HIV type-1 (HIV-1) can establish a state of latency in infected patients, most notably in resting CD4+ T-cells. This long-lived reservoir allows for rapid re-emergence of viraemia upon cessation of highly active antiretroviral therapy, even after extensive and seemingly effective treatment. Successful depletion of such latent reservoirs is probably essential to ‘cure’ HIV-1 infection and will require therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. The mechanisms underlying HIV-1 latency are not well characterized, and it is becoming clear that numerous factors, both cell- and virus-derived, are involved in the maintenance of proviral latency. The interplay of these various factors in the context of viral reactivation is still poorly understood. In this article, we review the current knowledge regarding the mechanisms underlying maintenance of HIV-1 latency, both transcriptional and post-transcriptional, with a focus on potential targets that might be exploited to therapeutically purge latent proviral reservoirs from infected patients.
FlexnerC. HIV drug development: The next 25 years. Nat Rev Drug Discov2007; 6: 959–966.
3.
Antiviral briefs. FDA approves maraviroc tablets. AIDS Patient Care STDS2007; 21: 702.
4.
Antiviral briefs.FDA approves raltegravir tablets. AIDS Patient Care STDS2007; 21: 889.
5.
JohnsonVABrun-VezinetFClotetB. Update of the drug resistance mutations in HIV-1: 2007. Top HIV Med2007; 15: 119–125.
6.
ChunTWNickleDCJustementJS. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis2008; 197: 714–720.
7.
HavlirDVStrainMCClericiM. 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 Virol2003; 77: 11212–11219.
8.
PiersonTMcArthurJSilicianoRF. Reservoirs for HIV-1: Mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol2000; 18: 665–708.
9.
PersaudDZhouYSilicianoJMSilicianoRF. Latency in human immunodeficiency virus type 1 infection: No easy answers. J Virol2003; 77: 1659–1665.
10.
CohenJ. AIDS research. Promising AIDS vaccine's failure leaves field reeling. Science2007; 318: 28–29.
11.
DaveyRTJrBhatNYoderC. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A1999; 96: 15109–15114.
12.
GlassJDJohnsonRT. Human immunodeficiency virus and the brain. Annu Rev Neurosci1996; 19: 1–26.
13.
ZhangHDornadulaGBeumontM. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med1998; 339: 1803–1809.
14.
SilicianoRF. Latency and reservoirs for HIV-1. AIDS1999; 3Suppl A: S49–S58.
15.
KeeleBFTaziLGartnerS. Characterization of the follicular dendritic cell reservoir of human immunodeficiency virus type 1. J Virol2008; 82: 5548–5561.
16.
ShenLSilicianoRF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. J Allergy Clin Immunol2008; 122: 22–28.
17.
FinziDHermankovaMPiersonT. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science1997; 278: 1295–1300.
18.
FinziDBlanksonJSilicianoJD. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med1999; 5: 512–517.
19.
BrenchleyJMHillBJAmbrozakDR. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: Implications for HIV pathogenesis. J Virol2004; 78: 1160–1168.
20.
ChunTWCarruthLFinziD. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature1997; 387: 183–188.
21.
LehrmanGHogueIBPalmerS. Depletion of latent HIV-1 infection in vivo: A proof-of-concept study. Lancet2005; 366: 549–555.
22.
ClouseKAPowellDWashingtonI. Monokine regulation of human immunodeficiency virus–1 expression in a chronically infected human T cell clone. J Immunol1989; 142: 431–438.
23.
PerezVLRoweTJustementJSButeraSTJuneCHFolksTM. An HIV-1-infected T cell clone defective in IL–2 production and Ca2+ mobilization after CD3 stimulation. J Immunol1991; 147: 3145–3148.
24.
LeonardJParrottCBuckler-WhiteAJ. The NF-kappa B binding sites in the human immunodeficiency virus type 1 long terminal repeat are not required for virus infectivity. J Virol1989; 63: 4919–4924.
25.
JordanABisgroveDVerdinE. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J2003; 22: 1868–1877.
26.
FolksTMJustementJKinterADinarelloCAFauciAS. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science1987; 238: 800–802.
27.
BrooksDGKitchenSGKitchenCMScripture-AdamsDDZackJA. Generation of HIV latency during thymopoiesis. Nat Med2001; 7: 459–464.
28.
BosqueAPlanellesV. Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood2009; 113: 58–65.
29.
JordanADefechereuxPVerdinE. The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation. EMBO J2001; 20: 1726–1738.
30.
WuXBurgessSM. Integration target site selection for retroviruses and transposable elements. Cell Mol Life Sci2004; 61: 2588–2596.
31.
HanYLassenKMonieD. 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 Virol2004; 78: 6122–6133.
32.
LewinskiMKBisgroveDShinnP. Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J Virol2005; 79: 6610–6619.
33.
SchroderARShinnPChenHBerryCEckerJRBushmanF. HIV-1 integration in the human genome favors active genes and local hotspots. Cell2002; 110: 521–529.
34.
LenasiTContrerasXPeterlinBM. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe2008; 4: 123–133.
35.
HanYLinYBAnW. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe2008; 4: 134–146.
36.
HeGYlisastiguiLMargolisDM. The regulation of HIV-1 gene expression: The emerging role of chromatin. DNA Cell Biol2002; 21: 697–705.
37.
BeckerPBHorzW. ATP-dependent nucleosome remodeling. Annu Rev Biochem2002; 71: 247–273.
38.
StrahlBDAllisCD. The language of covalent histone modifications. Nature2000; 403: 41–45.
39.
Van LintCEmilianiSOttMVerdinE. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J1996; 15: 1112–1120.
40.
HeGMargolisDM. 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 Biol2002; 22: 2965–2973.
41.
ImaiKOkamotoT. Transcriptional repression of human immunodeficiency virus type 1 by AP–4. J Biol Chem2006; 281: 12495–12505.
42.
WilliamsSAChenLFKwonHRuiz-JaraboCMVerdinEGreeneWC. NF-kappa B p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J2006; 25: 139–149.
43.
TyagiMKarnJ. CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J2007; 26: 4985–4995.
44.
JiangGEspesethAHazudaDJMargolisDM. C-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter. J Virol2007; 81: 10914–10923.
45.
Van LintCEmilianiSVerdinE. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr1996; 5: 245–253.
46.
LaughlinMAChangGYOakesJWGonzalez-ScaranoFPomerantzRJ. Sodium butyrate stimulation of HIV-1 gene expression: A novel mechanism of induction independent of NF-kappa B. J Acquir Immune Defic Syndr Hum Retrovirol1995; 9: 332–339.
47.
YlisastiguiLArchinNMLehrmanGBoschRJMargolisDM. Coaxing HIV-1 from resting CD4 T cells: Histone deacetylase inhibition allows latent viral expression. AIDS2004; 18: 1101–1108.
48.
RodriquezMAquinoMBrunoIDeMGTaddeiMGomez-PalomaL. Chemistry and biology of chromatin remodeling agents: State of art and future perspectives of HDAC inhibitors. Curr Med Chem2006; 13: 1119–1139.
49.
VarierRAKunduTK. Chromatin modifications (acetylation/deacetylation/methylation) as new targets for HIV therapy. Curr Pharm Des2006; 12: 1975–1993.
50.
KhorasanizadehS. The nucleosome: From genomic organization to genomic regulation. Cell2004; 116: 259–272.
51.
GottlicherMMinucciSZhuP. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J2001; 20: 6969–6978.
52.
MarksPADokmanovicM. Histone deacetylase inhibitors: Discovery and development as anticancer agents. Expert Opin Investig Drugs2005; 14: 1497–1511.
53.
CoullJJHeGMelanderCRuckerVCDervanPBMargolisDM. Targeted derepression of the human immunodeficiency virus type 1 long terminal repeat by pyrrole-imidazole polyamides. J Virol2002; 76: 12349–12354.
54.
YlisastiguiLCoullJJRuckerVC. Polyamides reveal a role for repression in latency within resting T cells of HIV-infected donors. J Infect Dis2004; 190: 1429–1437.
55.
PereiraLABentleyKPeetersAChurchillMJDeaconNJ. A compilation of cellular transcription factor interactions with the HIV-1 LTR promoter. Nucleic Acids Res2000; 28: 663–668.
56.
StevensMDeCEBalzariniJ. The regulation of HIV-1 transcription: Molecular targets for chemotherapeutic intervention. Med Res Rev2006; 26: 595–625.
57.
DuhEJMauryWJFolksTMFauciASRabsonAB. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A1989; 86: 5974–5978.
58.
WilliamsSAKwonHChenLFGreeneWC. Sustained induction of NF-kappa B is required for efficient expression of latent human immunodeficiency virus type 1. J Virol2007; 81: 6043–6056.
59.
BaldwinASJr. The NF-kappa B and I kappa B proteins: New discoveries and insights. Annu Rev Immunol1996; 14: 649–683.
60.
BrooksDGHamerDHArlenPA. Molecular characterization, reactivation, and depletion of latent HIV. Immunity2003; 19: 413–423.
61.
WilliamsSAChenLFKwonH. Prostratin antagonizes HIV latency by activating NF-kappa B. J Biol Chem2004; 279: 42008–42017.
62.
AdamsMSharmeenLKimptonJ. Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts. Proc Natl Acad Sci U S A1994; 91: 3862–3866.
63.
KaoSYCalmanAFLuciwPAPeterlinBM. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature1987; 330: 489–493.
64.
LassenKGBaileyJRSilicianoRF. Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J Virol2004; 78: 9105–9114.
65.
EmilianiSVanLCFischleW. A point mutation in the HIV-1 Tat responsive element is associated with postintegration latency. Proc Natl Acad Sci U S A1996; 93: 6377–6381.
66.
GhoseRLiouLYHerrmannCHRiceAP. Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. J Virol2001; 75: 11336–11343.
67.
KlichkoVArchinNKaurRLehrmanGMargolisD. Hexamethylbisacetamide remodels the human immunodeficiency virus type 1 (HIV-1) promoter and induces Tat-independent HIV-1 expression but blunts cell activation. J Virol2006; 80: 4570–4579.
68.
ChoudharySKArchinNMMargolisDM. Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells. J Infect Dis2008; 197: 1162–1170.
PomerantzRJSeshammaTTronoD. Efficient replication of human immunodeficiency virus type 1 requires a threshold level of Rev: Potential implications for latency. J Virol1992; 66: 1809–1813.
71.
LassenKGRamyarKXBaileyJRZhouYSilicianoRF. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog2006; 2: e68.
KlaseZKalePWinogradR. HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol Biol2007; 8: 63.
86.
BennasserYLeSYYeungMLJeangKT. HIV-1 encoded candidate micro-RNAs and their cellular targets. Retrovirology2004; 1: 43.
87.
CouturierJPRoot-BernsteinRS. HIV may produce inhibitory microRNAs (miRNAs) that block production of CD28, CD4 and some interleukins. J Theor Biol2005; 235: 169–184.
88.
HuangJWangFArgyrisE. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med2007; 13: 1241–1247.
89.
ChunTWEngelDMizellSB. 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. Nat Med1999; 5: 651–655.
90.
KulkoskyJNunnariGOteroM. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J Infect Dis2002; 186: 1403–1411.
91.
PrinsJMJurriaansSvan PraagRM. Immuno-activation with anti-CD3 and recombinant human IL–2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS1999; 13: 2405–2410.
92.
GribbleEJSivakumarPVPonceRAHughesSD. Toxicity as a result of immunostimulation by biologics. Expert Opin Drug Metab Toxicol2007; 3: 209–234.
93.
PonceR. Adverse consequences of immunostimulation. J Immunotoxicol2008; 5: 33–41.
94.
SuntharalingamGPerryMRWardS. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med2006; 355: 1018–1028.
95.
FolksTMClouseKAJustementJ. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A1989; 86: 2365–2368.
96.
FraserCFergusonNMGhaniAC. Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS2000; 14: 659–669.
97.
LafeuilladeAPoggiCChadapaudS. Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission. J Acquir Immune Defic Syndr2001; 26: 44–55.
98.
StellbrinkHJvan LunzenJWestbyM. Effects of interleukin–2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS2002; 16: 1479–1487.
99.
FolksTMJustementJKinterA. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol–12-myristate acetate. J Immunol1988; 140: 1117–1122.
100.
BohanCYorkDSrinivasanA. Sodium butyrate activates human immunodeficiency virus long terminal repeat-directed expression. Biochem Biophys Res Commun1987; 148: 899–905.
101.
SilicianoJDKajdasJFinziD. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med2003; 9: 727–728.
102.
RamratnamBRibeiroRHeT. Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication. J Acquir Immune Defic Syndr2004; 35: 33–37.
103.
SteelAClarkSTeoI. No change to HIV-1 latency with valproate therapy. AIDS2006; 20: 1681–1682.
104.
SilicianoJDLaiJCallenderM. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J Infect Dis2007; 195: 833–836.
105.
Sagot-LerolleNLamineAChaixML. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS2008; 22: 1125–1129.
106.
ArchinNMEronJJPalmerS. Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells. AIDS2008; 22: 1131–1135.
107.
HanYWind-RotoloMYangHCSilicianoJDSilicianoRF. Experimental approaches to the study of HIV-1 latency. Nat Rev Microbiol2007; 5: 95–106.
108.
MarksPABreslowR. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol2007; 25: 84–90.
109.
LenasiTContrerasXPeterlinBM. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe2008; 4: 123–133.
110.
Micheva-VitevaSPacchiaALRonYPeltzSWDoughertyJP. Human immunodeficiency virus type 1 latency model for high-throughput screening. Antimicrob Agents Chemother2005; 49: 5185–5188.
111.
SaksenaNKRodesBWangBSorianoV. Elite HIV controllers: Myth or reality?AIDS Rev2007; 9: 195–207.
112.
ChiuYLGreeneWC. The APOBEC3 cytidine deaminases: An innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu Rev Immunol2008; 26: 317–353.
113.
JonesLEPerelsonAS. Transient viremia, plasma viral load, and reservoir replenishment in HIV-infected patients on antiretroviral therapy. J Acquir Immune Defic Syndr2007; 45: 483–493.
114.
JonesJRodgersJHeilM. High throughput drug screening for human immunodeficiency virus type 1 reactivating compounds. Assay Drug Dev Technol2007; 5: 181–189.
115.
KrishnanVZeichnerSL. Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency. J Virol2004; 78: 9458–9473.
116.
BrassALDykxhoornDMBenitaY. Identification of host proteins required for HIV infection through a functional genomic screen. Science2008; 319: 921–926.
