Topotarget and Spectrum Pharmaceuticals; Denmark
  • CD4 T cells Sorting of resting memory CD4 T cells. Cryopreserved blood mononuclear cells were thawed and CD4 + T cells were enriched using EasySep Human CD4 T-cell enrichment kit (StemCell Technologies, USA ).
  • CD4 + T cells were then stained with Aqua LIVE/DEAD stain kit (4°C; 15 min) and then with anti-CD4 FITC, anti-CD45RA ECD, anti-HLA-DR PB, anti-CD25 PE-Cy7 and anti-CD69 PerCp-Cy5.5 (4°C; 25 min) and viable resting memory (CD4 + CD25 " CD69 " HLA-DR " ) CD4 T cell populations were sorted using FACSAria (Beckton & Dickinson). In all sorting experiments the grade of purity of the sorted cell populations was >97%.
  • Vorinostat 400 nM
  • romidepsin 5 nM
  • panobinostat 15 nM
  • givinostat 400 nM
  • belinostat 400 nM
  • complete RPMI a positive control
  • cells were stimulated for 3 days with anti-CD3/anti-CD28 imAb coated plates (10 ⁇ g/mL). All cell conditions were cultured in complete RPMI supplemented with IL-2 (50 units/mL) and IL-7 (10 ng/mL) for 14 days. Medium was replaced at day 5, and re-supplemented with HDACi and cytokines. Supernatants were collected at day 5, 14 and 21 . The presence of p24 antigen was assessed by ECL.
  • HIV-1 RNA was assessed by COBAS® AmpliPrep/TaqMan® HIV-1 Test (Roche; Switzerland) following 1/10 medium dilution in basement matrix buffer (RUWAG bottles AG).
  • RUPM 29 and IUPM 21 induced by anti-CD3/anti- CD28 imAbs coated plates were calculated by conventional limiting dilution methods using Extreme Limiting Dilution analysis (http://bioinf.wehi.edu.au/software/elda/).
  • Integrated HIV-1 DNA quantification Resting memory CD4 T cells were sorted as described above and lysed using lysis buffer (10 mM Tris-HCI, pH 8.0, 50 nM KCI, 400 ⁇ g/ml proteinase K; Invitrogen) and integrated HIV DNA and CD3 gene copy numbers were determined using a cross-clade ultrasensitive nested Alu PCR, as previously described. The frequency of HIV-1 integrated DNA per million of cells was calculated as previously described.
  • the frequencies of inducible replication competent virus from latently HIV-1 infected cells was determined by measuring both RNA-unit per million (RUPM) and Infectious Unit per million (IUPM) in ten aviremic long-term treated patients (duration of treatment 2-8 years, average 4.2 years) using a modified (see below) virus growth assay (VOA2) after stimulation with anti-CD3/anti-CD28 imAbs.
  • VOA2 virus growth assay
  • VOA modified viral outgrowth assay
  • Fig. 2A The presence of HIV-1 RNA and p24 in the culture supernatants were measured using validated diagnostic assays (Fig. 2A). It is important to underscore that the concentrations of HDACis used in the modified VOA assay corresponded to the clinical doses used in patients.
  • P24 production was also measured in the cell cultures treated with HDACis as compared to HDACis untreated cell cultures (Fig. 2C and 2E).
  • anti-CD3/CD28 and givinostat were able to induce p24 in a higher proportion of subjects (60 and 50%, respectively), as compared to the other HDACis (p24 production detected in 10-30% of subjects) (Fig. 2C).
  • the proportion of subjects with positive p24 was significantly different (P ⁇ 0.05) only for anti-CD3/CD28-treated and givinostat-treated cultures (Fig. 2C).
  • HDACis are potent reactivators of HIV-1 replication in primary resting memory CD4 T cells isolated from aviremic long-term treated HIV-1 infected subjects as indicated by the high levels of HIV RNA and p24 production measured in the culture supernatants. More importantly, it also demonstrates that the HIV reactivated in the cell cultures is not only replication competent but also infectious. Interestingly, givinostat and to a lesser extent belinostat, two HDACis that have not been investigated in clinical trials were more potent than vorinostat, panobinostat and romidepsin in reversing HIV-1 latency in vitro and inducing p24 production.
  • Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A 86, 2365- 2368 (1989).
  • SWI/SNF chromatin-remodeling complex is a cofactor for Tat transactivation of the HIV promoter. J Biol Che m 281 , 19960-19968 (2006).
  • HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays, in AIDS2014 (Melbourne, Australia, 2014).

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Abstract

La présente invention concerne des réactifs et des procédés de réactivation de la réplication in vitro et in vivo du VIH.
PCT/IB2015/058168 2014-10-23 2015-10-22 Réactifs et procédés de réactivation du vih latent WO2016063251A1 (fr)

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WO2022088047A1 (fr) * 2020-10-30 2022-05-05 中国科学院深圳先进技术研究院 Application de itf2357 dans la préparation d'un médicament destiné à prévenir et à traiter les coronavirus

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WO2019245993A1 (fr) * 2018-06-19 2019-12-26 Nantcell, Inc. Compositions et méthodes de traitement du vih
CN112334572A (zh) * 2018-06-19 2021-02-05 南特细胞公司 Hiv治疗组合物和方法
US11311603B2 (en) 2018-06-19 2022-04-26 Nantcell, Inc. HIV treatment compositions and methods
US11786577B2 (en) 2018-06-19 2023-10-17 Nantcell, Inc. HIV treatment compositions and methods
WO2020068992A1 (fr) * 2018-09-27 2020-04-02 Kulpa Deanna Alene Méthodes d'identification de réservoirs de vih latents
WO2022088047A1 (fr) * 2020-10-30 2022-05-05 中国科学院深圳先进技术研究院 Application de itf2357 dans la préparation d'un médicament destiné à prévenir et à traiter les coronavirus

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