Current views on HIV-1 latency, persistence, and cure

Folia Microbiologica

Volumn 62, Issue 1, 2017, Pages 73-87

  Melkova, Zora ^a   Shankaran, Prakash ^a   Madlenakova, Michaela ^a   Bodor, Josef ^a  

^a CHARLES UNIVERSITY   (Czech Republic)

Author keywords

[No Author keywords available]

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT;

DRUG DEVELOPMENT; DRUG EFFECTS; HIV INFECTIONS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; MEDICAL RESEARCH; PHYSIOLOGY; TRENDS; VIROLOGY; VIRUS LATENCY;

ANTI-HIV AGENTS; BIOMEDICAL RESEARCH; DRUG DISCOVERY; HIV INFECTIONS; HIV-1; HUMANS; VIRUS LATENCY;

EID: 84990834308     PISSN: 00155632     EISSN: 18749356     Source Type: Journal    
DOI: 10.1007/s12223-016-0474-7     Document Type: Review

References (197)

1. Archin NM et al (2012) Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487:482–485. doi:10.1038/nature11286
2. Archin NM et al (2014a) HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. The Journal of infectious diseases 210:728–735. doi:10.1093/infdis/jiu155
3. Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM (2014b) Eradicating HIV-1 infection: seeking to clear a persistent pathogen nature reviews. Microbiology 12:750–764. doi:10.1038/nrmicro3352
4. Avalos CR et al (2016) Quantitation of productively infected monocytes and macrophages of SIV-infected macaques. J Virol. doi:10.1128/JVI.00290-16
5. Banga R, Procopio FA, Cavassini M, Perreau M (2016) In vitro reactivation of replication-competent and infectious HIV-1 by histone deacetylase inhibitors. J Virol 90:1858–1871. doi:10.1128/JVI.02359-15
6. Bednarik DP, Cook JA, Pitha PM (1990) Inactivation of the HIV LTR by DNA CpG methylation: evidence for a role in latency. EMBO J 9:1157–1164
7. Bennasser Y, Le SY, Yeung ML, Jeang KT (2004) HIV-1 encoded candidate micro-RNAs and their cellular targets. Retrovirology 1:43. doi:10.1186/1742-4690-1-43
8. Bhatt D, Ghosh S (2014) Regulation of the NF-kappaB-mediated transcription of inflammatory genes. Front Immunol 5:71. doi:10.3389/fimmu.2014.00071
9. Biancotto 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. J Virol 78:10507–10515. doi:10.1128/JVI.78.19.10507-10515.2004
10. Blazkova J et al (2009) CpG methylation controls reactivation of HIV from latency. PLoS Pathog 5:e1000554. doi:10.1371/journal.ppat.1000554
11. Blazkova J et al (2012) Paucity of HIV DNA methylation in latently infected, resting CD4+ T cells from infected individuals receiving antiretroviral therapy. J Virol 86:5390–5392. doi:10.1128/JVI.00040-12
12. Blum KS, Pabst R (2007) Lymphocyte numbers and subsets in the human blood. Do they mirror the situation in all organs? Immunol Lett 108:45–51. doi:10.1016/j.imlet.2006.10.009
13. Bodor J (2006) Regulation of HIV-1 and IL-2 transcription by inducible CAMP early repressor ICER. Retrovirology 3(Suppl 1):S81
14. Boehm D et al (2013) BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle 12:452–462. doi:10.4161/cc.23309
15. Bosque A, Planelles V (2009) Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood 113:58–65. doi:10.1182/blood-2008-07-168393
16. Bosque A, Famiglietti M, Weyrich AS, Goulston C, Planelles V (2011) Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells. PLoS Pathog 7:e1002288. doi:10.1371/journal.ppat.1002288
17. Brooks DG, Kitchen SG, Kitchen CM, Scripture-Adams DD, Zack JA (2001) Generation of HIV latency during thymopoiesis. Nat Med 7:459–464. doi:10.1038/86531
18. Bruner KM, Hosmane NN, Siliciano RF (2015) Towards an HIV-1 cure: measuring the latent reservoir. Trends Microbiol 23:192–203. doi:10.1016/j.tim.2015.01.013
19. Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20:425–429. doi:10.1038/nm.3489
20. Buzon MJ et al (2014) HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med 20:139–142. doi:10.1038/nm.3445
21. Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J, Bixby D, Savona MR, Collins KL (2010) HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med 16:446–451. doi:10.1038/nm.2109
22. Caskey M et al (2015) Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522:487–491. doi:10.1038/nature14411
23. Chan JK, Bhattacharyya D, Lassen KG, Ruelas D, Greene WC (2013) Calcium/calcineurin synergizes with prostratin to promote NF-kappaB dependent activation of latent HIV. PLoS One 8:e77749. doi:10.1371/journal.pone.0077749
24. Chege D et al (2011) Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy. AIDS 25:741–749. doi:10.1097/QAD.0b013e328344cefb
25. Cheng AS et al (2011) EZH2-mediated concordant repression of Wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res 71:4028–4039. doi:10.1158/0008-5472.CAN-10-3342
26. Chirullo B et al (2013) A candidate anti-HIV reservoir compound, auranofin, exerts a selective ‘anti-memory’ effect by exploiting the baseline oxidative status of lymphocytes. Cell Death Dis 4:e944. doi:10.1038/cddis.2013.473
27. Chomont N et al (2009) HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15:893–900. doi:10.1038/nm.1972
28. Choudhary SK, Archin NM, Cheema M, Dahl NP, Garcia JV, Margolis DM (2012) Latent HIV-1 infection of resting CD4(+) T cells in the humanized Rag2(−)/(−) gamma c(−)/(−) mouse. J Virol 86:114–120. doi:10.1128/JVI.05590-11
29. Chun TW, Fauci AS (1999) Latent reservoirs of HIV: obstacles to the eradication of virus. Proc Natl Acad Sci U S A 96:10958–10961
30. Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS (1998) Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med 188:83–91
31. Cillo AR, Sobolewski MD, Bosch RJ, Fyne E, Piatak M Jr, Coffin JM, Mellors JW (2014) Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 111:7078–7083. doi:10.1073/pnas.1402873111
32. Clouse KA et al (1989) Monokine regulation of human immunodeficiency virus-1 expression in a chronically infected human T cell clone. J Immunol 142:431–438
33. Clutton G, Archin N, Xu Y, Margolis DM, Goonetilleke N (2015) Differential effects of HIV latency-reversing agents on T cell phenotype and function: implications for HIV cure. Journal of Virus Eradication 1:8
34. Contreras X, Barboric M, Lenasi T, Peterlin BM (2007) HMBA releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and activates HIV transcription. PLoS Pathog 3:1459–1469. doi:10.1371/journal.ppat.0030146
35. Crooks AM et al (2015) Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. The Journal of Infectious Diseases 212:1361–1365. doi:10.1093/infdis/jiv218
36. Dar RD, Hosmane NN, Arkin MR, Siliciano RF, Weinberger LS (2014) Screening for noise in gene expression identifies drug synergies. Science 344:1392–1396. doi:10.1126/science.1250220
37. Deeks SG (2012) HIV: shock and kill. Nature 487:439–440. doi:10.1038/487439a
38. Denton PW et al (2012) Generation of HIV latency in humanized BLT mice. J Virol 86:630–634. doi:10.1128/JVI.06120-11
39. Dienz O et al (2007) Accumulation of NFAT mediates IL-2 expression in memory, but not naive, CD4+ T cells. Proc Natl Acad Sci U S A 104:7175–7180. doi:10.1073/pnas.0610442104
40. Doitsh G et al (2014) Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505:509–514. doi:10.1038/nature12940
41. Donahue DA, Wainberg MA (2013) Cellular and molecular mechanisms involved in the establishment of HIV-1 latency. Retrovirology 10:11. doi:10.1186/1742-4690-10-11
42. Doyon G, Zerbato J, Mellors JW, Sluis-Cremer N (2013) Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog. AIDS 27:F7–F11. doi:10.1097/QAD.0b013e3283570620
43. du Chene I et al (2007) Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J 26:424–435. doi:10.1038/sj.emboj.7601517
44. Farber D (2015) Tissue localization of human T cell responses. Journal of Virus Eradication 1:6
45. Farber DL, Yudanin NA, Restifo NP (2014) Human memory T cells: generation, compartmentalization and homeostasis nature reviews. Immunology 14:24–35. doi:10.1038/nri3567
46. Finzi D et al (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278:1295–1300
47. 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. doi:10.1038/8394
48. Fletcher CV et al (2014) Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A 111:2307–2312. doi:10.1073/pnas.1318249111
49. Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS (1987) Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science 238:800–802
50. Folks TM, Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, Fauci AS (1989) Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A 86:2365–2368
51. Friedman J, Cho WK, Chu CK, Keedy KS, Archin NM, Margolis DM, Karn J (2011) Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol 85:9078–9089. doi:10.1128/JVI.00836-11
52. Fujinaga K, Barboric M, Li Q, Luo Z, Price DH, Peterlin BM (2012) PKC phosphorylates HEXIM1 and regulates P-TEFb activity. Nucleic Acids Res 40:9160–9170. doi:10.1093/nar/gks682
53. Fukazawa Y et al (2015) B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med 21:132–139. doi:10.1038/nm.3781
54. Gao D et al (2013) Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–906. doi:10.1126/science.1240933
55. Garcia-Rodriguez C, Rao A (1998) Nuclear factor of activated T cells (NFAT)-dependent transactivation regulated by the coactivators p300/CREB-binding protein (CBP). J Exp Med 187:2031–2036
56. Gardner MB, Luciw PA (2008) Macaque models of human infectious disease. ILAR Journal/National Research Council, Institute of Laboratory Animal Resources 49:220–255
57. Giffin MJ, Stroud JC, Bates DL, von Koenig KD, Hardin J, Chen L (2003) Structure of NFAT1 bound as a dimer to the HIV-1 LTR kappa B element. Nat Struct Biol 10:800–806. doi:10.1038/nsb981
58. Gludish DW, Mwandumba HC, Jambo KC, Amie SM, Russel DG (2015) The human lung is a site of productive HIV infection during long-term ART: novel tools to study ART-durable HIV reservoirs. Journal of Virus Eradication 1:7
59. Gondois-Rey F et al (2006) R5 variants of human immunodeficiency virus type 1 preferentially infect CD62L- CD4+ T cells and are potentially resistant to nucleoside reverse transcriptase inhibitors. J Virol 80:854–865. doi:10.1128/JVI.80.2.854-865.2006
60. Han Y et al (2008) Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe 4:134–146. doi:10.1016/j.chom.2008.06.008
61. He G, Margolis DM (2002) 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 22:2965–2973
62. Henrich TJ et al (2013) Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. The Journal of Infectious Diseases 207:1694–1702. doi:10.1093/infdis/jit086
63. Herrmann CH, Rice AP (1995) Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. J Virol 69:1612–1620
64. Hezareh M et al (2004) Mechanisms of HIV receptor and co-receptor down-regulation by prostratin: role of conventional and novel PKC isoforms. Antiviral Chemistry & Chemotherapy 15:207–222
65. Hilldorfer BB, Cillo AR, Besson GJ, Bedison MA, Mellors JW (2012) New tools for quantifying HIV-1 reservoirs: plasma RNA single copy assays and beyond. Current HIV/AIDS Reports 9:91–100. doi:10.1007/s11904-011-0104-6
66. Hirsch VM, Olmsted RA, Murphey-Corb M, Purcell RH, Johnson PR (1989) An African primate lentivirus (SIVsm) closely related to HIV-2. Nature 339:389–392. doi:10.1038/339389a0
67. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–126. doi:10.1038/373123a0
68. Ho YC et al (2013) Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155:540–551. doi:10.1016/j.cell.2013.09.020
69. Hofmann H et al (2012) The Vpx lentiviral accessory protein targets SAMHD1 for degradation in the nucleus. J Virol 86:12552–12560. doi:10.1128/JVI.01657-12
70. Honeycutt JB, Wahl A, Archin N, Choudhary S, Margolis D, Garcia JV (2013) HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model. Retrovirology 10:121. doi:10.1186/1742-4690-10-121
71. Honeycutt JB et al (2016) Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest 126:1353–1366. doi:10.1172/JCI84456
72. Howell BJ et al (2015) Developing and applying ultrasensitive p24 protein immunoassay for HIV latency. Journal of Virus Eradication 1:5
73. Huang J et al (2007) Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 13:1241–1247. doi:10.1038/nm1639
74. Huang Y et al (2016) Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site. J Antimicrob Chemother. doi:10.1093/jac/dkw046
75. Huet T, Cheynier R, Meyerhans A, Roelants G, Wain-Hobson S (1990) Genetic organization of a chimpanzee lentivirus related to HIV-1. Nature 345:356–359. doi:10.1038/345356a0
76. Hutter G, Bodor J, Ledger S, Boyd M, Millington M, Tsie M, Symonds G (2015) CCR5 targeted cell therapy for HIV and prevention of viral escape. Viruses 7:4186–4203. doi:10.3390/v7082816
77. 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. doi:10.1074/jbc.M110.103531
78. Iordanskiy S, Kashanchi F (2016) Potential of radiation-induced cellular stress for reactivation of latent HIV-1 and killing of infected cells. AIDS Res Hum Retrovir 32:120–124. doi:10.1089/AID.2016.0006
79. Iordanskiy S et al (2015) Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology 485:1–15. doi:10.1016/j.virol.2015.06.021
80. Jiang Y, Tian B, Saifuddin M, Agy MB, Emau P, Cairns JS, Tsai CC (2009) RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models. AIDS Res Ther 6:23. doi:10.1186/1742-6405-6-23
81. Jiang G et al (2014) Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cdelta-NF-kappaB signaling. AIDS 28:1555–1566. doi:10.1097/QAD.0000000000000289
82. Jiang G et al (2015) Synergistic reactivation of latent HIV expression by Ingenol-3-Angelate, PEP005, targeted NF-kB signaling in combination with JQ1 induced p-TEFb activation. PLoS Pathog 11:e1005066. doi:10.1371/journal.ppat.1005066
83. Jimenez JL, Gonzalez-Nicolas J, Alvarez S, Fresno M, Munoz-Fernandez MA (2001) Regulation of human immunodeficiency virus type 1 replication in human T lymphocytes by nitric oxide. J Virol 75:4655–4663. doi:10.1128/JVI.75.10.4655-4663.2001
84. 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. doi:10.1093/emboj/cdg188
85. Kao SY, Calman AF, Luciw PA, Peterlin BM (1987) Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 330:489–493. doi:10.1038/330489a0
86. Karn J (2013) A new BET on the control of HIV latency. Cell Cycle 12:545–546. doi:10.4161/cc.23679
87. Karpel ME, Boutwell CL, Allen TM (2015) BLT humanized mice as a small animal model of HIV infection. Current Opinion in Virology 13:75–80. doi:10.1016/j.coviro.2015.05.002
88. Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E (2009) Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog 5:e1000495. doi:10.1371/journal.ppat.1000495
89. Keedy KS, Archin NM, Gates AT, Espeseth A, Hazuda DJ, Margolis DM (2009) A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression. J Virol 83:4749–4756. doi:10.1128/JVI.02585-08
90. Kim M, Siliciano RF (2016) Reservoir expansion by T-cell proliferation may be another barrier to curing HIV infection. Proc Natl Acad Sci U S A 113:1692–1694. doi:10.1073/pnas.1600097113
91. Kim YK, Mbonye U, Hokello J, Karn J (2011) T-cell receptor signaling enhances transcriptional elongation from latent HIV proviruses by activating P-TEFb through an ERK-dependent pathway. J Mol Biol 410:896–916. doi:10.1016/j.jmb.2011.03.054
92. Kiselinova M, Pasternak AO, De Spiegelaere W, Vogelaers D, Berkhout B, Vandekerckhove L (2014) Comparison of droplet digital PCR and seminested real-time PCR for quantification of cell-associated HIV-1 RNA. PLoS One 9:e85999. doi:10.1371/journal.pone.0085999
93. 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. doi:10.1186/1471-2199-8-63
94. 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. doi:10.1016/j.virol.2012.10.032
95. Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, Boyd MR, Pomerantz RJ (2001) Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 98:3006–3015
96. Kumar A, Darcis G, Van Lint C, Herbein G (2015) Epigenetic control of HIV-1 post integration latency: implications for therapy. Clinical Rpigenetics 7:103. doi:10.1186/s13148-015-0137-6
97. Lassen KG, Bailey JR, Siliciano RF (2004) Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J Virol 78:9105–9114. doi:10.1128/JVI.78.17.9105-9114.2004
98. Lassen KG, Ramyar KX, Bailey JR, Zhou Y, Siliciano RF (2006) Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog 2:e68. doi:10.1371/journal.ppat.0020068
99. Lassen KG, Hebbeler AM, Bhattacharyya D, Lobritz MA, Greene WC (2012) A flexible model of HIV-1 latency permitting evaluation of many primary CD4 T-cell reservoirs. PLoS One 7:e30176. doi:10.1371/journal.pone.0030176
100. Lavender KJ et al (2013) BLT-humanized C57BL/6 Rag2−/−gammac−/−CD47−/− mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood 122:4013–4020. doi:10.1182/blood-2013-06-506949
101. 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. doi:10.1074/jbc.M111.235077)
102. Levere RD, Gong YF, Kappas A, Bucher DJ, Wormser GP, Abraham NG (1991) Heme inhibits human immunodeficiency virus 1 replication in cell cultures and enhances the antiviral effect of zidovudine. Proc Natl Acad Sci U S A 88:1756–1759
103. Lewinski MK et al (2005) Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J Virol 79:6610–6619. doi:10.1128/JVI.79.11.6610-6619.2005
104. Lewinski MK et al (2006) Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog 2:e60. doi:10.1371/journal.ppat.0020060
105. Lewis MG et al (2011) Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS 25:1347–1356. doi:10.1097/QAD.0b013e328347bd77
106. Lorenzo-Redondo R et al (2016) Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530:51–56. doi:10.1038/nature16933
107. Lusic M, Marini B, Ali H, Lucic B, Luzzati R, Giacca M (2013) Proximity to PML nuclear bodies regulates HIV-1 latency in CD4+ T cells. Cell Host Microbe 13:665–677. doi:10.1016/j.chom.2013.05.006
108. Maldarelli F et al (2007) ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 3:e46. doi:10.1371/journal.ppat.0030046
109. Malhotra D, Fletcher AL, Turley SJ (2013) Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity. Immunol Rev 251:160–176. doi:10.1111/imr.12023
110. Marban C et al (2007) Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J 26:412–423. doi:10.1038/sj.emboj.7601516
111. Margolis DM, Salzwedel K, Chomont N, Psomas C, Routy JP, Poli G, Lafeuillade A (2016) Highlights from the seventh international workshop on HIV persistence during therapy, 8–11 December 2015, Miami, Florida, USA. Journal of Virus Eradication 2:57–65
112. Maricato JT et al (2015) Epigenetic modulations in activated cells early after HIV-1 infection and their possible functional consequences. PLoS One 10:e0119234. doi:10.1371/journal.pone.0119234
113. Marsden MD et al (2012) HIV latency in the humanized BLT mouse. J Virol 86:339–347. doi:10.1128/JVI.06366-11
114. Marsden MD et al (2015) Evaluation of HIV latency reversal using designed PKC modulators in humanized BLT mice. Journal of Virus Eradication 1:1
115. Massanella M, Richman DD (2016) Measuring the latent reservoir in vivo. J Clin Invest 126:464–472. doi:10.1172/JCI80567
116. Massanella M, Fromentin R, Chomont N (2016) Residual inflammation and viral reservoirs: alliance against an HIV cure current opinion in HIV and. AIDS 11:234–241. doi:10.1097/COH.0000000000000230
117. Matsuda Y, Kobayashi-Ishihara M, Fujikawa D, Ishida T, Watanabe T, Yamagishi M (2015) Epigenetic heterogeneity in HIV-1 latency establishment. Scientific Reports 5:7701. doi:10.1038/srep07701
118. Mbonye U, Karn J (2014) Transcriptional control of HIV latency: cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology 454–455:328–339. doi:10.1016/j.virol.2014.02.008
119. McKinstry KK, Strutt TM, Swain SL (2010) The potential of CD4 T-cell memory. Immunology 130:1–9. doi:10.1111/j.1365-2567.2010.03259.x
120. Mehla R et al (2010) Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One 5:e11160. doi:10.1371/journal.pone.0011160
121. Melkova Z, Bruckova M, Pitha PM (2000) The effect of nitric oxide on HIV-1 replication. Poster. First International Conference on Biology, Chemistry, and Therapeutic Applications of Nitric Oxide, San Francisco, USA
122. Melkova Z, Shankaran P, Hajkova V, Jilich D (2015a) Reactivation of latent HIV-1 by iron-mediated redox stressh. Cytokine 76:92. doi:10.1016/j.cyto.2015.08.166
123. Melkova Z, Shankaran P, Hajkova V, Jilich D, Fujikura Y (2015b) Effects of heme degradation products on reactivation of latent HIV-1. Journal of Virus Eradication 1 (Suppl. 1):42
124. Mendez-Lagares G, Jaramillo-Ruiz D, Pion M, Leal M, Munoz-Fernandez MA, Pacheco YM, Correa-Rocha R (2014) HIV infection deregulates the balance between regulatory T cells and IL-2-producing CD4 T cells by decreasing the expression of the IL-2 receptor in Treg. J Acquir Immune Defic Syndr 65:278–282. doi:10.1097/QAI.0000000000000092
125. Metcalf Pate KA et al (2015) A murine viral outgrowth assay to detect residual HIV type 1 in patients with undetectable viral loads. The Journal of Infectious Diseases 212:1387–1396. doi:10.1093/infdis/jiv230
126. Miles B et al (2015) Follicular regulatory T cells impair follicular T helper cells in HIV and SIV infection. Nat Commun 6:8608. doi:10.1038/ncomms9608
127. Modjarrad K, Vermund SH (2010) Effect of treating co-infections on HIV-1 viral load: a systematic review. Lancet Infect Dis 10:455–463. doi:10.1016/S1473-3099(10)70093-1
128. Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC (2014) IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343:428–432. doi:10.1126/science.1243640
129. Mottamal M, Zheng S, Huang TL, Wang G (2015) Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 20:3898–3941. doi:10.3390/molecules20033898
130. Mousseau G, Kessing CF, Fromentin R, Trautmann L, Chomont N, Valente ST (2015) The Tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from latency. MBio 6:e00465. doi:10.1128/mBio.00465-15
131. Murray JM et al (2014) HIV DNA subspecies persist in both activated and resting memory CD4+ T cells during antiretroviral therapy. J Virol 88:3516–3526. doi:10.1128/JVI.03331-13
132. Ndung’u T et al (2001) Infectious simian/human immunodeficiency virus with human immunodeficiency virus type 1 subtype C from an African isolate: rhesus macaque model. J Virol 75:11417–11425. doi:10.1128/JVI.75.23.11417-11425.2001
133. Omoto S et al (2004) HIV-1 nef suppression by virally encoded microRNA. Retrovirology 1:44. doi:10.1186/1742-4690-1-44
134. Ott M, Verdin E (2013) Three rules for HIV latency: location, location, and location. Cell Host Microbe 13:625–626. doi:10.1016/j.chom.2013.05.016
135. Pace GW, Leaf CD (1995) The role of oxidative stress in HIV disease. Free Radic Biol Med 19:523–528
136. Palmer S et al (2003) New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 41:4531–4536
137. Palmer S et al (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 105:3879–3884. doi:10.1073/pnas.0800050105
138. Pasternak AO, Adema KW, Bakker M, Jurriaans S, Berkhout B, Cornelissen M, Lukashov VV (2008) Highly sensitive methods based on seminested real-time reverse transcription-PCR for quantitation of human immunodeficiency virus type 1 unspliced and multiply spliced RNA and proviral DNA. J Clin Microbiol 46:2206–2211. doi:10.1128/JCM.00055-08
139. Pasternak AO, Lukashov VV, Berkhout B (2013) Cell-associated HIV RNA: a dynamic biomarker of viral persistence. Retrovirology 10:41. doi:10.1186/1742-4690-10-41
140. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD (1996) HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271:1582–1586
141. Perelson AS et al (1997) Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387:188–191. doi:10.1038/387188a0
142. Perkins ND, Edwards NL, Duckett CS, Agranoff AB, Schmid RM, Nabel GJ (1993) A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation. EMBO J 12:3551–3558
143. Ploquin MJ, Silvestri G, Muller-Trutwin M (2016) Immune activation in HIV infection: what can the natural hosts of simian immunodeficiency virus teach us? Current opinion in HIV and. AIDS 11:201–208. doi:10.1097/COH.0000000000000238
144. Policicchio BB, Pandrea I, Apetrei C (2016) Animal models for HIV cure research. Front Immunol 7:12. doi:10.3389/fimmu.2016.00012
145. Price DH (2000) P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol 20:2629–2634
146. Procopio FA et al (2015) A novel assay to measure the magnitude of the inducible viral reservoir in HIV-infected individuals. EBioMedicine 2:872–881. doi:10.1016/j.ebiom.2015.06.019
147. Pyo CW, Yang YL, Yoo NK, Choi SY (2008) Reactive oxygen species activate HIV long terminal repeat via post-translational control of NF-kappaB. Biochem Biophys Res Commun 376:180–185. doi:10.1016/j.bbrc.2008.08.114
148. Rasmussen TA et al (2013) Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Human Vaccines & Immunotherapeutics 9:993–1001. doi:10.4161/hv.23800
149. Rasmussen TA et al (2014) Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. The Lancet HIV 1:e13–e21. doi:10.1016/S2352-3018(14)70014-1
150. Romerio F, Zapata JC (2015) Detection and enrichment to near purity of rare HIV-1 infected cells by PrimeFlow RNA. Journal of Virus Eradication 1:5
151. Saison J et al (2014) Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients. Clin Exp Immunol 176:401–409. doi:10.1111/cei.12278
152. Saleh S, Solomon A, Wightman F, Xhilaga M, Cameron PU, Lewin SR (2007) CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency. Blood 110:4161–4164. doi:10.1182/blood-2007-06-097907
153. Sanchez G, Xu X, Chermann JC, Hirsch I (1997) Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J Virol 71:2233–2240
154. Schopman NC et al (2012) Deep sequencing of virus-infected cells reveals HIV-encoded small RNAs. Nucleic Acids Res 40:414–427. doi:10.1093/nar/gkr719
155. Schuetz A et al (2014) Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog 10:e1004543. doi:10.1371/journal.ppat.1004543
156. Serrao E, Engelman AN (2016) Sites of retroviral DNA integration: from basic research to clinical applications. Crit Rev Biochem Mol Biol 51:26–42. doi:10.3109/10409238.2015.1102859
157. Shan L, Siliciano RF (2013) From reactivation of latent HIV-1 to elimination of the latent reservoir: the presence of multiple barriers to viral eradication. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 35:544–552. doi:10.1002/bies.201200170
158. 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. doi:10.1128/JVI.02536-10
159. Shan L, Rabi SA, Laird GM, Eisele EE, Zhang H, Margolick JB, Siliciano RF (2013) A novel PCR assay for quantification of HIV-1 RNA. J Virol 87:6521–6525. doi:10.1128/JVI.00006-13
160. Shankaran P, Vlkova L, Liskova J, Melkova Z (2011) Heme arginate potentiates latent HIV-1 reactivation while inhibiting the acute infection. Antivir Res 92:434–446. doi:10.1016/j.antiviral.2011.09.011
161. Sharp PM, Hahn BH (2011) Origins of HIV and the AIDS pandemic. Cold Spring Harbor Perspectives in Medicine 1:a006841. doi:10.1101/cshperspect.a006841
162. Siliciano JD, Siliciano RF (2005) Enhanced culture assay for detection and quantitation of latently infected, resting CD4+ T-cells carrying replication-competent virus in HIV-1-infected individuals. Methods Mol Biol 304:3–15. doi:10.1385/1-59259-907-9:003
163. 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. doi:10.1038/nm880
164. Sloan DD et al (2015) Targeting HIV reservoir in infected CD4 T cells by dual-affinity re-targeting molecules (DARTs) that bind HIV envelope and recruit cytotoxic T cells. PLoS Pathog 11:e1005233. doi:10.1371/journal.ppat.1005233
165. Sogaard OS et al (2015) The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog 11:e1005142. doi:10.1371/journal.ppat.1005142
166. Soriano-Sarabia N et al (2015) Peripheral Vgamma9Vdelta2 T cells are a novel reservoir of latent HIV infection. PLoS Pathog 11:e1005201. doi:10.1371/journal.ppat.1005201
167. Spina CA et al (2013) An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog 9:e1003834. doi:10.1371/journal.ppat.1003834
168. Spivak AM et al (2014) A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America 58:883–890. doi:10.1093/cid/cit813
169. 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. doi:10.1371/journal.ppat.1000263
170. Tae S, Karkhanis V, Velasco K, Yaneva M, Erdjument-Bromage H, Tempst P, Sif S (2011) Bromodomain protein 7 interacts with PRMT5 and PRC2, and is involved in transcriptional repression of their target genes. Nucleic Acids Res 39:5424–5438. doi:10.1093/nar/gkr170
171. Thompson MR et al (2014) Interferon gamma-inducible protein (IFI) 16 transcriptionally regulates type i interferons and other interferon-stimulated genes and controls the interferon response to both DNA and RNA viruses. J Biol Chem 289:23568–23581. doi:10.1074/jbc.M114.554147
172. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG (2004) Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304:104–107. doi:10.1126/science.1093933
173. Tran TA et al (2008) Resting regulatory CD4 T cells: a site of HIV persistence in patients on long-term effective antiretroviral therapy. PLoS One 3:e3305. doi:10.1371/journal.pone.0003305
174. 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. Clinical Epigenetics 8. doi:10.1186/s13148-016-0185-6
175. Triboulet R et al (2007) Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 315:1579–1582. doi:10.1126/science.1136319
176. Tyagi M, Karn J (2007) CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J 26:4985–4995. doi:10.1038/sj.emboj.7601928
177. Tyagi M, Pearson RJ, Karn J (2010) Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J Virol 84:6425–6437. doi:10.1128/JVI.01519-09
178. Van Lint C, Bouchat S, Marcello A (2013) HIV-1 transcription and latency: an update. Retrovirology 10:67. doi:10.1186/1742-4690-10-67
179. 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
180. Vire E et al (2006) The polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874. doi:10.1038/nature04431
181. Wang L, de Zoeten EF, Greene MI, Hancock WW (2009) Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells. Nat Rev Drug Discov 8:969–981. doi:10.1038/nrd3031
182. Wang X, Cho B, Suzuki K, Xu Y, Green JA, An J, Cyster JG (2011) Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers. J Exp Med 208:2497–2510. doi:10.1084/jem.20111449
183. Wei X et al (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373:117–122. doi:10.1038/373117a0
184. Wei P, Garber ME, Fang SM, Fischer WH, Jones KA (1998) A novel CDK9-associated C-type cyclin interacts directly with HIV-1 tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 92:451–462
185. Weinberger LS (2015) A minimal fate-selection switch. Curr Opin Cell Biol 37:111–118. doi:10.1016/j.ceb.2015.10.005
186. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV (2005) Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell 122:169–182. doi:10.1016/j.cell.2005.06.006
187. Weinberger LS, Dar RD, Simpson ML (2008) Transient-mediated fate determination in a transcriptional circuit of HIV. Nat Genet 40:466–470. doi:10.1038/ng.116
188. Wightman F et al (2010) Both CD31(+) and CD31(−) naive CD4(+) T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. The Journal of Infectious Diseases 202:1738–1748. doi:10.1086/656721
189. Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC (2006) NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J 25:139–149. doi:10.1038/sj.emboj.7600900
190. Wires ES, Alvarez D, Dobrowolski C, Wang Y, Morales M, Karn J, Harvey BK (2012) Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells. Journal of Neurovirology 18:400–410. doi:10.1007/s13365-012-0103-4
191. Xing S et al (2011) Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation. J Virol 85:6060–6064. doi:10.1128/JVI.02033-10
192. Yamada T, Yamaguchi Y, Inukai N, Okamoto S, Mura T, Handa H (2006) P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation. Mol Cell 21:227–237. doi:10.1016/j.molcel.2005.11.024
193. Yang HC, Shen L, Siliciano RF, Pomerantz JL (2009a) Isolation of a cellular factor that can reactivate latent HIV-1 without T cell activation. Proc Natl Acad Sci U S A 106:6321–6326. doi:10.1073/pnas.0809536106
194. Yang HC et al (2009b) Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J Clin Invest 119:3473–3486. doi:10.1172/JCI39199
195. Yoh SM et al (2015) PQBP1 is a proximal sensor of the cGAS-dependent innate response to HIV-1. Cell 161:1293–1305. doi:10.1016/j.cell.2015.04.050
196. Zhang J, Scadden DT, Crumpacker CS (2007) Primitive hematopoietic cells resist HIV-1 infection via p21. J Clin Invest 117:473–481. doi:10.1172/JCI28971
197. 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