Key Points
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Latent HIV-1 reservoirs are established early during primary infection in CD4+ T cells and constitute a major barrier to HIV-1 eradication, even in the presence of highly active antiretroviral therapy.
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Resting CD4+ T cells represent an extremely restrictive environment for HIV-1 replication. By contrast, immune activation in CD4+ T cells provides an optimal environment for robust HIV-1 replication.
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Most factors involved in the maintenance of HIV-1 latency operate at the transcriptional level; examples include the chromosome environment at the site of integration and the availability of viral and host transcription factors.
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HIV-1 integration and expression can be restrained or enhanced by different host cell factors, such as inhibitor of nuclear factor-κB α-subunit (IκBα), COMMD1 (copper metabolism (Murr1) domain-containing protein 1), APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G), lens epithelium-derived growth factor (LEDGF) and emerin.
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Both cellular and viral microRNAs could be involved in maintaining HIV-1 latency or in controlling low ongoing viral replication. HIV-1 modifies the miRNA expression profile of the host cell and, in addition, has developed strategies to overcome the cellular miRNA restriction machinery.
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The existence of cellular elements that restrict retroviral replication and actively inhibit the viral transcriptional machinery provides a new paradigm for HIV-1 latency. As a result, latency should not be considered a merely passive process but rather an active process that is tightly regulated by cellular and viral factors.
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New insights into the molecular mechanisms of HIV-1 latency have led to the characterization of targets that are useful for designing new drugs. In particular, attractive possibilities for specific drug development include the modification of chromatin conformation through histone deacetylase inhibitors and the activation of kinase pathways that lead to the activation of transcription factors.
Abstract
HIV-1 can infect both activated and resting, non-dividing cells, following which the viral genome can be permanently integrated into a host cell chromosome. Latent HIV-1 reservoirs are established early during primary infection and constitute a major barrier to eradication, even in the presence of highly active antiretroviral therapy. This Review analyses the molecular mechanisms that are necessary for the establishment of HIV-1 latency and their relationships with different cellular and anatomical reservoirs, and discusses the current treatment strategies for targeting viral persistence in reservoirs, their main limitations and future perspectives.
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References
Barré-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).
Centers for Disease Control and Prevention. Pneumocystis pneumonia — Los Angeles. MMWR Morb. Mortal Wkly Rep. 30, 250–252 (1981).
Pomerantz, R. J. & Horn, D. L. Twenty years of therapy for HIV-1 infection. Nature Med. 9, 867–874 (2003).
Pomerantz, R. J. Reservoirs of human immunodeficiency virus type 1: the main obstacles to viral eradication. Clin. Inf. Dis. 34, 91–97 (2002).
Shen, L. & Siliciano, R. F. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. J. Allergy Clin. Immunol. 122, 22–28 (2008).
Goff, S. P. in Fields' Virology (eds Knipe D. M. & Howley P. M.) 1871–1939 (Lippincott Williams & Wilkins, Philadelphia, 2001).
Loetscher, P., Moser, B. & Baggiolini, M. Chemokines and their receptors in lymphocyte traffic and HIV infection. Adv. Immunol. 74, 127–180 (2000).
Stevenson, M. HIV-1 pathogenesis. Nature Med. 9, 853–860 (2003).
Huthoff, H. & Towers, G. J. Restriction of retroviral replication by APOBEC3G/F and TRIM5α. Trends Microbiol. 16, 612–619 (2008).
He, G., Ylisastigui, L. & Margolis, D. M. The regulation of HIV-1 gene expression: the emerging role of chromatin. DNA Cell Biol. 21, 697–705 (2002).
Du, T. & Zamore, P. D. Beginning to understand microRNA function. Cell Res. 17, 661–663 (2007).
Han, Y., Wind-Rotolo, M., Yang, H. C., Siliciano, J. D. & Siliciano, R. F. Experimental approaches to the study of HIV-1 latency. Nature Rev. Microbiol. 5, 95–106 (2007).
Lassen, K., Han, Y., Zhou, Y., Siliciano, J. & Siliciano, R. F. The multifactorial nature of HIV-1 latency. Trends Mol. Med. 10, 525–531 (2004).
Bukrinsky, M. I., Stanwick, T. L., Dempsey, M. P. & Stevenson, M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 254, 423–427 (1991). The identification of quiescent T cells as a source of extrachromosomal HIV-1 DNA that retains the ability to integrate on T cell activation in vitro.
Piller, S. C., Caly, L. & Jans, D. A. Nuclear import of the pre-integration complex (PIC): the Achilles heel of HIV? Curr. Drug Targets 4, 409–429 (2003).
Arhel, N. J. et al. HIV-1 DNA Flap formation promotes uncoating of the pre-integration complex at the nuclear pore. EMBO J. 26, 3025–3037 (2007). The first observation, by scanning electron microscopy, that the uncoating of HIV-1 is not an immediate post-fusion event but, instead, intact intracellular capsids can reach the nuclear pore.
Farnet, C. & Bushman, F. D. HIV-1 cDNA integration: requirement of HMG I(Y) protein for function of preintegration complexes in vitro. Cell 88, 1–20 (1997).
Shun, M. C. et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21, 1767–1778 (2007).
McDonald, D. et al. Visualization of the intracellular behavior of HIV in living cells. J. Cell Biol. 159, 441–452 (2002).
Llano, M. An essential role for LEDGF/p75 in HIV integration. Science 314, 461–464 (2006).
Jacque, J. M. & Stevenson, M. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity. Nature 441, 641–645 (2006).
Shun, M. C., Daigle, J. E., Vandegraaff, N. & Engelman, A. Wild-type levels of human immunodeficiency virus type 1 infectivity in the absence of cellular emerin protein. J. Virol. 81, 166–172 (2007).
Guntaka, R. V. Transcription termination and polyadenylation in retroviruses. Microbiol. Rev. 57, 511–521 (1993).
Nabel, G. & Baltimore, D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326, 711–713 (1987). The first description of the binding consensus sites for NF-κB in the HIV-1 LTR promoter and of the synergic interaction of this factor with the viral protein Tat to enhance HIV-1 transcription in T cells.
Corthésy, B. & Kao, P. N. Purification by DNA affinity chromatography of two polypeptides that contact the NF-AT DNA binding site in the interleukin 2 promoter. J. Biol. Chem. 269, 20682–20690 (1994).
Jones, K. A., Kadonaga, J. T., Luciw, P. A. & Tjian, R. Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1. Science 232, 755–759 (1986).
Dingwall, C. et al. HIV-1 Tat protein stimulates transcription by binding to a U-rich bulge in the stem of the TAR RNA structure. EMBO J. 9, 4145–4153 (1990).
Garber, M. E., Wei, P. & Jones, K. A. HIV-1 Tat interacts with cyclin T1 to direct the P-TEFb CTD kinase complex to TAR RNA. Cold Spring Harb. Symp. Quant. Biol. 63, 371–380 (1998).
Zhou, M. et al. Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription. Mol. Cell. Biol. 20, 5077–5086 (2000).
Pollard, V. W. & Malim, M. H. The HIV-1 Rev protein. Annu. Rev. Microbiol. 52, 491–532 (1998).
Ganser-Pornillos, B. K., Yeager. M. & Sundquist, W. I. The structural biology of HIV assembly. Curr. Opin. Struct. Biol. 18, 203–217 (2008).
Bleul, C. C., Wu, L., Hoxie, J. A. & Springer, T. A., Mackay, C. R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc. Natl Acad. Sci. USA 94, 1925–1930 (1997).
Zack, J. A. et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 61, 213–222 (1990). The first description of pre-integration latency by an incomplete retrotranscription of the HIV-1 genome in infected quiescent T cells that, despite its frailty, persists as a latent form.
Meyerhans, A. et al. Restriction and enhancement of human immunodeficiency virus type 1 replication by modulation of intracellular deoxynucleoside triphosphate pools. J. Virol. 68, 535–540 (1994). This work shows that resting blood CD4+ T cells are highly resistant to infection with HIV-1 and that viral retrotranscrition results in incomplete, labile transcripts, thereby proving that successful HIV-1 infection requires T cell activation.
Bukrinsky, M. I. et al. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc. Natl Acad. Sci. USA 89, 6580–6584 (1992).
Chiu, Y. L. et al. Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature 435, 108–114 (2005). This study finds that low-molecular-mass APOBEC3G functions as a potent post-entry restriction factor for HIV-1 in resting CD4+ T cells, whereas high-molecular-mass APOBEC3G is permissive for HIV-1 infection in activated CD4+ T cells.
Pierson, T. C. et al. Molecular characterization of preintegration latency in human immunodeficiency virus type 1 infection. J. Virol. 76, 8518–8531 (2002).
Zhou, Y. et al. Kinetics of human immunodeficiency virus type 1 decay following entry into resting CD4+ T cells. J. Virol. 79, 2199–2210 (2005).
Sakai, H. et al. Integration is essential for efficient gene expression of human immunodeficiency virus type 1. J. Virol. 67, 1169–11174 (1993).
Wu, Y. & Marsh, J. W. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 293, 1503–1506 (2001).
Kelly, J. et al. Human macrophages support persistent transcription from unintegrated HIV-1 DNA. Virology 3672, 300–312 (2008).
Swingler, S. et al. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature 424, 213–219 (2003).
Chun, T. W. et al. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nature Med. 1, 1284–1290 (1995).
Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).
Persaud, D. et al. A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children. J. Clin. Invest. 105, 995–1003 (2000).
Blankson, J. N. et al. Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J. Virol. 81, 2508–2518 (2007).
Chun, T. W. et al. Early establishment of a pool of latently infected resting CD4+ T cells during primary HIV-1 infection. Proc. Natl Acad. Sci. USA 95, 8869–8873 (1998).
Chun, T. W. et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183–188 (1997). In this investigation, the whole pool of latently infected resting CD4+ T cells containing a replication-competent integrated provirus was quantified as ∼107 cells.
Jung, A. et al. Multiply infected spleen cells in HIV patients. Nature 418, 144 (2002).
Lassen, K. G., Bailey, J. R. & Siliciano, R. F. Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J. Virol. 78, 9105–9114 (2004).
Finzi, D. et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Med. 5, 512–517 (1999).
Siliciano, J. D. et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Med. 9, 727–728 (2003).
Haase, A. T. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu. Rev. Immunol. 17, 625–656 (1999).
Spina, C. A., Prince, H, E. & Richman, D. D. Preferential replication of HIV-1 in the CD45RO memory cell subset of primary CD4 lymphocytes in vitro. J. Clin. Invest. 99, 1774–1785 (1997).
Blaak, H. et al. In vivo HIV-1 infection of CD45RA+CD4+ T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4+ T cell decline. Proc. Natl Acad. Sci. USA 97, 1269–1274 (2000).
Chomont, N. et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nature Med. 15, 893–900 (2009).
Ostrowski, M. A. et al. Both memory and CD45RA+/CD62L+ naive CD4+ T cells are infected in human immunodeficiency virus type 1-infected individuals. J. Virol. 73, 6430–6435 (1999).
Brooks, D. G., Kitchen, S. G. & Kitchen, C. M. Scripture-Adams, D. D., Zack, J. A. Generation of HIV latency during thymopoiesis. Nature Med. 7, 459–464 (2001).
Williams, S. A. & Greene, W. C. Regulation of HIV-1 latency by T-cell activation. Cytokine 39, 63–74 (2007).
Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Med. 2, 1365–1371 (2006).
Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002).
Guadalupe, M. et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J. Virol. 77, 11708–11717 (2003).
Mehandru, S. et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J. Exp. Med. 200, 761–770 (2004).
Brenchley, J. M., Price, D. A. & Douek, D. C. HIV disease: fallout from a mucosal catastrophe?. Nature Immunol. 7, 235–239 (2006).
Mattapallil, J. J. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093–1097 (2005).
Zhang, Z. et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286, 1353–1357 (1999).
Eckstein, D. A. et al. HIV-1 actively replicates in naive CD4+ T cells residing within human lymphoid tissues. Immunity 15, 671–682 (2001).
Chou, C. S., Ramilo, O. & Vitetta, E. S. Highly purified CD25− resting T cells cannot be infected de novo with HIV-1. Proc. Natl Acad. Sci. USA 94, 1361–1365 (1997).
Unutmaz, D., KewalRamani, V. N., Marmon, S. & Littman, D. R. Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. J. Exp. Med. 189, 1735–1746 (1999).
Chun, T. W., Engel, D., Mizell, S. B., Ehler, L. A. & Fauci, A. S. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J. Exp. Med. 188, 83–91 (1998).
Wang, F. X. et al. IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J. Clin. Invest. 115, 128–137 (2005).
Kreisberg, J. F., Yonemoto, W. & Greene, W. C. Endogenous factors enhance HIV-1 infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation. J. Exp. Med. 203, 865–870 (2006).
Koenig, S. et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233, 1089–1093 (1986).
Sharkey, M. E. et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active antiretroviral therapy. Nature Med. 6, 76–81 (2006).
Swingler, S. et al. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nature Med. 5, 997–103 (1999).
Sharova, N., Swingler, C., Sharkey, M. & Stevenson, M. Macrophages archive HIV-1 virions for dissemination in trans. EMBO J. 24, 2481–2489 (2005).
Deneka, M., Pelchen-Matthews, A., Byland, R., Ruiz-Mateos, E. & Marsh, M. In macrophages, HIV-1 assembles into an intracellular plasma membrane domain containing the tetraspanins CD81, CD9, and CD53. J. Cell Biol. 177, 329–341 (2007).
Welsch, S. et al. HIV-1 buds predominantly at the plasma membrane of primary human macrophages. PLoS Pathog. 3, e36 (2007).
Joshi, A., Ablan, S. D., Soheilian, F., Nagashima, K. & Freed, E. O. Evidence that productive human immunodeficiency virus type 1 assembly can occur in an intracellular compartment. J. Virol. 83, 5375–5387 (2009).
Wu, L. & KewalRamani, V. N. Dendritic-cell interactions with HIV: infection and viral dissemination. Nature Rev. Immunol. 6, 859–868 (2006).
Smith-Franklin, B. A. et al. Follicular dendritic cells and the persistence of HIV infectivity: the role of antibodies and Fcγ receptors. J. Immunol. 166, 690–696 (2002).
Keele, B. F. et al. Characterization of the follicular dendritic cell reservoir of human immunodeficiency virus type 1. J. Virol. 82, 5548–5561 (2008).
Mitchell, R. S. et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2, E234 (2004).
Schröder, A. R. et al. HIV-1 integration in the human genome favours active genes and local hotspots. Cell 110, 521–529 (2002). This work shows that HIV-1 provirus integration is strongly favoured in active genes and preferentially those that are activated after viral infection.
Wang, G. P., Ciuffi, A., Leipzig, J., Berry, C. C., Bushman, F. D. HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 17, 1186–1194 (2007).
Han, Y. et al. Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J. Virol. 78, 6122–6133 (2004).
Lewinski, M. K. et al. Genome wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J. Virol. 79, 6610–6619 (2005).
Han, Y. et al. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe 4, 134–146 (2008). This study describes how read-through transcription of actively transcribed host genes may interfere with the gene expression of a nearby integrated HIV-1 provirus, inducing viral latency depending on the site and orientation of the provirus.
Callen, B. P., Shearwin, K. E. & Egan J. B. Transcriptional interference between convergent promoters caused by elongation over the promoter. Mol. Cell. 14, 647–656 (2004).
Crampton, N., Bonass, W. A., Kirkham, J., Rivetti, C. & Thomson, N. H. Collision events between RNA polymerases in convergent transcription studied by atomic force microscopy. Nucleic Acids Res. 34, 5416–5425 (2006).
Hu, W. Y., Bushman, F. D. & Siva, A. C. RNA interference against retroviruses. Virus Res. 102, 59–64 (2004).
Morris, K. V., Chan, S. W., Jacobsen, S. E. & Looney D. J. Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305, 1289–1292 (2004).
Scherer, L. J. & Rossi, J. J. Approaches for the sequence-specific knockdown of mRNA. Nature Biotech. 21, 1457–1465 (2003).
Martens, J. A., Laprade, L. & Winston, F. Intergenic transcription is required to repress the Saccharomyes cerevisiae SER3 gene. Nature 429, 571–574 (2004).
Lenasi, T., Contreras, X. & Peterlin, B. M. Transcriptional interference antagonizes proviral gene expression to promote HIV-1 latency. Cell Host Microbe 4, 123–133 (2008).
Perkins, K. J. & Proudfoot, N. J. An ungracious host for an unwelcome guest. Cell Host Microbe 4, 89–91 (2008).
Mazo, A., Hodgson, J. W., Petruk, S., Sedkov, Y. & Brock, H. W. Transcriptional interference: an unexpected layer of complexity in gene regulation. J. Cell Sci. 120, 2755–2761 (2007).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Carteau, S., Hoffmann, C. & Bushman, F. D. Chromosome structure and HIV-1 cDNA integration: centromeric alphoid repeats are a disfavored target. J. Virol. 72, 4005–4014 (1998).
Jordan, A., Bisgrove, D. & Verdin, E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 22, 1868–1877 (2003).
Zamborlini, A. et al. Centrosomal pre-integration latency of HIV-1 in quiescent cells. Retrovirology 4, 63 (2007).
He, G. & Margolis, D. M. Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat. Mol. Cell Biol. 22, 2965–2273 (2002). This paper shows that recruitment of HDAC1 at nucleosome 1 of an integrated HIV-1 LTR counteracts Tat activation and represses viral gene expression, whereas decreased HDAC1 occupancy by HDAC inhibitors results in LTR-dependent transcription activation.
Gordon, S., Akopyan, G., Garban, H. & Bonavida, B. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 25, 1125–1142 (2006).
Ylisastigui, L. et al. Polyamides reveal a role for repression in latency within resting T cells of HIV-infected donors. J. Infect. Dis. 190, 1429–1437 (2004).
Williams, S. A. et al. NF-κB p50 promotes HIV-1 latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25, 139–149 (2006). This study finds that NF-κB subunit p50 can form a complex (with HDAC1) that binds constitutively to the HIV-1 LTR and induces repressive changes in chromatin structure that impair transcription initiation.
Tyagi, M. & Karn, J. CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J. 26, 4985–4995 (2007).
du Chene, I. et al. Suv39H1 and HP1γ are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J. 26, 424–435 (2007). This work shows that the SUV39H1-mediated trimethylation of histone H3 at lysine 9 — which is necessary to form heterochromatin, as it recruits HP1γ — leads to HIV-1 transcriptional silencing and post-integration latency that can be overcome by RNAi of HP1γ.
Lusic, M., Marcello, A., Cereseto, A. & Giacca, M. Regulation of HIV-1 gene expression by histone acetylation and factor recruitment at the LTR promoter. EMBO J. 22, 6550–6561 (2003).
Jiang, G., Espeseth, A., Hazuda, D. J. & Margolis, D. M. c-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter. J. Virol. 81, 10914–10923 (2007).
Chen, L. F., Fischle, W., Verdin, E. & Greene, W. C. Duration of nuclear NF-κB action regulated by reversible acetylation. Science 293, 1653–1657 (2001).
Doetzlhofer, A. et al. Histone deacetylase 1 can repress transcription by binding to Sp1. Mol. Cell. Biol. 19, 5504–5511 (1999).
Ansari, K. I., Mishra, B. P. & Mandal, S. S. MLL histone methylases in gene expression, hormone signalling and cell cycle. Front. Biosci. 14, 3483–3495 (2009).
Grewal, S. I. & Moazed, D. Heterochromatin and epigenetic control of gene expression. Science 301, 798–802 (2003).
Marban, C. et al. Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J. 26, 412–423 (2007).
Pearson, R. et al. Epigenetic silencing of HIV-1 transcription by formation of restrictive chromatin structures at the viral LTR drives the progressive entry of HIV-1 into latency. J. Virol. 82, 12291–12303 (2008).
Weil, R. & Israel, A. T-cell-receptor- and B-cell-receptor-mediated activation of NF-κB in lymphocytes. Curr. Opin. Immunol. 16, 374–381 (2004).
Bachelerie, F. et al. Nuclear export signal of IκBα interferes with the Rev-dependent posttranscriptional regulation of human immunodeficiency virus type I. J. Cell Sci. 110, 2883–2893 (1997).
Coiras, M., López-Huertas, M. R., Rullas, J., Mittelbrunn, M. & Alcamí, J. Basal shuttle of NF-κB/IκBα in resting T lymphocytes regulates HIV-1 LTR dependent expression. Retrovirology 4, 56 (2007). This study shows that the low-level HIV-1 replication in resting CD25− CD4+ T cells is due to the basal NF-κB activity that is necessary for cell survival.
Amini, S., Saunders, M., Kelley, K., Khalili, K. & Sawaya, B. E. Interplay between HIV-1 Vpr and Sp1 modulates p21WAF1 gene expression in human astrocytes. J. Biol. Chem. 279, 46046–46056 (2004).
Zhang, J., Scadden, D. T. & Crumpacker, C. S. Primitive hematopoietic cells resist HIV-1 infection via p21. J. Clin. Invest. 117, 473–481 (2007).
Dorr, A. et al. Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. EMBO J. 21, 2715–2723 (2002).
Col, E. et al. The histone acetyltransferase, hGCN5, interacts with and acetylates the HIV transactivator, Tat. J. Biol. Chem. 276, 28179–28184 (2001).
Ott, M. et al. Tat acetylation: a regulatory switch between early and late phases in HIV transcription elongation. Novartis Found. Symp. 259, 182–196 (2004).
Amini, S. et al. p73 interacts with human immunodeficiency virus type 1 Tat in astrocytic cells and prevents its acetylation on lysine 28. Mol. Cell. Biol. 25, 8126–8138 (2005).
Pagans, S. et al. SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol. 3, e41 (2005).
Sabò, A., Lusic, M., Cereseto, A. & Giacca, M. Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription. Mol. Cell Biol. 28, 2201–2212 (2008).
Boulanger, M. C. et al. Methylation of Tat by PRMT6 regulates human immunodeficiency virus type 1 gene expression. J. Virol. 79, 124–131 (2005).
Xie, B., Invernizzi, C. F., Richard, S. & Wainberg, M. A. Arginine methylation of the human immunodeficiency virus type 1 Tat protein by PRMT6 negatively affects Tat interactions with both cyclin T1 and the Tat transactivation region. J. Virol. 81, 4226–4234 (2007).
Ganesh, L. et al. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 426, 853–857 (2003). This is the first demonstration that COMMD1 (formerly known as Murr1)inhibits HIV-1 replication in resting CD4+ T cells by blocking NF-κB activity, thereby contributing to viral latency.
Burstein, E. et al. COMMD proteins: a novel family of structural and functional homologs of MURR1. J. Biol. Chem. 280, 22222–22232 (2005).
Maine, G. N., Mao, X., Komarck, C. M. & Burstein, E. COMMD1 promotes the ubiquitination of NF-κB subunits through a cullin-containing ubiquitin ligase. EMBO J. 26, 436–447 (2007).
Mangeat, B. et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424, 99–103 (2004).
Shirakawa, K. et al. Phosphorylation of APOBEC3G by protein kinase A regulates its interaction with HIV-1 Vif. Nature Struct. Mol. Biol. 15, 1184–1191 (2008).
Xu, H. et al. Stoichiometry of the antiviral protein APOBEC3G in HIV-1 virions. Virology 360, 247–256 (2007).
Corbeau, P. Interfering RNA and HIV: reciprocal interferences. PLoS Pathog. 4, e1000162 (2008).
Kim, D. H. & Rossi, J. J. Strategies for silencing human disease using RNA interference. Nature Rev. Genet. 8, 173–184 (2007).
Huang, J. et al. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nature Med. 13, 1241–1247 (2007). This paper shows that cellular miRNAs miR-28, miR-125b, miR-150, miR-223 and miR-382 potently inhibit HIV-1 production in resting primary CD4+ T cells and are essential for the establishment and maintenance of viral latency.
Han, Y. & Siliciano, R. F. Keeping quiet: microRNAs in HIV-1 latency. Nature Med. 13, 1138–1140 (2007).
Omoto, S. et al. HIV-1 nef suppression by virally encoded microRNA. Retrovirology 1, 44 (2004).
Omoto, S. & Fujii, Y. R. Regulation of human immunodeficiency virus 1 transcription by nef microRNA. J. Gen. Virol. 86, 751–755 (2005).
Bennasser, Y., Le, S. Y., Yeung, M. L. & Jeang, K. T. MicroRNAs in human immunodeficiency virus-1 infection. Methods Mol. Biol. 342, 241–225 (2006).
Bennasser, Y., Le, S. Y., Yeung, M. L. & Jeang, K. T. HIV-1 encoded candidate micro-RNAs and their cellular targets. Retrovirology 1, 43 (2004).
Couturier, J. P. & Root-Bernstein, R. S. HIV may produce inhibitory microRNAs (miRNAs) that block production of CD28, CD4 and some interleukins. J. Theor. Biol. 235, 169–184 (2005).
Cook, J. A., Albacker, L., August, A. & Henderson, A. J. CD28-dependent HIV-1 transcription is associated with Vav, Rac, and NF-κB activation. J. Biol. Chem. 278, 35812–35818 (2003).
Asjö, B., Cefai, D., Debré, P., Dudoit, Y. & Autran, B. A novel mode of human immunodeficiency virus type 1 (HIV-1) activation: ligation of CD28 alone induces HIV-1 replication in naturally infected lymphocytes. J. Virol. 67, 4395–4398 (1993).
Lin, J. & Cullen, B. R. Analysis of the interaction of primate retroviruses with the human RNA interference machinery. J. Virol. 81, 12218–12226 (2007).
Bennasser, Y., Le, S. Y., Benkirane, M. & Jeang, K. T. Evidence that HIV-1 encodes an siRNA and a Suppressor of RNA Silencing. Immunity 22, 607–619 (2005). This is the first evidence that HIV-1 encodes siRNA precursors in its genome and that Tat hijacks Dicer to avoid the processing of pre-miRNAs.
Bennasser, Y. & Jeang, K. T. HIV-1 Tat interaction with Dicer: requirement for RNA. Retrovirology 3, 95 (2006).
Gatignol, A., Lainé, S. & Clerzius, G. Dual role of TRBP in HIV replication and RNA interference: viral diversion of a cellular pathway or evasion from antiviral immunity? Retrovirology 2, 65 (2005).
Christensen, H. S. et al. Small interfering RNA against the TAR RNA binding protein TRBP, a Dicer cofactor, inhibit human immunodeficiency virus type 1 long terminal repeat expression and viral production. J. Virol. 81, 5121–5131 (2007).
Triboulet, R. et al. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 315, 1579–1582 (2007). This article shows that the cellular endonucleases Dicer and Drosha inhibit HIV-1 replication in latently infected cells, whereas HIV-1 suppresses the expression of miRNAs. This suppression is necessary for the efficient viral replication that is mediated by the interaction between Tat and PCAF.
Yeung, M. L. et al. Changes in microRNA expression profiles in HIV-1-transfected human cells. Retrovirology 2, 81 (2005).
Ouellet, D. L. et al. Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element. Nucleic Acids Res. 36, 2353–2365 (2008).
Kumar, A. & Jeang, K. T. Insights into cellular microRNAs and human immunodeficiency virus type 1 (HIV-1). J. Cell Physiol. 216, 327–331 (2008).
Perelson, A. S., Neumann, A. U., Markowitz. M., Leonard, J. M. & Ho, D. D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation. Science 271, 1582–1586 (1996).
Strain, M. C. et al. Heterogeneous clearance rates of long lived lymphocytes infected with HIV-1: intrinsic stability predicts lifelong persistence. Proc. Natl Acad. Sci. USA 100, 4819–4824 (2003).
Palmer, S. et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc. Natl Acad. Sci. USA 105, 3879–3884 (2008).
Chun, T. W. et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J. Clin. Invest. 11, 3250–3255 (2005).
Lambotte, O. et al. The lymphocyte HIV reservoir in patients on long-term HAART is a memory of virus evolution. AIDS 18, 1147–1158 (2004).
Bailey, J. R. et al. 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. J. Virol. 80, 6441–6457 (2006).
Tobin, N. H. et al. Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus. J. Virol. 79, 9625–9634 (2005).
Havlir, D. V. et al. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J. Virol. 77, 11212–11219 (2003).
Frenkel, L. M. et al. Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy. J. Virol. 77, 5721–5730 (2003).
Dinoso, J. B. et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 106, 9403–9408 (2009).
Shen, L. et al. Dose-response curve slope sets class-specific limits on inhibitory potencial of anti-HIV drugs. Nature Med. 14, 762–766 (2008).
Ruiz, L. et al. Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue. AIDS 13, F1–F8 (1999).
Guadalupe, M. et al. Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection. J. Virol. 80, 8236–8247 (2006).
Chun, T. W. et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J. Infect. Dis. 197, 714–720 (2008).
Poles, M. A. et al. Lack of decay of HIV-1 in gut-associated lymphoid tissue reservoirs in maximally suppressed individuals. J. Acquir. Immune. Defic. Syndr. 43, 65–68 (2006).
Koelsch, K. K. et al. Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J. Infect. Dis. 197, 411–419 (2008).
Yerly, S., Perneger, T. V., Vora, S., Hirschel, B. & Perrin, L. Decay of cell-associated HIV-1 DNA correlates with residual replication in patients treated during acute HIV-1 infection. AIDS 14, 2805–2812 (2000).
Ramratnam, B. et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nature Med. 6, 82–85 (2000).
Chun, T. W. et al. Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J. Infect. Dis. 195, 1762–1764 (2007).
Brennan, T. P. et al. Analysis of human immunodeficiency virus type-1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. J. Virol. 83, 8470-8481 (2009).
Gulick, R. M. et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N. Engl. J. Med. 359, 429–441 (2008).
Steigbigel, R. T. et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N. Engl. J. Med. 359, 339–354 (2008).
Abrams, D. I. et al. Dehydroepiandrosterone (DHEA) effects on HIV replication and host immunity: a randomized placebo-controlled study. AIDS Res. Hum. Retroviruses 23, 77–85 (2007).
Chapuis, A. G. et al. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nature Med. 6, 762–768 (2000).
García, F. et al. Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection: a randomized pilot study. J. Acquir. Immune Defic. Syndr. 36, 823–830 (2004).
Rizzardi, G. P. et al. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J. Clin. Invest. 109, 681–688 (2002).
García, F. et al. A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study. AIDS 17, 43–51 (2003).
Barreiro, P. et al. Hydroxyurea plus didanosine as maintenance therapy for HIV-infected patients on long-term successful highly active antiretroviral therapy. HIV Clin. Trials 4, 361–371 (2003).
Makonkawkeyoon, S., Limson-Pobre, R. N., Moreira, A. L., Schauf, V. & Kaplan, G. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 90, 5974–5978 (1993).
Chun, T. W. et al. 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 Med. 5, 651–655 (1999).
Stellbrink, H. J. et al. Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS 16, 1479–1487 (2002).
Van Praag, R. M. et al. OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. J. Clin. Immunol. 21, 218–226 (2001).
Esportès, C. et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J. Exp. Med. 205, 1701–1714 (2008).
Rullas, J. et al. Prostratin induces HIV activation and downregulates HIV receptors in peripheral blood lymphocytes. Antivir. Ther. 9, 545–554 (2004).
Wender, P. A., Kee, J. M. & Warrington, J. M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV-1. Science 320, 649–652 (2008).
Marquez, N. et al. Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation. Biochem. Pharmacol. 75, 1370–1380 (2008).
Bedoya, L. M. et al. SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro. Biochem. Pharmacol. 77, 965–978 (2009).
Choudhary, S. K., Archin, N. M. & Margolis, D. M. Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4+ T cells. J. Infect. Dis. 197, 1162–1170 (2008).
Martín-Serrano, J. et al. In vitro selective elimination of HIV-infected cells from peripheral blood in AIDS patients by the immunotoxin DAB389CD4. AIDS 12, 859–863. (1998)
Brooks, D. G. et al. Molecular characterization, reactivation, and depletion of latent HIV. Immunity 19, 413–423 (2003).
Ramachandran, R. V., Katzenstein, D. A., Wood, R., Batts, D. H. & Merigan, T. C. Failure of short-term CD4-PE40 infusions to reduce virus load in human immunodeficiency virus-infected persons. J. Infect. Dis. 170, 1009–1013 (1994).
Lehrman, G. et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366, 549–555 (2005).
Sagot-Lerolle, N. et al. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS 22, 1125–1129 (2008).
Siliciano, J. D. et al. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J. Infect. Dis. 195, 833–836 (2007).
Acknowledgements
We thank P. Perez-Romero, M. J. McConnell, S. Moreno and A. Alcamí for helpful suggestions. The research of our laboratory is supported by grants from the European Union (EUROPRISE), the Instituto de Salud Carlos III (RETIC RD06/0006 and the Intrasalud programme), the Comunidad de Madrid (VIRHOST Network) and FIPSE (Fundación para la investigación y prevención del SIDA en España).
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Glossary
- Highly active antiretroviral therapy
-
A combination of three or more potent anti-HIV-1 drugs that reduces viral load below detection limits by standard techniques.
- Reservoir
-
A cell type or anatomical site in which a replication-competent virus persists for much longer than it does in the main pool of productive infected cells, thereby sustaining the infection. Integrated proviral genomes and cells that persistently replicate HIV-1 in the presence of highly active antiretroviral therapy can be considered viral reservoirs.
- Provirus
-
Viral genomic double-stranded cDNA that has permanently integrated into the host cell genome and that acts as a template for the synthesis of viral RNAs.
- Direct repeats
-
Two or more identical or nearly identical repeats of specific nucleotide sequences that are in the same direction in the DNA molecule.
- Blunt end
-
The end of a double-stranded DNA molecule that terminates in paired bases, rather than with uneven ends, such that one strand overhangs.
- Enhancer element
-
A DNA consensus site, usually located 5′ from the basal gene promoter, that is bound to by specific transcription factors to increase the rate of transcription of the gene that it controls. An enhancer element may be placed thousands of bases upstream or downstream of the transcription initiation site of this gene.
- Tat
-
A regulatory HIV-1 protein that is essential for viral transcript elongation through its interaction with the Tat response element and several host factors, such as the positive transcription elongation factor b.
- Rev
-
A regulatory HIV-1 protein that controls the nuclear export of viral mRNA species through its interaction with the Rev response element that is found in unspliced or incompletly spliced HIV-1 RNAs.
- Naive T cell
-
A mature T cell from the acquired immune system that has not yet made contact with its cognate antigen and that therefore lacks both activation and memory markers on the cell surface.
- Memory T cell
-
A T cell that persists for a long time after its exposure to a specific foreign antigen and that can be promptly expanded to effector T cells after contact with the same antigen to initiate a faster and stronger immune response.
- Retroviral restriction factor
-
A component of the innate immune system that aids the survival of a host cell after retroviral infection by interfering with viral replication at different steps of the viral life cycle.
- Elite controller
-
A patient infected with HIV whose immune system can limit viral RNA to below 50 copies per ml for at least 12 months in the absence of highly active antiretroviral therapy.
- Gut-associated lymphoid tissue
-
The intestinal mucosa-associated lymphoid tissue that constitutes 70% of the whole immune system and may be the main site of HIV-1 activity, despite the use of highly active antiretrovial therapy.
- Transcriptional interference
-
Interruption of RNA transcription that is caused by adjacent active promoters owing to the competition for transcription factors or the collision of RNA polymerase II elongation complexes.
- Basal transcription machinery
-
The complex that regulates the initiation and elongation of transcription by binding to a core promoter that is located ∼50 bp upstream of the transcription initiation site and contains the highly conserved TATA box. The complex consists of RNA polymerase II and several transcription factors and co-activators.
- Predominant plasma clone
-
The main plasma clone of infected cells that is responsible for most of the residual viraemia in patients on highly active antiretroviral therapy. This clone is replication competent and shows a specific sequence for each patient that cannot be easily found in the patient's activated or resting CD4+ T cells.
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Coiras, M., López-Huertas, M., Pérez-Olmeda, M. et al. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nat Rev Microbiol 7, 798–812 (2009). https://doi.org/10.1038/nrmicro2223
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DOI: https://doi.org/10.1038/nrmicro2223
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