Using animal models to overcome temporal, spatial and combinatorial challenges in HIV persistence research

Journal of Translational Medicine

Volumn 14, Issue 1, 2016, Pages

  Denton, Paul W ^a,b   Søgaard, Ole S ^a,b   Tolstrup, Martin ^a,b  

^a AARHUS UNIVERSITY   (Denmark)

^b AARHUS UNIVERSITY HOSPITAL   (Denmark)

Author keywords

HIV; Humanized mice; Latency; Non human primates; SHIV; SIV; Viral persistence

Indexed keywords

ANIMAL EXPERIMENT; ANIMAL MODEL; DISEASE MODEL; ERADICATION THERAPY; EXPERIMENTAL MODEL; HUMAN IMMUNODEFICIENCY VIRUS; MODEL; NONHUMAN; PUBLICATION; ANIMAL; COMBINATION DRUG THERAPY; HIV INFECTIONS; HUMAN; MEDICAL RESEARCH; PATHOLOGY; TIME FACTOR;

ANIMALS; BIOMEDICAL RESEARCH; DISEASE MODELS, ANIMAL; DRUG THERAPY, COMBINATION; HIV INFECTIONS; HUMANS; TIME FACTORS;

EID: 84968306824     PISSN: None     EISSN: 14795876     Source Type: Journal    
DOI: 10.1186/s12967-016-0807-y     Document Type: Review

References (135)

1. Chun TW, Fauci AS. HIV reservoirs: pathogenesis and obstacles to viral eradication and cure. AIDS. 2012;26:1261-8.
2. Josefsson L, Dahl V, Palmer S. Can HIV infection be eradicated through use of potent antiviral agents? Curr Opin Infect Dis. 2010;23:628-32.
3. Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Mascio MD, Katlama C, et al. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol. 2012;12:607-14.
4. Wightman F, Ellenberg P, Churchill M, Lewin SR. HDAC inhibitors in HIV. Immunol Cell Biol. 2012;90:47-54.
5. Katlama C, Deeks SG, Autran B, Martinez-Picado J, van Lunzen J, Rouzioux C, Miller M, Vella S, Schmitz JE, Ahlers J, et al. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013;381:2109-17.
6. Kent SJ, Reece JC, Petravic J, Martyushev A, Kramski M, De Rose R, Cooper DA, Kelleher AD, Emery S, Cameron PU, et al. The search for an HIV cure: tackling latent infection. Lancet Infect Dis. 2013;13:614-21.
7. Marsden MD, Zack JA. HIV/AIDS eradication. Bioorg Med Chem Lett. 2013;23:4003-10.
8. Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12:750-64.
9. Bruner KM, Hosmane NN, Siliciano RF. Towards an HIV-1 cure: measuring the latent reservoir. Trends Microbiol. 2015;23:192-203.
10. Chun TW, Moir S, Fauci AS. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat Immunol. 2015;16:584-9.
11. + T lymphocytes in vivo during the asymptomatic phase of infection. Retrovirology. 2012;9:12.
12. + T cells isolated from feline immunodeficiency virus-infected cats during the asymptomatic phase is not associated with hypermethylation of the proviral promoter. Virus Res. 2012;169:117-26.
13. Barber SA, Gama L, Dudaronek JM, Voelker T, Tarwater PM, Clements JE. Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model. J Infect Dis. 2006;193:963-70.
14. Shytaj IL, Chirullo B, Wagner W, Ferrari MG, Sgarbanti R, Corte AD, LaBranche C, Lopalco L, Palamara AT, Montefiori D, et al. Investigational treatment suspension and enhanced cell-mediated immunity at rebound followed by drug-free remission of simian AIDS. Retrovirology. 2013;10:71.
15. Shytaj IL, Nickel G, Arts E, Farrell N, Biffoni M, Pal R, Chung HK, LaBranche C, Montefiori D, Vargas-Inchaustegui D, et al. A two-year follow-up of macaques developing intermittent control of the HIV homolog SIVmac251 in the chronic phase of the infection. J Virol. 2015;89:7521-35.
16. Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J, Stephenson KE, Chang HW, Shekhar K, Gupta S, et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature. 2013;503:224-8.
17. Dinoso JB, Rabi SA, Blankson JN, Gama L, Mankowski JL, Siliciano RF, Zink MC, Clements JE. A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J Virol. 2009;83:9247-57.
18. Fukazawa Y, Lum R, Okoye AA, Park H, Matsuda K, Bae JY, Hagen SI, Shoemaker R, Deleage C, Lucero C, et al. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med. 2015;21:132-9.
19. Hansen SG, Piatak M Jr, Ventura AB, Hughes CM, Gilbride RM, Ford JC, Oswald K, Shoemaker R, Li Y, Lewis MS, et al. Immune clearance of highly pathogenic SIV infection. Nature. 2013;502:100-4.
20. Horiike M, Iwami S, Kodama M, Sato A, Watanabe Y, Yasui M, Ishida Y, Kobayashi T, Miura T, Igarashi T. Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy. Virology. 2012;423:107-18.
21. North TW, Higgins J, Deere JD, Hayes TL, Villalobos A, Adamson L, Shacklett BL, Schinazi RF, Luciw PA. Viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for AIDS. J Virol. 2010;84:2913-22.
22. Queen SE, Mears BM, Kelly KM, Dorsey JL, Liao Z, Dinoso JB, Gama L, Adams RJ, Zink MC, Clements JE, et al. Replication-competent simian immunodeficiency virus (SIV) Gag escape mutations archived in latent reservoirs during antiretroviral treatment of SIV-infected macaques. J Virol. 2011;85:9167-75.
23. + T lymphocytes but not thymocytes provide a latent viral reservoir in a simian immunodeficiency virus-Macaca nemestrina model of human immunodeficiency virus type 1-infected patients on highly active antiretroviral therapy. J Virol. 2003;77:4938-49.
24. Shen A, Yang HC, Zhou Y, Chase AJ, Boyer JD, Zhang H, Margolick JB, Zink MC, Clements JE, Siliciano RF. Novel pathway for induction of latent virus from resting CD4(+) T cells in the simian immunodeficiency virus/macaque model of human immunodeficiency virus type 1 latency. J Virol. 2007;81:1660-70.
25. Shytaj IL, Norelli S, Chirullo B, Della Corte A, Collins M, Yalley-Ogunro J, Greenhouse J, Iraci N, Acosta EP, Barreca ML, et al. A highly intensified ART regimen induces long-term viral suppression and restriction of the viral reservoir in a simian AIDS model. PLoS Pathog. 2012;8:e1002774.
26. Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, Parenteau L, Cabral C, Shields J, Blackmore S, et al. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature. 2014;512:74-7.
27. Zink MC, Brice AK, Kelly KM, Queen SE, Gama L, Li M, Adams RJ, Bartizal C, Varrone J, Rabi SA, et al. Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA. J Infect Dis. 2010;202:161-70.
28. Clements JE, Li M, Gama L, Bullock B, Carruth LM, Mankowski JL, Zink MC. The central nervous system is a viral reservoir in simian immunodeficiency virus-infected macaques on combined antiretroviral therapy: a model for human immunodeficiency virus patients on highly active antiretroviral therapy. J Neurovirol. 2005;11:180-9.
29. Deere JD, Kauffman RC, Cannavo E, Higgins J, Villalobos A, Adamson L, Schinazi RF, Luciw PA, North TW. Analysis of multiply spliced transcripts in lymphoid tissue reservoirs of rhesus macaques infected with RT-SHIV during HAART. PLoS One. 2014;9:e87914.
30. Okoye AA, Rohankhedkar M, Reyes M, Clock J, Duell D, Fukazawa Y, Lum R, Park H, Lifson JD, Picker LJ. Early treatment in acute SIV infection limits the size and distribution of the viral reservoir. 2014 conference on retroviruses and opportunistic infections. Boston: 2014. Paper 136LB.
31. Whitney JB, Lim S-Y, Osuna CE, S. S, Barnes TL, Hraber PT, Cihlar T, Geleziunas R, Hesselgesser J. Treatment with a TLR7 agonist induces transient viremia in SIV-Infected ART suppressed monkeys. 2015 CROI, Seattle: 2015. Paper 108.
32. North TW, Villalobos A, Hurwitz SJ, Deere JD, Higgins J, Chatterjee P, Tao S, Kauffman RC, Luciw PA, Kohler JJ, Schinazi RF. Enhanced antiretroviral therapy in rhesus macaques improves RT-SHIV viral decay kinetics. Antimicrob Agents Chemother. 2014;58:3927-33.
33. Matusali G, Dereuddre-Bosquet N, Le Tortorec A, Moreau M, Satie AP, Mahe D, Roumaud P, Bourry O, Sylla N, Bernard-Stoecklin S, et al. Detection of simian immunodeficiency virus in semen, urethra, and male reproductive organs during efficient highly active antiretroviral therapy. J Virol. 2015;89:5772-87.
34. Mavigner M, Watkins B, Lawson B, Lee ST, Chahroudi A, Kean L, Silvestri G. Persistence of virus reservoirs in ART-treated SHIV-infected rhesus macaques after autologous hematopoietic stem cell transplant. PLoS Pathog. 2014;10:e1004406.
35. Kline C, Ndjomou J, Franks T, Kiser R, Coalter V, Smedley J, Piatak M Jr, Mellors JW, Lifson JD, Ambrose Z. Persistence of viral reservoirs in multiple tissues after antiretroviral therapy suppression in a macaque RT-SHIV model. PLoS One. 2013;8:e84275.
36. Dunham RM, Gordon SN, Vaccari M, Piatak M, Huang Y, Deeks SG, Lifson J, Franchini G, McCune JM. Preclinical evaluation of HIV eradication strategies in the simian immunodeficiency virus-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenase. AIDS Res Hum Retroviruses. 2013;29:207-14.
37. Del Prete GQ, Shoemaker R, Oswald K, Lara A, Trubey CM, Fast R, Schneider DK, Kiser R, Coalter V, Wiles A, et al. Effect of suberoylanilide hydroxamic acid (SAHA) administration on the residual virus pool in a model of combination antiretroviral therapy-mediated suppression in SIVmac239-infected indian rhesus macaques. Antimicrob Agents Chemother. 2014;58:6790-806.
38. Ling B, Piatak M Jr, Rogers L, Johnson AM, Russell-Lodrigue K, Hazuda DJ, Lifson JD, Veazey RS. 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. 2014;9:e102795.
39. Bourry O, Mannioui A, Sellier P, Roucairol C, Durand-Gasselin L, Dereuddre-Bosquet N, Benech H, Roques P, Le Grand R. Effect of a short-term HAART on SIV load in macaque tissues is dependent on time of initiation and antiviral diffusion. Retrovirology. 2010;7:78.
40. ++ monocytes but does not alter the tissue virus reservoir. AIDS Res Hum Retroviruses. 2015;31:115-26.
41. Santangelo PJ, Rogers KA, Zurla C, Blanchard EL, Gumber S, Strait K, Connor-Stroud F, Schuster DM, Amancha PK, Hong JJ, et al. Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nat Methods. 2015;12:427-32.
42. + T cell epitope recognition paradigms. Science. 2013;340:1237874.
43. Sharp PM, Hahn BH. Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med. 2011;1:a006841.
44. Akkina R. New generation humanized mice for virus research: comparative aspects and future prospects. Virology. 2013;435:14-28.
45. Berges BK, Rowan MR. The utility of the new generation of humanized mice to study HIV-1 infection: transmission, prevention, pathogenesis, and treatment. Retrovirology. 2011;8:65.
46. Denton PW, Garcia JV. Humanized mouse models of HIV infection. AIDS Rev. 2011;13:135-48.
47. Ito R, Takahashi T, Katano I, Ito M. Current advances in humanized mouse models. Cell Mol Immunol. 2012;9:208-14.
48. King M, Pearson T, Rossini AA, Shultz LD, Greiner DL. Humanized mice for the study of type 1 diabetes and beta cell function. Ann N Y Acad Sci. 2008;1150:46-53.
49. Koo GC, Hasan A, O'Reilly RJ. Use of humanized severe combined immunodeficient mice for human vaccine development. Expert Rev Vaccines. 2009;8:113-20.
50. Legrand N, Ploss A, Balling R, Becker PD, Borsotti C, Brezillon N, Debarry J, de Jong Y, Deng H, Di Santo JP, et al. Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe. 2009;6:5-9.
51. Nischang M, Gers-Huber G, Audiga A, Akkina R, Speck R. Modeling HIV infection and therapies in humanized mice. Swiss Med Wkly. 2012;142:w13618.
52. Olesen R, Wahl A, Denton PW, Victor Garcia J. Immune reconstitution of the female reproductive tract of humanized BLT mice and their susceptibility to human immunodeficiency virus infection. J Reprod Immunol. 2011;88:195-203.
53. Seung E, Tager AM. Humoral immunity in humanized mice: a work in progress. J Infect Dis. 2013;208(Suppl 2):S155-9.
54. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12:786-98.
55. Yoshizato K, Tateno C. In vivo modeling of human liver for pharmacological study using humanized mouse. Expert Opin Drug Metab Toxicol. 2009;5:1435-46.
56. Zhang L, Meissner E, Chen J, Su L. Current humanized mouse models for studying human immunology and HIV-1 immuno-pathogenesis. Sci China Life Sci. 2010;53:195-203.
57. Zhou XL, Sullivan GJ, Sun P, Park IH. Humanized murine model for HBV and HCV using human induced pluripotent stem cells. Arch Pharm Res. 2012;35:261-9.
58. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7:118-30.
59. Denton PW, Nochi T, Lim A, Krisko JF, Martinez-Torres F, Choudhary SK, Wahl A, Olesen R, Zou W, Di Santo JP, et al. IL-2 receptor gamma-chain molecule is critical for intestinal T-cell reconstitution in humanized mice. Mucosal Immunol. 2012;5:555-66.
60. Nochi T, Denton PW, Wahl A, Garcia JV. Cryptopatches are essential for the development of human GALT. Cell Rep. 2013;3:1874-84.
61. Brooks DG, Kitchen SG, Kitchen CM, Scripture-Adams DD, Zack JA. Generation of HIV latency during thymopoiesis. Nat Med. 2001;7:459-64.
62. Brooks DG, Zack JA. Effect of latent human immunodeficiency virus infection on cell surface phenotype. J Virol. 2002;76:1673-81.
63. Brooks DG, Hamer DH, Arlen PA, Gao L, Bristol G, Kitchen CM, Berger EA, Zack JA. Molecular characterization, reactivation, and depletion of latent HIV. Immunity. 2003;19:413-23.
64. Brooks DG, Arlen PA, Gao L, Kitchen CM, Zack JA. Identification of T cell-signaling pathways that stimulate latent HIV in primary cells. Proc Natl Acad Sci USA. 2003;100:12955-60.
65. Choudhary SK, Archin NM, Cheema M, Dahl NP, Garcia JV, Margolis DM. Latent HIV-1 infection of resting CD4(+) T cells in the humanized Rag2(-)/(-) gammac(-)/(-) mouse. J Virol. 2012;86:114-20.
66. Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015;517:381-5.
67. Denton PW, Olesen R, Choudhary SK, Archin NM, Wahl A, Swanson MD, Chateau M, Nochi T, Krisko JF, Spagnuola RA, et al. Generation of HIV latency in BLT humanized mice. J Virol. 2012;86:630-4.
68. Denton PW, Long JM, Wietgrefe SW, Sykes C, Spagnuolo RA, Snyder OD, Perkey K, Archin NM, Choudhary SK, Yang K, et al. Targeted cytotoxic therapy kills persisting HIV infected cells during ART. PLoS Pathog. 2014;10:e1003872.
69. Honeycutt JB, Wahl A, Archin N, Choudhary S, Margolis D, Garcia JV. HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model. Retrovirology. 2013;10:121.
70. Korin YD, Brooks DG, Brown S, Korotzer A, Zack JA. Effects of prostratin on T-cell activation and human immunodeficiency virus latency. J Virol. 2002;76:8118-23.
71. Marsden MD, Kovochich M, Suree N, Shimizu S, Mehta R, Cortado R, Bristol G, An DS, Zack JA. HIV latency in the humanized BLT mouse. J Virol. 2012;86:339-47.
72. Scripture-Adams DD, Brooks DG, Korin YD, Zack JA. Interleukin-7 induces expression of latent human immunodeficiency virus type 1 with minimal effects on T-cell phenotype. J Virol. 2002;76:13077-82.
73. Bournazos S, Klein F, Pietzsch J, Seaman MS, Nussenzweig MC, Ravetch JV. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell. 2014;158:1243-53.
74. Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S, Nogueira L, Eisenreich TR, Liu C, Gazumyan A, Schaefer U, et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell. 2014;158:989-99.
75. Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, Tretiakova A, Eisenreich TR, Malbec M, Gravemann S, Billerbeck E, Dorner M, et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci USA. 2013;110:16538-43.
76. Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S, Mouquet H, Spatz LA, Diskin R, Abadir A, et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature. 2012;492:118-22.
77. Honeycutt JB, Wahl A, Foster JL, Spagnuolo RA, Garcia JV. In vivo analysis of HIV replication and persistence in the myeloid compartment. In Towards an HIV Cure Symposium. Melbourne: 2014.
78. Nixon CC, Vatakis DN, Reichelderfer SN, Dixit D, Kim SG, Uittenbogaart CH, Zack JA. HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice. Blood. 2013;122:2195-204.
79. Carter CC, McNamara LA, Onafuwa-Nuga A, Shackleton M, Riddell J 4th, Bixby D, Savona MR, Morrison SJ, Collins KL. HIV-1 utilizes the CXCR4 chemokine receptor to infect multipotent hematopoietic stem and progenitor cells. Cell Host Microbe. 2011; 9:223-34.
80. Li Q, Tso FY, Kang G, Lu W, Li Y, Fan W, Yuan Z, Destache CJ, Wood C. Early initiation of antiretroviral therapy can functionally control productive HIV-1 infection in humanized-BLT mice. J Acquir Immune Defic Syndr. 2015;69:519-27.
81. Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, Crooks GM, Kohn DB, Gregory PD, Holmes MC, Cannon PM. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010;28:839-47.
82. Kitchen SG, Levin BR, Bristol G, Rezek V, Kim S, Aguilera-Sandoval C, Balamurugan A, Yang OO, Zack JA. In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells. PLoS Pathog. 2012;8:e1002649.
83. Shimizu S, Ringpis GE, Marsden MD, Cortado RV, Wilhalme HM, Elashoff D, Zack JA, Chen IS, An DS. RNAi-mediated CCR5 knockdown provides HIV-1 resistance to memory T cells in humanized BLT mice. Mol Ther Nucleic Acids. 2015;4:e227.
84. Neff CP, Zhou J, Remling L, Kuruvilla J, Zhang J, Li H, Smith DD, Swiderski P, Rossi JJ, Akkina R. An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. Sci Transl Med. 2011;3:66ra66.
85. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H, et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA. 2008;105:7552-7.
86. Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L, Heldebrant C, Smith R, Conrad A, Kleinman SH, Busch MP. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS. 2003;17:1871-9.
87. Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M Jr, Chun TW, Strain M, Richman D, Luzuriaga K. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013;369:1828-35.
88. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997;387:183-8.
89. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278:1295-300.
90. + T cells in acute human immunodeficiency virus type 1 infection. J Infect Dis. 2000;182:1636-42.
91. Siliciano JD, Lai J, Callender M, Pitt E, Zhang H, Margolick JB, Gallant JE, Cofrancesco J Jr, Moore RD, Gange SJ, Siliciano RF. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J Infect Dis. 2007;195:833-6.
92. Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, Bosch RJ, Lai J, Chioma S, Emad F, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 2013;9:e1003174.
93. Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, Lai J, Blankson JN, Siliciano JD, Siliciano RF. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013;155:540-51.
94. Laird GM, Eisele EE, Rabi SA, Lai J, Chioma S, Blankson JN, Siliciano JD, Siliciano RF. Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS Pathog. 2013;9:e1003398.
95. + T cells. AIDS. 2008;22:1131-5.
96. + cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci USA. 2012;109:9523-8.
97. Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005;366:549-55.
98. Chun TW, Justement JS, Murray D, Hallahan CW, Maenza J, Collier AC, Sheth PM, Kaul R, Ostrowski M, Moir S, et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS. 2010;24:2803-8.
99. Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M, Rainwater-Lovett K, Mellors JW, Rosenbloom D, Persaud D. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med. 2015;372:786-8.
100. Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, Robles YP, Davis BT, Li JZ, Heisey A, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161:319-27.
101. Rosenbloom DIS, Elliott O, Hill AL, Henrich TJ, Siliciano JM, Siliciano RF. Designing and interpreting limiting dilution assays: general principles and applications to the latent reservoir for HIV-1. Open Forum Infect Dis. 2015;2:ofv123.
102. + T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5:512-7.
103. Chun TW. Tracking replication-competent HIV reservoirs in infected individuals. Curr Opin HIV AIDS. 2013;8:111-6.
104. Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487:482-5.
105. Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014;20:425-9.
106. Fletcher CV, Staskus K, Wietgrefe SW, Rothenberger M, Reilly C, Chipman JG, Beilman GJ, Khoruts A, Thorkelson A, Schmidt TE, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci USA. 2014;111:2307-12.
107. + adults. PLoS One. 2015;10:e0121290.
108. Greiner DL, Shultz LD, Yates J, Appel MC, Perdrizet G, Hesselton RM, Schweitzer I, Beamer WG, Shultz KL, Pelsue SC, et al. Improved engraftment of human spleen cells in NOD/LtSz-scid/scid mice as compared with C.B-17-scid/scid mice. Am J Pathol. 1995;146:888-902.
109. + hematopoietic progenitors. Blood. 2003;102:3302-10.
110. + hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. 2012;205:1014-8.
111. + T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200:749-59.
112. + T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels. Mucosal Immunol. 2010;3:172-81.
113. + T cells. Nature. 2005;434:1148-52.
114. + T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med. 2004;200:761-70.
115. + 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. 2003;77:11708-17.
116. + T cells in multiple tissues during acute SIV infection. Nature. 2005;434:1093-7.
117. Lerner P, Guadalupe M, Donovan R, Hung J, Flamm J, Prindiville T, Sankaran-Walters S, Syvanen M, Wong JK, George MD, Dandekar S. The gut mucosal viral reservoir in HIV-infected patients is not the major source of rebound plasma viremia following interruption of highly active antiretroviral therapy. J Virol. 2011;85:4772-82.
118. van Marle G, Gill MJ, Kolodka D, McManus L, Grant T, Church DL. Compartmentalization of the gut viral reservoir in HIV-1 infected patients. Retrovirology. 2007;4:87.
119. Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, Choi AL, Girling V, Ho T, Li P, et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis. 2010;202:1553-61.
120. Yukl SA, Shergill AK, McQuaid K, Gianella S, Lampiris H, Hare CB, Pandori M, Sinclair E, Gunthard HF, Fischer M, et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS. 2010;24:2451-60.
121. Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, Kottilil S, Moir S, Mican JM, Mullins JI, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197:714-20.
122. Anton PA, Mitsuyasu RT, Deeks SG, Scadden DT, Wagner B, Huang C, Macken C, Richman DD, Christopherson C, Borellini F, et al. Multiple measures of HIV burden in blood and tissue are correlated with each other but not with clinical parameters in aviremic subjects. AIDS. 2003;17:53-63.
123. Chege D, Sheth PM, Kain T, Kim CJ, Kovacs C, Loutfy M, Halpenny R, Kandel G, Chun TW, Ostrowski M, Kaul R. Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy. AIDS. 2011;25:741-9.
124. Evering TH, Mehandru S, Racz P, Tenner-Racz K, Poles MA, Figueroa A, Mohri H, Markowitz M. Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection. PLoS Pathog. 2012;8:e1002506.
125. Nakagawa F, May M, Phillips A. Life expectancy living with HIV: recent estimates and future implications. Curr Opin Infect Dis. 2013;26:17-25.
126. Geeraert L, Kraus G, Pomerantz RJ. Hide-and-seek: the challenge of viral persistence in HIV-1 infection. Annu Rev Med. 2008;59:487-501.
127. + T cell reservoir for HIV-1 in the setting of HAART. BMC Infect Dis. 2008;8:2.
128. Williams SA, Greene WC. Regulation of HIV-1 latency by T-cell activation. Cytokine. 2007;39:63-74.
129. Deeks SG. HIV: shock and kill. Nature. 2012;487:439-40.
130. Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10:e1004473.
131. Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, Winckelmann A, Palmer S, Dinarello C, Buzon M, et al. 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. Lancet HIV. 2014;1:e13-21.
132. Søgaard O, Graversen M, Leth S, Brinkmann C, Kjær A-S, Olesen R, Denton P, Nissen S, Sommerfelt M, Rasmussen T, et al. The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays. In 20th International AIDS Conference (AIDS 2014). Melbourne: 2014.
133. + T cells after multiple doses of vorinostat. J Infect Dis. 2014;210:728-35.
134. Berger EA, Pastan I. Immunotoxin complementation of HAART to deplete persisting HIV-infected cell reservoirs. PLoS Pathog. 2010;6:e1000803.
135. Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, Meyerowitz J, Willberg C, Koelsch KK, Robinson N, et al. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nat Commun. 2015;6:8495.