Abstract
The HIV latent reservoirs are considered as the main hurdle to viral eradication. Numerous mechanisms lead to the establishment of HIV latency and act at the transcriptional and post-transcriptional levels. A better understanding of latency is needed in order to ultimately achieve a cure for HIV. The mechanisms underlying latency vary between patients, tissues, anatomical compartments, and cell types. From this point of view, simian immunodeficiency virus (SIV) infection and the use of nonhuman primate (NHP) models that recapitulate many aspects of HIV-associated latency establishment and disease progression are essential tools since they allow extensive tissue sampling as well as a control of infection parameters (virus type, dose, route, and time).
Gilles Darcis, Benoit Van Driessche—Equal contribution.
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References
Abdel-Mohsen M et al (2016) Human galectin-9 is a potent mediator of HIV transcription and reactivation. PLoS Pathog 12:e1005677
Abu-Farha M et al (2008) The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics 7:560–572
Adelman K, Lis JT (2012) Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet 13:720–731
Boehm D et al (2017) SMYD2-mediated histone methylation contributes to HIV-1 latency. Cell Host Microbe 21:569–579 e566
Alexaki A, Liu Y, Wigdahl B (2008) Cellular reservoirs of HIV-1 and their role in viral persistence. Curr HIV Res 6:388–400
Avettand-Fenoel V et al (2016) Total HIV-1 DNA, a marker of viral reservoir dynamics with clinical implications. Clin Microbiol Rev 29:859–880
Barber SA et al (2006) Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model. J Infect Dis 193:963–970
Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM (2001) NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell 8:327–337
Berkhout B (1992) Structural features in TAR RNA of human and simian immunodeficiency viruses: a phylogenetic analysis. Nucleic Acids Res 20:27–31
Besnard E et al (2016) The mTOR complex controls HIV latency. Cell Host Microbe 20:785–797
Bignami F et al (2012) Stable changes in CD4+ T lymphocyte miRNA expression after exposure to HIV-1. Blood 119:6259–6267
Blazkova J et al (2009) CpG methylation controls reactivation of HIV from latency. PLoS Pathog 5:e1000554
Brady J, Kashanchi F (2005) Tat gets the “green” light on transcription initiation. Retrovirology 2:69
Brown MA, Sims RJ 3rd, Gottlieb PD, Tucker PW (2006) Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer 5:26
Budhiraja S, Famiglietti M, Bosque A, Planelles V, Rice AP (2013) Cyclin T1 and CDK9 T-loop phosphorylation are downregulated during establishment of HIV-1 latency in primary resting memory CD4+ T cells. J Virol 87:1211–1220
Capelson M, Doucet C, Hetzer MW (2010) Nuclear pore complexes: guardians of the nuclear genome. Cold Spring Harb Symp Quant Biol 75:585–597
Chen HC, Martinez JP, Zorita E, Meyerhans A, Filion GJ (2017) Position effects influence HIV latency reversal. Nat Struct Mol Biol 24:47–54
Cherrier T et al (2013) CTIP2 is a negative regulator of P-TEFb. Proc Natl Acad Sci USA 110:12655–12660
Chiang K, Rice AP (2012) MicroRNA-mediated restriction of HIV-1 in resting CD4+ T cells and monocytes. Viruses 4:1390–1409
Chiang K, Sung TL, Rice AP (2012) Regulation of cyclin T1 and HIV-1 Replication by microRNAs in resting CD4+ T lymphocytes. J Virol 86:3244–3252
Choudhary SK, Archin NM, Margolis DM (2008) Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells. J Infect Dis 197:1162–1170
Chun TW et al (1995) In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1:1284–1290
Chun TW et al (1997) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387:183–188
Chun TW et al (2000) Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nat Med 6:757–761
Coley W et al (2010) Absence of DICER in monocytes and its regulation by HIV-1. J Biol Chem 285:31930–31943
Colin L, Van Lint C (2009) Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies. Retrovirology 6:111
Crise B et al (2005) Simian immunodeficiency virus integration preference is similar to that of human immunodeficiency virus type 1. J Virol 79:12199–12204
Darcis G et al (2015) An in-depth comparison of latency-reversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified bryostatin-1+ JQ1 and ingenol-B+ JQ1 to potently reactivate viral gene expression. PLoS Pathog 11:e1005063
Darcis G et al (2017) Reactivation capacity by latency-reversing agents ex vivo correlates with the size of the HIV-1 reservoir. AIDS 31:181–189
Das AT, Harwig A, Berkhout B (2011) The HIV-1 Tat protein has a versatile role in activating viral transcription. J Virol 85:9506–9516
Davey RT Jr et al (1999) 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 USA 96:15109–15114
Deleage C, Turkbey B, Estes JD (2016) Imaging lymphoid tissues in nonhuman primates to understand SIV pathogenesis and persistence. Curr Opin Virol 19:77–84
Doucas V, Tini M, Egan DA, Evans RM (1999) Modulation of CREB binding protein function by the promyelocytic (PML) oncoprotein suggests a role for nuclear bodies in hormone signaling. Proc Natl Acad Sci U S A 96:2627–2632
Duverger A et al (2013) An AP-1 binding site in the enhancer/core element of the HIV-1 promoter controls the ability of HIV-1 to establish latent infection. J Virol 87:2264–2277
Eilebrecht S et al (2014) HMGA1 recruits CTIP2-repressed P-TEFb to the HIV-1 and cellular target promoters. Nucleic Acids Res 42:4962–4971
Finzi D et al (1999) Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 5:512–517
Fortin JF, Barat C, Beausejour Y, Barbeau B, Tremblay MJ (2004) Hyper-responsiveness to stimulation of human immunodeficiency virus-infected CD4+ T cells requires Nef and Tat virus gene products and results from higher NFAT, NF-kappaB, and AP-1 induction. J Biol Chem 279:39520–39531
Friedman J et al (2011) Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol 85:9078–9089
Gama L et al (2017) Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS 31:5–14
Goffin V et al (2005) Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity. Nucleic Acids Res 33:4285–4310
Hayes AM, Qian S, Yu L, Boris-Lawrie K (2011) Tat RNA silencing suppressor activity contributes to perturbation of lymphocyte miRNA by HIV-1. Retrovirology 8:36
Hematti P et al (2004) Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells. PLoS Biol 2:e423
Heusinger E, Kirchhoff F (2017) Primate Lentiviruses Modulate NF-kappaB Activity by Multiple Mechanisms to Fine-Tune Viral and Cellular Gene Expression. Front Microbiol 8:198
Hogan TH et al (2003) Structural and functional evolution of human immunodeficiency virus type 1 long terminal repeat CCAAT/enhancer binding protein sites and their use as molecular markers for central nervous system disease progression. J Neurovirol 9:55–68
Houzet L et al (2008) MicroRNA profile changes in human immunodeficiency virus type 1 (HIV-1) seropositive individuals. Retrovirology 5:118
Huang J et al (2007) Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 13:1241–1247
Imai K, Togami H, Okamoto T (2010) Involvement of histone H3 lysine 9 (H3K9) methyltransferase G9a in the maintenance of HIV-1 latency and its reactivation by BIX01294. J Biol Chem 285:16538–16545
Imam H, Bano AS, Patel P, Holla P, Jameel S (2015) The lncRNA NRON modulates HIV-1 replication in a NFAT-dependent manner and is differentially regulated by early and late viral proteins. Sci Rep 5:8639
Jiang G, Espeseth A, Hazuda DJ, Margolis DM (2007) 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
Jordan A, Bisgrove D, Verdin E (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J 22:1868–1877
Karn J, Stoltzfus CM (2012) Transcriptional and posttranscriptional regulation of HIV-1 gene expression. Cold Spring Harb Perspect Med 2:a006916
Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E (2009) Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog 5:e1000495
Khalid M et al (2012) Efficient Nef-mediated downmodulation of TCR-CD3 and CD28 is associated with high CD4+ T cell counts in viremic HIV-2 infection. J Virol 86:4906–4920
Klase Z et al (2007) HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol Biol 8:63
Kula A, Marcello A (2012) Dynamic post-transcriptional regulation of HIV-1 gene expression. Biology (Basel) 1:116–133
Kula A, Gharu L, Marcello A (2013) HIV-1 pre-mRNA commitment to Rev mediated export through PSF and Matrin 3. Virology 435:329–340
Kumar A, Abbas W, Herbein G (2014) HIV-1 latency in monocytes/macrophages. Viruses 6:1837–1860
Lamond AI, Sleeman JE (2003) Nuclear substructure and dynamics. Curr Biol 13:R825–828
Le Douce V, Cherrier T, Riclet R, Rohr O, Schwartz C (2014) The many lives of CTIP2: from AIDS to cancer and cardiac hypertrophy. J Cell Physiol 229:533–537
Lelek M et al (2015) Chromatin organization at the nuclear pore favours HIV replication. Nat Commun 6:6483
Lenasi T, Peterlin BM, Barboric M (2011) Cap-binding protein complex links pre-mRNA capping to transcription elongation and alternative splicing through positive transcription elongation factor b (P-TEFb). J Biol Chem 286:22758–22768
Lewinski MK et al (2005) Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J Virol 79:6610–6619
Li J et al (2016) Long noncoding RNA NRON contributes to HIV-1 latency by specifically inducing tat protein degradation. Nat Commun 7:11730
Ling B et al (2014) Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV-infected Chinese rhesus macaques. PLoS ONE 9:e102795
Liu Y, Nonnemacher MR, Wigdahl B (2009) CCAAT/enhancer-binding proteins and the pathogenesis of retrovirus infection. Future Microbiol 4:299–321
Lusic M et al (2013) Proximity to PML nuclear bodies regulates HIV-1 latency in CD4+ T cells. Cell Host Microbe 13:665–677
Marban C et al (2005) COUP-TF interacting protein 2 represses the initial phase of HIV-1 gene transcription in human microglial cells. Nucleic Acids Res 33:2318–2331
Marban C et al (2007) Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J 26:412–423
Marcello A et al (2003) Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein. EMBO J 22:2156–2166
Marini B et al (2015) Nuclear architecture dictates HIV-1 integration site selection. Nature 521:227–231
Marsili G, Remoli AL, Sgarbanti M, Battistini A (2004) Role of acetylases and deacetylase inhibitors in IRF-1-mediated HIV-1 long terminal repeat transcription. Ann N Y Acad Sci 1030:636–643
Misteli T (2007) Beyond the sequence: cellular organization of genome function. Cell 128:787–800
Nguyen K, Das B, Dobrowolski C, Karn J (2017) Multiple histone lysine methyltransferases are required for the establishment and maintenance of HIV-1 latency. MBio 8
Omoto S et al (2004) HIV-1 nef suppression by virally encoded microRNA. Retrovirology 1:44
Ouellet DL et al (2008) Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element. Nucleic Acids Res 36:2353–2365
Perkins ND et al (1997) Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science 275:523–527
Purcell DF, Martin MA (1993) Alternative splicing of human immunodeficiency virus type 1 mRNA modulates viral protein expression, replication, and infectivity. J Virol 67:6365–6378
Qian S et al (2009) HIV-1 Tat RNA silencing suppressor activity is conserved across kingdoms and counteracts translational repression of HIV-1. Proc Natl Acad Sci U S A 106:605–610
Ravimohan S, Gama L, Barber SA, Clements JE (2010) Regulation of SIV mac 239 basal long terminal repeat activity and viral replication in macrophages: functional roles of two CCAAT/enhancer-binding protein beta sites in activation and interferon beta-mediated suppression. J Biol Chem 285:2258–2273
Ravimohan S, Gama L, Engle EL, Zink MC, Clements JE (2012) Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. PLoS ONE 7:e42801
Schindler M et al (2006) Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 125:1055–1067
Schindler M et al (2008) Inefficient Nef-mediated downmodulation of CD3 and MHC-I correlates with loss of CD4+ T cells in natural SIV infection. PLoS Pathog 4:e1000107
Schrijvers R et al (2012) LEDGF/p75-independent HIV-1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs. PLoS Pathog 8:e1002558
Shan L et al (2011) Influence of host gene transcription level and orientation on HIV-1 latency in a primary-cell model. J Virol 85:5384–5393
Siliciano JD et al (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 9:727–728
Sung TL, Rice AP (2009) miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1. PLoS Pathog 5:e1000263
Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9:465–476
Trejbalova K et al (2016) Development of 5’ LTR DNA methylation of latent HIV-1 provirus in cell line models and in long-term-infected individuals. Clin Epigenetics 8:19
Triboulet R et al (2007) Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 315:1579–1582
van der Velden GJ, Vink MA, Berkhout B, Das AT (2012) Tat has a dual role in simian immunodeficiency virus transcription. J Gen Virol 93:2279–2289
Van Lint C, Emiliani S, Ott M, Verdin E (1996) Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J 15:1112–1120
Van Lint C, Bouchat S, Marcello A (2013) HIV-1 transcription and latency: an update. Retrovirology 10:67
Verdin E, Paras P Jr, Van Lint C (1993) Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation. EMBO J 12:3249–3259
Vire E et al (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874
Wagner TA et al (2014) HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345:570–573
Witwer KW, Watson AK, Blankson JN, Clements JE (2012) Relationships of PBMC microRNA expression, plasma viral load, and CD4+ T-cell count in HIV-1-infected elite suppressors and viremic patients. Retrovirology 9:5
Wong RW, Mamede JI, Hope TJ (2015) The impact of nucleoporin mediated chromatin localization and nuclear architecture on HIV integration site selection. J Virol
Yang G, Thompson MA, Brandt SJ, Hiebert SW (2007) Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein. Oncogene 26:91–101
Yedavalli VS, Jeang KT (2011) Matrin 3 is a co-factor for HIV-1 Rev in regulating post-transcriptional viral gene expression. Retrovirology 8:61
Zhang Q, Chen CY, Yedavalli VS, Jeang KT (2013) NEAT1 long noncoding RNA and paraspeckle bodies modulate HIV-1 posttranscriptional expression. MBio 4:e00596–00512
Zolotukhin AS et al (2003) PSF acts through the human immunodeficiency virus type 1 mRNA instability elements to regulate virus expression. Mol Cell Biol 23:6618–6630
Funding
This project has received funding from the Belgian Fund for Scientific Research (FRS-FNRS, Belgium), the European Union’s Horizon 2020 research and innovation programme (grant agreement N° 691119 EU4HIVCURE H2020-MSCA-RISE-2015), the ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), the “Fondation Roi Baudouin”, the NEAT Program, the Walloon Region (the Excellence Program “Cibles” and the “Fond de maturation” program), the ARC program (ULB) and the Internationale Brachet Stiftung (IBS). BVD and SB are postdoctoral fellows (ARC program and PDR project from the FRS-FNRS, respectively). CVL is “Directeur de Recherches” of the FRS-FNRS (Belgium).
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Darcis, G., Van Driessche, B., Bouchat, S., Kirchhoff, F., Van Lint, C. (2017). Molecular Control of HIV and SIV Latency. In: Silvestri, G., Lichterfeld, M. (eds) HIV-1 Latency. Current Topics in Microbiology and Immunology, vol 417. Springer, Cham. https://doi.org/10.1007/82_2017_74
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