1932

Abstract

Human immunodeficiency virus (HIV) remains a significant source of morbidity and mortality worldwide. No effective vaccine is available to prevent HIV transmission, and although antiretroviral therapy can prevent disease progression, it does not cure HIV infection. Substantial effort is therefore currently directed toward basic research on HIV pathogenesis and persistence and developing methods to stop the spread of the HIV epidemic and cure those individuals already infected with HIV. Humanized mice are versatile tools for the study of HIV and its interaction with the human immune system. These models generally consist of immunodeficient mice transplanted with human cells or reconstituted with a near-complete human immune system. Here, we describe the major humanized mouse models currently in use, and some recent advances that have been made in HIV research/therapeutics using these models.

Keyword(s): AIDSBLTHIVhumanized micemodel
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2017-09-29
2024-04-17
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Literature Cited

  1. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT. 1.  et al. 1981. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N. Engl. J. Med. 305:1425–31 [Google Scholar]
  2. 2. UNAIDS. 2016. UNAIDS Fact Sheet November 2016. Global HIV Statistics. Geneva: UNAIDS http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf
  3. Marsden MD, Zack JA. 3.  2013. HIV/AIDS eradication. Bioorg. Med. Chem. Lett 234003–10 [Google Scholar]
  4. Gardner MB, Luciw PA. 4.  2008. Macaque models of human infectious disease. ILAR J 49:220–55 [Google Scholar]
  5. Hatziioannou T, Evans DT. 5.  2012. Animal models for HIV/AIDS research. Nat. Rev. Microbiol. 10:852–67 [Google Scholar]
  6. Morrow WJ, Wharton M, Lau D, Levy JA. 6.  1987. Small animals are not susceptible to human immunodeficiency virus infection. J. Gen. Virol. 68:Pt. 82253–57 [Google Scholar]
  7. Bieniasz PD, Cullen BR. 7.  2000. Multiple blocks to human immunodeficiency virus type 1 replication in rodent cells. J. Virol. 74:9868–77 [Google Scholar]
  8. Browning J, Horner JW, Pettoello-Mantovani M, Raker C, Yurasov S. 8.  et al. 1997. Mice transgenic for human CD4 and CCR5 are susceptible to HIV infection. PNAS 94:14637–41 [Google Scholar]
  9. Potash MJ, Chao W, Bentsman G, Paris N, Saini M. 9.  et al. 2005. A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness. PNAS 102:3760–65 [Google Scholar]
  10. Leonard JM, Abramczuk JW, Pezen DS, Rutledge R, Belcher JH. 10.  et al. 1988. Development of disease and virus recovery in transgenic mice containing HIV proviral DNA. Science 242:1665–70 [Google Scholar]
  11. Hanna Z, Kay DG, Rebai N, Guimond A, Jothy S, Jolicoeur P. 11.  1998. Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell 95:163–75 [Google Scholar]
  12. Marsden MD, Zack JA. 12.  2015. Studies of retroviral infection in humanized mice. Virology 479–80:297–309 [Google Scholar]
  13. Flanagan SP. 13.  1966. ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8:295–309 [Google Scholar]
  14. Bosma GC, Custer RP, Bosma MJ. 14.  1983. A severe combined immunodeficiency mutation in the mouse. Nature 301:527–30 [Google Scholar]
  15. Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T. 15.  1994. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372:103–7 [Google Scholar]
  16. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. 16.  1992. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68:869–77 [Google Scholar]
  17. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V. 17.  et al. 1992. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68:855–67 [Google Scholar]
  18. Murphy WJ, Kumar V, Bennett M. 18.  1987. Rejection of bone marrow allografts by mice with severe combined immune deficiency (SCID). Evidence that natural killer cells can mediate the specificity of marrow graft rejection. J. Exp. Med. 165:1212–17 [Google Scholar]
  19. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL. 19.  et al. 1995. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2:223–38 [Google Scholar]
  20. DiSanto JP, Muller W, Guy-Grand D, Fischer A, Rajewsky K. 20.  1995. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. PNAS 92:377–81 [Google Scholar]
  21. Ohbo K, Suda T, Hashiyama M, Mantani A, Ikebe M. 21.  et al. 1996. Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain. Blood 87:956–67 [Google Scholar]
  22. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL. 22.  et al. 2000. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191:771–80 [Google Scholar]
  23. Ranson T, Vosshenrich CA, Corcuff E, Richard O, Muller W, Di Santo JP. 23.  2003. IL-15 is an essential mediator of peripheral NK-cell homeostasis. Blood 101:4887–93 [Google Scholar]
  24. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. 24.  2012. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 12:786–98 [Google Scholar]
  25. Shultz LD, Ishikawa F, Greiner DL. 25.  2007. Humanized mice in translational biomedical research. Nat. Rev. Immunol. 7:118–30 [Google Scholar]
  26. Akkina R, Allam A, Balazs AB, Blankson JN, Burnett JC. 26.  et al. 2016. Improvements and limitations of humanized mouse models for HIV research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary. AIDS Res. Hum. Retrovir. 32:109–19 [Google Scholar]
  27. Greenblatt MB, Vrbanac V, Tivey T, Tsang K, Tager AM, Aliprantis AO. 27.  2012. Graft versus host disease in the bone marrow, liver and thymus humanized mouse model. PLOS ONE 7:e44664 [Google Scholar]
  28. Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP. 28.  2000. Role of CD47 as a marker of self on red blood cells. Science 288:2051–54 [Google Scholar]
  29. Legrand N, Huntington ND, Nagasawa M, Bakker AQ, Schotte R. 29.  et al. 2011. Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. PNAS 108:13224–29 [Google Scholar]
  30. Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S. 30.  et al. 2007. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat. Immunol. 8:1313–23 [Google Scholar]
  31. Blazar BR, Lindberg FP, Ingulli E, Panoskaltsis-Mortari A, Oldenborg PA. 31.  et al. 2001. CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells. J. Exp. Med. 194:541–49 [Google Scholar]
  32. Wang H, Madariaga ML, Wang S, Van Rooijen N, Oldenborg PA, Yang YG. 32.  2007. Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells. PNAS 104:13744–49 [Google Scholar]
  33. Lavender KJ, Pang WW, Messer RJ, Duley AK, Race B. 33.  et al. 2013. BLT-humanized C57BL/6 Rag2/γc/CD47/ mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. . Blood 1224013–20
  34. Brehm MA, Shultz LD, Luban J, Greiner DL. 34.  2013. Overcoming current limitations in humanized mouse research. J. Infect. Dis. 208:Suppl. 2S125–30 [Google Scholar]
  35. Mosier DE, Gulizia RJ, Baird SM, Wilson DB. 35.  1988. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335:256–59 [Google Scholar]
  36. King MA, Covassin L, Brehm MA, Racki W, Pearson T. 36.  et al. 2009. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin. Exp. Immunol. 157:104–18 [Google Scholar]
  37. Harui A, Kiertscher SM, Roth MD. 37.  2011. Reconstitution of huPBL-NSG mice with donor-matched dendritic cells enables antigen-specific T-cell activation. J. Neuroimmune Pharmacol. 6:148–57 [Google Scholar]
  38. Thomas T, Seay K, Zheng JH, Zhang C, Ochsenbauer C. 38.  et al. 2016. High-throughput humanized mouse models for evaluation of HIV-1 therapeutics and pathogenesis. Methods Mol. Biol. 1354:221–35 [Google Scholar]
  39. Hatano R, Ohnuma K, Yamamoto J, Dang NH, Yamada T, Morimoto C. 39.  2013. Prevention of acute graft-versus-host disease by humanized anti-CD26 monoclonal antibody. Br. J. Haematol. 162:263–77 [Google Scholar]
  40. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. 40.  1990. HIV-1 entry into quiescent primary lymphocytes: Molecular analysis reveals a labile, latent viral structure. Cell 61:213–22 [Google Scholar]
  41. Rizza P, Santini SM, Logozzi MA, Lapenta C, Sestili P. 41.  et al. 1996. T-cell dysfunctions in hu-PBL-SCID mice infected with human immunodeficiency virus (HIV) shortly after reconstitution: in vivo effects of HIV on highly activated human immune cells. J. Virol. 70:7958–64 [Google Scholar]
  42. McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL. 42.  1988. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 241:1632–39 [Google Scholar]
  43. Honeycutt JB, Wahl A, Archin N, Choudhary S, Margolis D, Garcia JV. 43.  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 [Google Scholar]
  44. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC. 44.  et al. 2004. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304:104–7 [Google Scholar]
  45. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T. 45.  et al. 2005. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice. Blood 106:1565–73 [Google Scholar]
  46. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW. 46.  et al. 2006. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat. Med. 12:1316–22 [Google Scholar]
  47. Lan P, Tonomura N, Shimizu A, Wang S, Yang YG. 47.  2006. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 108:487–92 [Google Scholar]
  48. Islas-Ohlmayer M, Padgett-Thomas A, Domiati-Saad R, Melkus MW, Cravens PD. 48.  et al. 2004. Experimental infection of NOD/SCID mice reconstituted with human CD34+ cells with Epstein-Barr virus. J. Virol. 78:13891–900 [Google Scholar]
  49. Honeycutt JB, Wahl A, Baker C, Spagnuolo RA, Foster J. 49.  et al. 2016. Macrophages sustain HIV replication in vivo independently of T cells. J. Clin. Investig. 126:1353–66 [Google Scholar]
  50. Osokine I, Snell LM, Cunningham CR, Yamada DH, Wilson EB. 50.  et al. 2014. Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection. PNAS 111:7409–14 [Google Scholar]
  51. Wilson EB, Yamada DH, Elsaesser H, Herskovitz J, Deng J. 51.  et al. 2013. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340:202–7 [Google Scholar]
  52. Ivashkiv LB, Donlin LT. 52.  2014. Regulation of type I interferon responses. Nat. Rev. Immunol. 14:36–49 [Google Scholar]
  53. MacMicking JD. 53.  2012. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat. Rev. Immunol. 12:367–82 [Google Scholar]
  54. Sandler NG, Bosinger SE, Estes JD, Zhu RT, Tharp GK. 54.  et al. 2014. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511:601–5 [Google Scholar]
  55. Teijaro JR, Ng C, Lee AM, Sullivan BM, Sheehan KC. 55.  et al. 2013. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340:207–11 [Google Scholar]
  56. Zhen A, Rezek V, Youn C, Lam B, Chang N. 56.  et al. 2017. Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. J. Clin. Investig. 127:260–68 [Google Scholar]
  57. Cheng L, Ma J, Li J, Li D, Li G. 57.  et al. 2017. Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. J. Clin. Investig. 127:269–79 [Google Scholar]
  58. Lavender KJ, Gibbert K, Peterson KE, Van Dis E, Francois S. 58.  et al. 2016. Interferon alpha subtype-specific suppression of HIV-1 infection in vivo. J. Virol. 90:6001–13 [Google Scholar]
  59. Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM. 59.  et al. 2013. Pegylated interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J. Infect. Dis. 207:213–22 [Google Scholar]
  60. Asmuth DM, Murphy RL, Rosenkranz SL, Lertora JJ, Kottilil S. 60.  et al. 2010. Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial. J. Infect. Dis. 201:1686–96 [Google Scholar]
  61. Abraham S, Choi JG, Ortega NM, Zhang J, Shankar P, Manjunath N. 61.  2016. Gene therapy with plasmids encoding IFN-β or IFN-α14 confers long-term resistance to HIV-1 in humanized mice. Oncotarget 7:78412–20 [Google Scholar]
  62. Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J. 62.  2010. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11:1005–13 [Google Scholar]
  63. Wheeler LA, Trifonova RT, Vrbanac V, Barteneva NS, Liu X. 63.  et al. 2016. TREX1 knockdown induces an interferon response to HIV that delays viral infection in humanized mice. Cell Rep 15:1715–27 [Google Scholar]
  64. Kawamoto A, Kodama E, Sarafianos SG, Sakagami Y, Kohgo S. 64.  et al. 2008. 2′-deoxy-4′-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants. Int. J. Biochem. Cell Biol. 40:2410–20 [Google Scholar]
  65. Sohl CD, Singh K, Kasiviswanathan R, Copeland WC, Mitsuya H. 65.  et al. 2012. Mechanism of interaction of human mitochondrial DNA polymerase gamma with the novel nucleoside reverse transcriptase inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine indicates a low potential for host toxicity. Antimicrob. Agents Chemother. 56:1630–34 [Google Scholar]
  66. Shanmugasundaram U, Kovarova M, Ho PT, Schramm N, Wahl A. 66.  et al. 2016. Efficient inhibition of HIV replication in the gastrointestinal and female reproductive tracts of humanized BLT mice by EFdA. PLOS ONE 11:e0159517 [Google Scholar]
  67. Stoddart CA, Galkina SA, Joshi P, Kosikova G, Moreno ME. 67.  et al. 2015. Oral administration of the nucleoside EFdA (4′-ethynyl-2-fluoro-2′-deoxyadenosine) provides rapid suppression of HIV viremia in humanized mice and favorable pharmacokinetic properties in mice and the rhesus macaque. Antimicrob. Agents Chemother. 59:4190–98 [Google Scholar]
  68. Veselinovic M, Yang KH, Sykes C, Remling-Mulder L, Kashuba AD, Akkina R. 68.  2016. Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: implications for HIV pre-exposure prophylaxis. Virology 489:173–78 [Google Scholar]
  69. Andrews CD, Heneine W. 69.  2015. Cabotegravir long-acting for HIV-1 prevention. Curr. Opin. HIV AIDS 10:258–63 [Google Scholar]
  70. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY. 70.  et al. 2010. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N. Engl. J. Med. 363:2587–99 [Google Scholar]
  71. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD. 71.  et al. 2012. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367:399–410 [Google Scholar]
  72. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE. 72.  et al. 2012. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N. Engl. J. Med. 367:423–34 [Google Scholar]
  73. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J. 73.  et al. 2012. Preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 367:411–22 [Google Scholar]
  74. Jackson AG, Else LJ, Mesquita PM, Egan D, Back DJ. 74.  et al. 2014. A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis. Clin. Pharmacol. Ther. 96:314–23 [Google Scholar]
  75. Kovarova M, Swanson MD, Sanchez RI, Baker CE, Steve J. 75.  et al. 2016. A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J. Antimicrob. Chemother. 71:1586–96 [Google Scholar]
  76. Simek MD, Rida W, Priddy FH, Pung P, Carrow E. 76.  et al. 2009. Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J. Virol. 83:7337–48 [Google Scholar]
  77. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. 77.  2003. Predominant autoantibody production by early human B cell precursors. Science 301:1374–77 [Google Scholar]
  78. Klein F, Mouquet H, Dosenovic P, Scheid JF, Scharf L, Nussenzweig MC. 78.  2013. Antibodies in HIV-1 vaccine development and therapy. Science 341:1199–204 [Google Scholar]
  79. Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF. 79.  et al. 2012. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492:118–22 [Google Scholar]
  80. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr. 80.  et al. 2015. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522:487–91 [Google Scholar]
  81. Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY. 81.  et al. 2013. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503:224–28 [Google Scholar]
  82. Igarashi T, Brown C, Azadegan A, Haigwood N, Dimitrov D. 82.  et al. 1999. Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell-free virions from blood plasma. Nat. Med. 5:211–16 [Google Scholar]
  83. Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J. 83.  et al. 2016. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530:51–56 [Google Scholar]
  84. Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S. 84.  et al. 2014. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158:989–99 [Google Scholar]
  85. Marsden MD, Zack JA. 85.  2014. Neutralizing the HIV reservoir. Cell 158:971–72 [Google Scholar]
  86. Bournazos S, Klein F, Pietzsch J, Seaman MS, Nussenzweig MC, Ravetch JV. 86.  2014. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158:1243–53 [Google Scholar]
  87. Lu CL, Murakowski DK, Bournazos S, Schoofs T, Sarkar D. 87.  et al. 2016. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352:1001–4 [Google Scholar]
  88. Veselinovic M, Neff CP, Mulder LR, Akkina R. 88.  2012. Topical gel formulation of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 confers protection against HIV-1 vaginal challenge in a humanized mouse model. Virology 432:505–10 [Google Scholar]
  89. Balazs AB, Ouyang Y, Hong CM, Chen J, Nguyen SM. 89.  et al. 2014. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat. Med. 20:296–300 [Google Scholar]
  90. Balazs AB, Chen J, Hong CM, Rao DS, Yang L, Baltimore D. 90.  2012. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481:81–84 [Google Scholar]
  91. Hur EM, Patel SN, Shimizu S, Rao DS, Gnanapragasam PN. 91.  et al. 2012. Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice. Blood 120:4571–82 [Google Scholar]
  92. Deruaz M, Moldt B, Le KM, Power KA, Vrbanac VD. 92.  et al. 2016. Protection of humanized mice from repeated intravaginal HIV challenge by passive immunization: a model for studying the efficacy of neutralizing antibodies in vivo. J. Infect. Dis. 214:612–16 [Google Scholar]
  93. Sung JA, Pickeral J, Liu L, Stanfield-Oakley SA, Lam CY. 93.  et al. 2015. Dual-affinity re-targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells. J. Clin. Investig. 125:4077–90 [Google Scholar]
  94. Pegu A, Asokan M, Wu L, Wang K, Hataye J. 94.  et al. 2015. Activation and lysis of human CD4 cells latently infected with HIV-1. Nat. Commun. 6:8447 [Google Scholar]
  95. Bournazos S, Gazumyan A, Seaman MS, Nussenzweig MC, Ravetch JV. 95.  2016. Bispecific anti-HIV-1 antibodies with enhanced breadth and potency. Cell 165:1609–20 [Google Scholar]
  96. Huang Y, Yu J, Lanzi A, Yao X, Andrews CD. 96.  et al. 2016. Engineered bispecific antibodies with exquisite HIV-1-neutralizing activity. Cell 165:1621–31 [Google Scholar]
  97. Gottlieb GS, Eholie SP, Nkengasong JN, Jallow S, Rowland-Jones S. 97.  et al. 2008. A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS 22:2069–72 [Google Scholar]
  98. Campbell-Yesufu OT, Gandhi RT. 98.  2011. Update on human immunodeficiency virus (HIV)-2 infection. Clin. Infect. Dis. 52:780–87 [Google Scholar]
  99. Hu S, Neff CP, Kumar DM, Habu Y, Akkina SR. 99.  et al. 2017. A humanized mouse model for HIV-2 infection and efficacy testing of a single-pill triple-drug combination anti-retroviral therapy. Virology 501:115–18 [Google Scholar]
  100. Yuan Z, Kang G, Ma F, Lu W, Fan W. 100.  et al. 2016. Recapitulating cross-species transmission of simian immunodeficiency virus SIVcpz to humans by using humanized BLT mice. J. Virol. 90:7728–39 [Google Scholar]
  101. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. 101.  1995. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–26 [Google Scholar]
  102. Anthony IC, Bell JE. 102.  2008. The neuropathology of HIV/AIDS. Int. Rev. Psychiatry 20:15–24 [Google Scholar]
  103. Calantone N, Wu F, Klase Z, Deleage C, Perkins M. 103.  et al. 2014. Tissue myeloid cells in SIV-infected primates acquire viral DNA through phagocytosis of infected T cells. Immunity 41:493–502 [Google Scholar]
  104. Baxter AE, Russell RA, Duncan CJ, Moore MD, Willberg CB. 104.  et al. 2014. Macrophage infection via selective capture of HIV-1-infected CD4+ T cells. Cell Host Microbe 16:711–21 [Google Scholar]
  105. Arainga M, Su H, Poluektova LY, Gorantla S, Gendelman HE. 105.  2016. HIV-1 cellular and tissue replication patterns in infected humanized mice. Sci. Rep. 6:23513 [Google Scholar]
  106. Honeycutt JB, Sheridan PA, Matsushima GK, Garcia JV. 106.  2014. Humanized mouse models for HIV-1 infection of the CNS. J. Neurovirol. 21:301–9 [Google Scholar]
  107. Law KM, Komarova NL, Yewdall AW, Lee RK, Herrera OL. 107.  et al. 2016. In vivo HIV-1 cell-to-cell transmission promotes multicopy micro-compartmentalized infection. Cell Rep 15:2771–83 [Google Scholar]
  108. Del Portillo A, Tripodi J, Najfeld V, Wodarz D, Levy DN, Chen BK. 108.  2011. Multiploid inheritance of HIV-1 during cell-to-cell infection. J. Virol. 85:7169–76 [Google Scholar]
  109. Marsden MD, Zack JA. 109.  2010. Establishment and maintenance of HIV latency: model systems and opportunities for intervention. Future Virol 5:97–109 [Google Scholar]
  110. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA. 110.  et al. 1997. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. PNAS 94:13193–97 [Google Scholar]
  111. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C. 111.  et al. 1997. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278:1295–300 [Google Scholar]
  112. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC. 112.  et al. 1997. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278:1291–95 [Google Scholar]
  113. Marsden MD, Zack JA. 113.  2015. Experimental approaches for eliminating latent HIV. For. Immunopathol. Dis. Ther. 6:91–99 [Google Scholar]
  114. Brooks DG, Kitchen SG, Kitchen CM, Scripture-Adams DD, Zack JA. 114.  2001. Generation of HIV latency during thymopoiesis. Nat. Med. 7:459–64 [Google Scholar]
  115. Korin YD, Brooks DG, Brown S, Korotzer A, Zack JA. 115.  2002. Effects of prostratin on T-cell activation and human immunodeficiency virus latency. J Virol 76:8118–23 [Google Scholar]
  116. Brooks DG, Hamer DH, Arlen PA, Gao L, Bristol G. 116.  et al. 2003. Molecular characterization, reactivation, and depletion of latent HIV. Immunity 19:413–23 [Google Scholar]
  117. Brooks DG, Arlen PA, Gao L, Kitchen CM, Zack JA. 117.  2003. Identification of T cell-signaling pathways that stimulate latent HIV in primary cells. PNAS 100:12955–60 [Google Scholar]
  118. Marsden MD, Kovochich M, Suree N, Shimizu S, Mehta R. 118.  et al. 2012. HIV latency in the humanized BLT mouse. J. Virol. 86:339–47 [Google Scholar]
  119. Denton PW, Olesen R, Choudhary SK, Archin NM, Wahl A. 119.  et al. 2012. Generation of HIV latency in humanized BLT mice. J. Virol. 86:630–34 [Google Scholar]
  120. Choudhary SK, Archin NM, Cheema M, Dahl NP, Garcia JV, Margolis DM. 120.  2012. Latent HIV-1 infection of resting CD4+ T cells in the humanized Rag2−/− γc−/− mouse. J. Virol. 86:114–20 [Google Scholar]
  121. Tsai P, Wu G, Baker CE, Thayer WO, Spagnuolo RA. 121.  et al. 2016. In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection. Retrovirology 13:36 [Google Scholar]
  122. Joshi P, Maidji E, Stoddart CA. 122.  2016. Inhibition of heat shock protein 90 prevents HIV rebound. J. Biol. Chem. 291:10332–46 [Google Scholar]
  123. Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB. 123.  et al. 2013. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155:540–51 [Google Scholar]
  124. Metcalf Pate KA, Pohlmeyer CW, Walker-Sperling VE, Foote JB, Najarro KM. 124.  et al. 2015. A murine viral outgrowth assay to detect residual HIV type 1 in patients with undetectable viral loads. J. Infect. Dis. 212:1387–96 [Google Scholar]
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  • Article Type: Review Article
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