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Pharmaceutical approaches to eradication of persistent HIV infection

Published online by Cambridge University Press:  11 February 2009

Mary-Catherine Bowman ,
Nancie M. Archin  and
David M. Margolis
Mary-Catherine Bowman
Affiliation:
Departments of Medicine, Microbiology & Immunology, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7435, USA.
Nancie M. Archin
Affiliation:
Departments of Medicine, Microbiology & Immunology, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7435, USA.
David M. Margolis*
Affiliation:
Departments of Medicine, Microbiology & Immunology, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7435, USA.
*
*Corresponding author: David Margolis, 3302 Michael Hooker Research Bldg, CB#7435, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7435, USA. Tel: +1 919 966 6388; Fax: +1 919 966 0584; E-mail: dmargo@med.unc.edu
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Abstract

Highly active antiretroviral therapy (HAART) has markedly decreased morbidity and mortality in human immunodeficiency virus type 1 (HIV-1)-infected individuals in the developed world. Successful therapy often results in stable plasma levels of HIV-1 RNA below the limits of detection of commercial assays. Nonetheless, HIV-1 has not been cured by HAART. The causes of persistence of HIV infection in the face of current therapy appear to be multifactorial: latent but replication-competent provirus in resting CD4+ T cells, cryptic viral expression below the limits of detection of clinical assays, and viral sanctuary sites might all contribute to persistence. Clearance of HIV infection will almost certainly require a multimodality approach that includes potent suppression of HIV replication, therapies that reach all compartments of residual HIV replication and depletion of any reservoirs of persistent, quiescent proviral infection. This review highlights the basic mechanisms for the establishment and maintenance of viral reservoirs and pharmaceutical approaches towards their elimination.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e6
Copyright
Copyright © Cambridge University Press 2009

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References

References

1Palella, F.J. Jr. et al. (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. New England Journal of Medicine 338, 853-860CrossRefGoogle ScholarPubMed
2Perelson, A.S. et al. (1996) HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582-1586CrossRefGoogle ScholarPubMed
3Nickle, D.C. et al. (2003) Importance and detection of virus reservoirs and compartments of HIV infection. Current Opinion in Microbiology 6, 410-416Google Scholar
4Blankson, J.N., Persaud, D. and Siliciano, R.F. (2002) The challenge of viral reservoirs in HIV-1 infection. Annual Review of Medicine 53, 557-593CrossRefGoogle ScholarPubMed
5Pierson, T., McArthur, J. and Siliciano, R.F. (2000) Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annual Review of Immunology 18, 665-708Google Scholar
6Pomerantz, R.J. (2003) Reservoirs, sanctuaries, and residual disease: the hiding spots of HIV-1. HIV Clinical Trials 4, 137-143Google ScholarPubMed
7Perelson, A.S. et al. (1997) Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188-191CrossRefGoogle ScholarPubMed
8Ho, D.D. et al. (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123-126CrossRefGoogle ScholarPubMed
9Wei, X. et al. (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117-122CrossRefGoogle ScholarPubMed
10Polis, M.A. et al. (2001) Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy. Lancet 358, 1760-1765Google Scholar
11Louie, M. et al. (2003) Determining the relative efficacy of highly active antiretroviral therapy. Journal of Infectious Diseases 187, 896-900CrossRefGoogle ScholarPubMed
12Kuritzkes, D.R. et al. (2007) Plasma HIV-1 RNA dynamics in antiretroviral-naive subjects receiving either triple-nucleoside or efavirenz-containing regimens: ACTG A5166s. Journal of Infectious Diseases 195, 1169-1176Google Scholar
13Ho, D.D., Rota, T.R. and Hirsch, M.S. (1986) Infection of monocyte/macrophages by human T lymphotropic virus type III. Journal of Clinical Investigation 77, 1712-1715CrossRefGoogle ScholarPubMed
14Gartner, S. et al. (1986) The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215-219Google Scholar
15Sonza, S. et al. (2001) Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. Aids 15, 17-22Google Scholar
16Markowitz, M. et al. (2007) Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. Journal of Acquired Immune Deficiency Syndromes 46, 125-133Google Scholar
17Murray, J.M. et al. (2007) Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. Aids 21, 2315-2321Google Scholar
18Bonhoeffer, S. et al. (1997) Virus dynamics and drug therapy. Proceedings of the National Academy of Sciences of the United States of America 94, 6971-6976CrossRefGoogle ScholarPubMed
19Stevenson, M. (2003) HIV-1 pathogenesis. Nature Medicine 9, 853-860Google Scholar
20Haase, A.T. (2005) Perils at mucosal front lines for HIV and SIV and their hosts. Nature Reviews Immunology 5, 783-792Google Scholar
21Li, Q. et al. (2005) Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434, 1148-1152Google Scholar
22Heath, S.L. et al. (1995) Follicular dendritic cells and human immunodeficiency virus infectivity. Nature 377, 740-744CrossRefGoogle ScholarPubMed
23Geijtenbeek, T.B. et al. (2000) Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575-585CrossRefGoogle ScholarPubMed
24Cavert, W. et al. (1997) Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276, 960-964CrossRefGoogle ScholarPubMed
25Hlavacek, W.S. et al. (2000) Influence of follicular dendritic cells on decay of HIV during antiretroviral therapy. Proceedings of the National Academy of Sciences of the United States of America 97, 10966-10971CrossRefGoogle ScholarPubMed
26Garcia, J.A. et al. (2006) HIV-1 dynamics at different time scales under antiretroviral therapy. Journal of Theoretical Biology 238, 220-229Google Scholar
27Hlavacek, W.S. et al. (2002) Retention of antigen on follicular dendritic cells and B lymphocytes through complement-mediated multivalent ligand-receptor interactions: theory and application to HIV treatment. Mathematical Biosciences 176, 185-202Google Scholar
28Keele, B.F. et al. (2008) Characterization of the follicular dendritic cell reservoir of human immunodeficiency virus type 1. Journal of Virology 82, 5548-5561CrossRefGoogle ScholarPubMed
29Finzi, D. and Siliciano, R.F. (1998) Viral dynamics in HIV-1 infection. Cell 93, 665-671CrossRefGoogle ScholarPubMed
30Di Mascio, M. et al. (2003) In a subset of subjects on highly active antiretroviral therapy, human immunodeficiency virus type 1 RNA in plasma decays from 50 to <5 copies per milliliter, with a half-life of 6 months. Journal of Virology 77, 2271-2275Google Scholar
31Dornadula, G. et al. (1999) Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. Journal of the American Medical Association 282, 1627-1632Google Scholar
32Muller, V., Vigueras-Gomez, J.F. and Bonhoeffer, S. (2002) Decelerating decay of latently infected cells during prolonged therapy for human immunodeficiency virus type 1 infection. Journal of Virology 76, 8963-8965Google Scholar
33Strain, M.C. et al. (2003) Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence. Proceedings of the National Academy of Sciences of the United States of America 100, 4819-4824CrossRefGoogle ScholarPubMed
34Maldarelli, F. et al. (2007) ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. Public Library of Science Pathogens 3, e46Google Scholar
35Palmer, S. et al. (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proceedings of the National Academy of Sciences of the United States of America 105, 3879-3884Google Scholar
36Chun, T.W. et al. (1995) In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nature Medicine 1, 1284-1290Google Scholar
37Chun, T.W. et al. (1997) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183-188Google Scholar
38Chun, T.W. et al. (1997) Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proceedings of the National Academy of Sciences of the United States of America 94, 13193-13197Google Scholar
39Finzi, D. et al. (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295-1300CrossRefGoogle ScholarPubMed
40Wong, J.K. et al. (1997) Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291-1295Google Scholar
41Chun, T.W. et al. (2005) HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. Journal of Clinical Investigation 115, 3250-3255Google Scholar
42Siliciano, J.D. et al. (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Medicine 9, 727-728Google Scholar
43Siliciano, J.D. and Siliciano, R.F. (2004) A long-term latent reservoir for HIV-1: discovery and clinical implications. Journal of Antimicrobial Chemotherapy 54, 6-9Google Scholar
44Strain, M.C. et al. (2005) Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. Journal of Infectious Diseases 191, 1410-1418CrossRefGoogle ScholarPubMed
45Chun, T.W. et al. (2007) Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. Journal of Infectious Diseases 195, 1762-1764CrossRefGoogle Scholar
46Margolis, D.M. and Archin, N.M. (2007) Eliminating persistent HIV infection: getting to the end of the rainbow. Journal of Infectious Diseases 195, 1734-1736Google Scholar
47Williams, S.A. and Greene, W.C. (2005) Host factors regulating post-integration latency of HIV. Trends in Microbiology 13, 137-139Google Scholar
48Swiggard, W.J. et al. (2005) Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. Journal of Virology 79, 14179-14188CrossRefGoogle ScholarPubMed
49Swingler, S. et al. (2003) HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature 424, 213-219Google Scholar
50Brooks, D.G. et al. (2001) Generation of HIV latency during thymopoiesis. Nature Medicine 7, 459-464CrossRefGoogle ScholarPubMed
51Brenchley, J.M. et al. (2004) T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. Journal of Virology 78, 1160-1168Google Scholar
52Bailey, J.R. et al. (2006) Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. Journal of Virology 80, 6441-6457CrossRefGoogle ScholarPubMed
53Chun, T.W. et al. (2000) Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nature Medicine 6, 757-761CrossRefGoogle ScholarPubMed
54Zhu, T. et al. (2002) Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. Journal of Virology 76, 707-716CrossRefGoogle ScholarPubMed
55Lambotte, O. et al. (2000) Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 23, 114-119Google Scholar
56Ellery, P.J. et al. (2007) The CD16+ monocyte subset is more permissive to infection and preferentially harbors HIV-1 in vivo. Journal of Immunology 178, 6581-6589CrossRefGoogle ScholarPubMed
57Otero, M. et al. (2003) Peripheral blood Dendritic cells are not a major reservoir for HIV type 1 in infected individuals on virally suppressive HAART. AIDS Research and Human Retroviruses 19, 1097-1103CrossRefGoogle ScholarPubMed
58Mowat, A.M. and Viney, J.L. (1997) The anatomical basis of intestinal immunity. Immunological Reviews 156, 145-166CrossRefGoogle ScholarPubMed
59Veazey, R.S. et al. (1998) Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427-431CrossRefGoogle Scholar
60Chun, T.W. et al. (2008) Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. Journal of Infectious Diseases 197, 714-720CrossRefGoogle ScholarPubMed
61Polis, M.A. et al. (2003) Suppression of cerebrospinal fluid HIV burden in antiretroviral naive patients on a potent four-drug antiretroviral regimen. Aids 17, 1167-1172Google Scholar
62Bell, J.E. (2004) An update on the neuropathology of HIV in the HAART era. Histopathology 45, 549-559CrossRefGoogle ScholarPubMed
63Kramer-Hammerle, S. et al. (2005) Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Research 111, 194-213CrossRefGoogle ScholarPubMed
64Lambotte, O. et al. (2005) Persistence of replication-competent HIV in the central nervous system despite long-term effective highly active antiretroviral therapy. Aids 19, 217-218CrossRefGoogle ScholarPubMed
65Craigo, J.K. et al. (2004) Persistent HIV type 1 infection in semen and blood compartments in patients after long-term potent antiretroviral therapy. AIDS Research and Human Retroviruses 20, 1196-1209CrossRefGoogle ScholarPubMed
66Nunnari, G. et al. (2002) Residual HIV-1 disease in seminal cells of HIV-1-infected men on suppressive HAART: latency without on-going cellular infections. Aids 16, 39-45CrossRefGoogle ScholarPubMed
67Marras, D. et al. (2002) Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nature Medicine 8, 522-526Google Scholar
68Winston, J.A. et al. (2001) Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. New England Journal of Medicine 344, 1979-1984CrossRefGoogle ScholarPubMed
69Hamer, D.H. (2004) Can HIV be Cured? Mechanisms of HIV persistence and strategies to combat it. Current HIV Research 2, 99-111CrossRefGoogle Scholar
70Davey, R.T. Jr. et al. (1999) A randomized trial of high- versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection. Journal of Infectious Diseases 179, 849-858CrossRefGoogle ScholarPubMed
71Kovacs, J.A. et al. (1995) Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. New England Journal of Medicine 332, 567-575CrossRefGoogle ScholarPubMed
72Kovacs, J.A. et al. (2005) Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. Journal of Clinical Investigation 115, 2139-2148CrossRefGoogle ScholarPubMed
73Simonelli, C. et al. (1998) Interleukin-2 in combination with zidovudine and didanosine is able to maintain high levels of CD4 cells and undetectable HIV viraemia. Aids 12, 112-113Google Scholar
74Bich-Thuy, L.T. et al. (1987) Direct activation of human resting T cells by IL 2: the role of an IL 2 receptor distinct from the Tac protein. Journal of Immunology 139, 1550-1556CrossRefGoogle Scholar
75Chun, T.W. et al. (1999) Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nature Medicine 5, 651-655CrossRefGoogle ScholarPubMed
76Dybul, M. et al. (2002) Pilot study of the effects of intermittent interleukin-2 on human immunodeficiency virus (HIV)-specific immune responses in patients treated during recently acquired HIV infection. Journal of Infectious Diseases 185, 61-68CrossRefGoogle ScholarPubMed
77Kulkosky, J. et al. (2002) Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. Journal of Infectious Diseases 186, 1403-1411CrossRefGoogle ScholarPubMed
78Stellbrink, H.J. et al. (2002) Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). Aids 16, 1479-1487CrossRefGoogle ScholarPubMed
79Sereti, I. et al. (2005) In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients. Journal of Clinical Investigation 115, 1839-1847CrossRefGoogle ScholarPubMed
80Grant, C. et al. (2006) Foxp3 represses retroviral transcription by targeting both NF-kappaB and CREB pathways. Public Library of Science Pathogens 2, e33Google Scholar
81Prins, J.M. et al. (1999) Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. Aids 13, 2405-2410CrossRefGoogle ScholarPubMed
82van Praag, R.M. et al. (2001) OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. Journal of Clinical Immunology 21, 218-226Google Scholar
83Napolitano, L.A. et al. (2001) Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nature Medicine 7, 73-79CrossRefGoogle ScholarPubMed
84Llano, A. et al. (2001) Interleukin-7 in plasma correlates with CD4 T-cell depletion and may be associated with emergence of syncytium-inducing variants in human immunodeficiency virus type 1-positive individuals. Journal of Virology 75, 10319-10325CrossRefGoogle ScholarPubMed
85Ducrey-Rundquist, O., Guyader, M. and Trono, D. (2002) Modalities of interleukin-7-induced human immunodeficiency virus permissiveness in quiescent T lymphocytes. Journal of Virology 76, 9103-9111Google Scholar
86Lehrman, G. et al. (2004) Interleukin-7 induces HIV type 1 outgrowth from peripheral resting CD4+ T cells. J Acquir Immune Defic Syndr 36, 1103-1104CrossRefGoogle ScholarPubMed
87Wang, F.X. et al. (2005) IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. Journal of Clinical Investigation 115, 128-137CrossRefGoogle ScholarPubMed
88Sereti, I. et al. (2007) rhIL 7 in HIV-1 infected subjects with CD4 T-cell count > 100 cells/ul and viral load <50,000 copies/ml: results from a randomized, placebo-controlled, double-blinded study (ACTG 5214). Program and abstracts of the14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA+100+cells/ul+and+viral+load+<50,000+copies/ml:+results+from+a+randomized,+placebo-controlled,+double-blinded+study+(ACTG+5214).+Program+and+abstracts+of+the14th+Conference+on+Retroviruses+and+Opportunistic+Infections,+Los+Angeles,+CA>Google Scholar
89Trushin, S.A. et al. (2005) Human immunodeficiency virus reactivation by phorbol esters or T-cell receptor ligation requires both PKCalpha and PKCtheta. Journal of Virology 79, 9821-9830CrossRefGoogle ScholarPubMed
90Kulkosky, J. et al. (2001) Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 98, 3006-3015CrossRefGoogle ScholarPubMed
91Kulkosky, J. et al. (2004) Expression of latent HAART-persistent HIV type 1 induced by novel cellular activating agents. AIDS Research and Human Retroviruses 20, 497-505Google Scholar
92Williams, S.A. et al. (2004) Prostratin antagonizes HIV latency by activating NF-kappaB. Journal of Biological Chemistry 279, 42008-42017Google Scholar
93Biancotto, A. et al. (2004) Dual role of prostratin in inhibition of infection and reactivation of human immunodeficiency virus from latency in primary blood lymphocytes and lymphoid tissue. Journal of Virology 78, 10507-10515CrossRefGoogle ScholarPubMed
94Gulakowski, R.J. et al. (1997) Antireplicative and anticytopathic activities of prostratin, a non-tumor-promoting phorbol ester, against human immunodeficiency virus (HIV). Antiviral Research 33, 87-97Google Scholar
95Wender, P.A., Kee, J.M. and Warrington, J.M. (2008) Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV. Science 320, 649-652Google Scholar
96Melloni, E. et al. (1987) Protein kinase C activity and hexamethylenebisacetamide-induced erythroleukemia cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 84, 5282-5286CrossRefGoogle ScholarPubMed
97Zeichner, S.L. et al. (1992) Differentiation-dependent human immunodeficiency virus long terminal repeat regulatory elements active in human teratocarcinoma cells. Journal of Virology 66, 2268-2273CrossRefGoogle ScholarPubMed
98Zoumpourlis, V. and Spandidos, D.A. (1992) Hexamethylene bisacetamide stimulates the expression of human immunodeficiency virus long terminal repeat sequences in rat and human fibroblasts. Anti-Cancer Drugs 3, 163-167CrossRefGoogle ScholarPubMed
99Contreras, X. et al. (2007) HMBA releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and activates HIV transcription. Public Library of Science Pathogens 3, 1459-1469Google Scholar
100Choudhary, S.K., Archin, N.M. and Margolis, D.M. (2008) Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells. Journal of Infectious Diseases 197, 1162-1170Google Scholar
101Reuben, R.C., Rifkind, R.A. and Marks, P.A. (1980) Chemically induced murine erythroleukemic differentiation. Biochimica et Biophysica Acta 605, 325-346Google ScholarPubMed
102Gazitt, Y. et al. (1978) Changes in cyclic adenosine 3′:5′-monophosphate levels during induction of differentiation in murine erythroleukemia cells. Cancer Research 38, 3779-3783Google Scholar
103Andreeff, M. et al. (1992) Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation-inducing agent. Blood 80, 2604-2609CrossRefGoogle ScholarPubMed
104Klichko, V. et al. (2006) Hexamethylbisacetamide remodels the human immunodeficiency virus type 1 (HIV-1) promoter and induces Tat-independent HIV-1 expression but blunts cell activation. Journal of Virology 80, 4570-4579Google Scholar
105Sung, T.L. and Rice, A.P. (2006) Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4+ T cells. Retrovirology 3, 66CrossRefGoogle ScholarPubMed
106Pearson, R. et al. (2008) Epigenetic Silencing of HIV Transcription by Formation of Restrictive Chromatin Structures at the Viral LTR Drives the Progressive Entry of HIV into Latency. Journal of Virology 82, 12291-12303CrossRefGoogle Scholar
107Brady, J. and Kashanchi, F. (2005) Tat gets the “green” light on transcription initiation. Retrovirology 2, 69CrossRefGoogle ScholarPubMed
108He, N., Pezda, A.C. and Zhou, Q. (2006) Modulation of a P-TEFb functional equilibrium for the global control of cell growth and differentiation. Molecular and Cellular Biology 26, 7068-7076CrossRefGoogle ScholarPubMed
109Arlen, P.A. et al. (2006) Rapid expression of human immunodeficiency virus following activation of latently infected cells. Journal of Virology 80, 1599-1603Google Scholar
110Weinberger, L.S. et al. (2005) Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell 122, 169-182CrossRefGoogle Scholar
111Cho, J., Parks, M.E. and Dervan, P.B. (1995) Cyclic polyamides for recognition in the minor groove of DNA. Proceedings of the National Academy of Sciences of the United States of America 92, 10389-10392Google Scholar
112Coull, J.J. et al. (2002) Targeted derepression of the human immunodeficiency virus type 1 long terminal repeat by pyrrole-imidazole polyamides. Journal of Virology 76, 12349-12354CrossRefGoogle ScholarPubMed
113Ylisastigui, L. et al. (2004) Polyamides reveal a role for repression in latency within resting T cells of HIV-infected donors. Journal of Infectious Diseases 190, 1429-1437CrossRefGoogle ScholarPubMed
114Demonte, D. et al. (2004) Administration of HDAC inhibitors to reactivate HIV-1 expression in latent cellular reservoirs: implications for the development of therapeutic strategies. Biochemical Pharmacology 68, 1231-1238CrossRefGoogle ScholarPubMed
115Phiel, C.J. et al. (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. Journal of Biological Chemistry 276, 36734-36741CrossRefGoogle ScholarPubMed
116Moog, C. et al. (1996) Sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels. Journal of General Virology 77, 1993-1999Google Scholar
117Witvrouw, M. et al. (1997) Cell type-dependent effect of sodium valproate on human immunodeficiency virus type 1 replication in vitro. AIDS Research and Human Retroviruses 13, 187-192CrossRefGoogle ScholarPubMed
118Ylisastigui, L. et al. (2004) Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. Aids 18, 1101-1108CrossRefGoogle ScholarPubMed
119Lehrman, G. et al. (2005) Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366, 549-555CrossRefGoogle ScholarPubMed
120Archin, N.M. et al. (2008) Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells. Aids 22, 1131-1135CrossRefGoogle ScholarPubMed
121Jones, L.E. and Perelson, A.S. (2007) Transient viremia, plasma viral load, and reservoir replenishment in HIV-infected patients on antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 45, 483-493CrossRefGoogle ScholarPubMed
122Siliciano, J.D. et al. (2007) Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. Journal of Infectious Diseases 195, 833-836CrossRefGoogle ScholarPubMed
123Sagot-Lerolle, N. et al. (2008) Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. Aids 22, 1125-1129CrossRefGoogle Scholar
124Marks, P.A. and Breslow, R. (2007) Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotechnology 25, 84-90Google Scholar
125Bowman, M.C. et al. (2008) Inhibition of HIV fusion with multivalent gold nanoparticles. Journal of the American Chemical Society 130, 6896-6897CrossRefGoogle ScholarPubMed
126Kennedy, P.E. et al. (2006) Anti-HIV-1 immunotoxin 3B3(Fv)-PE38: enhanced potency against clinical isolates in human PBMCs and macrophages, and negligible hepatotoxicity in macaques. Journal of Leukocyte Biology 80, 1175-1182CrossRefGoogle ScholarPubMed
127Berger, E.A., Moss, B. and Pastan, I. (1998) Reconsidering targeted toxins to eliminate HIV infection: you gotta have HAART. Proceedings of the National Academy of Sciences of the United States of America 95, 11511-11513CrossRefGoogle ScholarPubMed
128McCoig, C. et al. (1999) An anti-CD45RO immunotoxin eliminates T cells latently infected with HIV-1 in vitro. Proceedings of the National Academy of Sciences of the United States of America 96, 11482-11485Google Scholar

Further reading, resources and contacts

Publications

Geeraert, L, Kraus, G, Pomerantz, RJ. (2008) Hide-and-seek: the challenge of viral persistence in HIV-1 infection. Annual Review of Medicine. 59, 487-501.CrossRefGoogle ScholarPubMed
Williams, S.A. and Greene, W.C. (2007) Regulation of HIV-1 latency by T-cell activation. Cytokine 39, 63-73CrossRefGoogle ScholarPubMed
Mok, H.P. and Lever, A.M. (2007) Chromatin, gene silencing and HIV latency. Genome Biol. 11, 228CrossRefGoogle Scholar
He, G., Ylisastigui, L. and Margolis, D.M. (2002) Chromatin Regulation of HIV-1 Expression. DNA and Cell Biology 21, 697-705CrossRefGoogle Scholar