A cure for AIDS: a matter of timing?

Retrovirology

Andrea Savarino¹  Iart Luca Shytaj¹ 

[1] Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome 00161, Italy

关键词: BSO;    Auranofin;    Therapeutic vaccine;    Vorinostat;    Stem cell transplantation;    Acute HIV infection;    Reservoirs;    Functional cure;    Eradication;   

Others  :  806046
DOI  :  10.1186/1742-4690-10-145

 received in 2013-10-13, accepted in 2013-11-12,  发布年份 2013

【 摘 要 】

Despite the huge clinical success of antiretroviral therapy, several factors such as side effects, requirement of life-long adherence, high cost, incomplete access to therapies and development of drug resistance make the quest for an ultimate cure of HIV/AIDS a worldwide priority of biomedical research. In this respect, several sterilizing or functional cures have been reported in the last years in both non-human primates and humans. This review provides a summary of the main results achieved so far, outlining their strengths as well as their limitations. A synthetic interpretation of these results could be pivotal in order to develop an effective and widely available cure.

【 授权许可】

   
2013 Shytaj and Savarino; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Margolis DM: Eradication therapies for HIV infection: time to begin again. AIDS Res Hum Retroviruses 2011, 27(4):347-353. doi: 10.1089/aid.2011.0017. Review
• [2]Trono D, Van Lint C, Rouzioux C, Verdin E, Barré-Sinoussi F, Chun TW, Chomont N: HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 2010, 329(5988):174-180. doi: 10.1126/science.1191047. Review
• [3]Kahn JO, Walker BD: Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998, 339(1):33-39. Review
• [4]Pantaleo G, Fauci AS: Immunopathogenesis of HIV infection. Annu Rev Microbiol 1996, 50:825-854. Review
• [5]Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF: Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997, 278(5341):1295-1300.
• [6]Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF: Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999, 5(5):512-517.
• [7]Migueles SA, Weeks KA, Nou E, Berkley AM, Rood JE, Osborne CM, Hallahan CW, Cogliano-Shutta NA, Metcalf JA, McLaughlin M, Kwan R, Mican JM, Davey RT Jr, Connors M: Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol 2009, 83(22):11876-11889. doi: 10.1128/JVI.01153-09
• [8]Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS: Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A 1998, 95(15):8869-8873.
• [9]Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF: Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003, 9(6):727-728.
• [10]Donahue DA, Wainberg MA: Cellular and molecular mechanisms involved in the establishment of HIV-1 latency. Retrovirology 2013, 10:11. doi: 10.1186/1742-4690-10-11. Review BioMed Central Full Text
• [11]Blankson JN, Persaud D, Siliciano RF: The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med 2002, 53:557-593. Review
• [12]Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sékaly RP: HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 2009, 15(8):893-900. doi: 10.1038/nm.1972
• [13]Koppensteiner H, Brack-Werner R, Schindler M: Macrophages and their relevance in human immunodeficiency virus type I infection. Retrovirology 2012, 9:82. doi: 10.1186/1742-4690-9-82 BioMed Central Full Text
• [14]Perelman P, Johnson WE, Roos C, Seuánez HN, Horvath JE, Moreira MA, Kessing B, Pontius J, Roelke M, Rumpler Y, Schneider MP, Silva A, O’Brien SJ, Pecon-Slattery J: A molecular phylogeny of living primates. PLoS Genet 2011, 7(3):e1001342. doi: 10.1371/journal.pgen.1001342
• [15]Del Prete GQ, Lifson JD: Considerations in the development of nonhuman primate models of combination antiretroviral therapy for studies of AIDS virus suppression, residual virus, and curative strategies. Curr Opin HIV AIDS 2013, 8(4):262-272. doi: 10.1097/COH.0b013e328361cf40
• [16]Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, Siliciano R, Walker B, Lori F: Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999, 340(21):1683-1684.
• [17]Vila J, Nugier F, Barguès G, Vallet T, Peyramond D, Hamedi-Sangsari F, Seigneurin JM: Absence of viral rebound after treatment of HIV-infected patients with didanosine and hydroxycarbamide. Lancet 1997, 350(9078):635-636.
• [18]Lori F, Lewis MG, Xu J, Varga G, Zinn DE Jr, Crabbs C, Wagner W, Greenhouse J, Silvera P, Yalley-Ogunro J, Tinelli C, Lisziewicz J: Control of SIV rebound through structured treatment interruptions during early infection. Science 2000, 290(5496):1591-1593.
• [19]Lori F, Lisziewicz J: Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug. Clin Infect Dis 2000, 30(Suppl 2):S193-S197. Review
• [20]Longhurst HJ, Pinching AJ: Drug points: pancreatitis associated with hydroxyurea in combination with didanosine. BMJ 2001, 322(7278):81.
• [21]Weissman SB, Sinclair GI, Green CL, Fissell WH: Hydroxyurea-induced hepatitis in human immunodeficiency virus-positive patients. Clin Infect Dis 1999, 29(1):223-224.
• [22]Lori F, De Forni D, Katabira E, Baev D, Maserati R, Calarota SA, Cahn P, Testori M, Rakhmanova A, Stevens MR: VS411 reduced immune activation and HIV-1 RNA levels in 28 days: randomized proof-of-concept study for antiviral-hyperactivation limiting therapeutics. PLoS One 2012, 7(10):e47485. doi: 10.1371/journal.pone.0047485
• [23]Van Rompay KK, Trott KA, Jayashankar K, Geng Y, LaBranche CC, Johnson JA, Landucci G, Lipscomb J, Tarara RP, Canfield DR, Heneine W, Forthal DN, Montefiori D, Abel K: Prolonged tenofovir treatment of macaques infected with K65R reverse transcriptase mutants of SIV results in the development of antiviral immune responses that control virus replication after drug withdrawal. Retrovirology 2012, 9:57. doi: 10.1186/1742-4690-9-57 BioMed Central Full Text
• [24]Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, Robbins GK, D’Aquila RT, Goulder PJ, Walker BD: Immune control of HIV-1 after early treatment of acute infection. Nature 2000, 407(6803):523-526.
• [25]Lampe FC, Porter K, Kaldor J, Law M, Kinloch-de Loes S, Phillips AN, CASCADE Collaboration: Effect of transient antiretroviral treatment during acute HIV infection: comparison of the quest trial results with CASCADE natural history study. Antivir Ther 2007, 12(2):189-193.
• [26]Volberding P, Demeter L, Bosch RJ, Aga E, Pettinelli C, Hirsch M, Vogler M, Martinez A, Little S, Connick E, ACTG 371 Team: Antiretroviral therapy in acute and recent HIV infection: a prospective multicenter stratified trial of intentionally interrupted treatment. AIDS 2009, 23(15):1987-1995. doi: 10.1097/QAD.0b013e32832eb285
• [27]Hocqueloux L, Prazuck T, Avettand-Fenoel V, Lafeuillade A, Cardon B, Viard JP, Rouzioux C: Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 2010, 24(10):1598-1601.
• [28]Lodi S, Meyer L, Kelleher AD, Rosinska M, Ghosn J, Sannes M, Porter K: Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Arch Intern Med 2012, 172(16):1252-1255. doi: 10.1001/archinternmed.2012.2719
• [29]Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard JP, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C: Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog 2013, 9(3):e1003211. doi: 10.1371/journal.ppat.1003211
• [30]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(19):1828-1835. doi: 10.1056/NEJMoa1302976
• [31]Desquilbet L, Goujard C, Rouzioux C, Sinet M, Deveau C, Chaix ML, Séréni D, Boufassa F, Delfraissy JF, Meyer L, PRIMO and SEROCO Study Groups: Does transient HAART during primary HIV-1 infection lower the virological set-point? AIDS 2004, 18(18):2361-2369.
• [32]Streeck H, Jessen H, Alter G, Teigen N, Waring MT, Jessen A, Stahmer I, van Lunzen J, Lichterfeld M, Gao X, Allen TM, Carrington M, Walker BD, Rockstroh JK, Altfeld M: Immunological and virological impact of highly active antiretroviral therapy initiated during acute HIV-1 infection. J Infect Dis 2006, 194(6):734-739.
• [33]Pantazis N, Touloumi G, Vanhems P, Gill J, Bucher HC, Porter K, CASCADE Collaboration: The effect of antiretroviral treatment of different durations in primary HIV infection. AIDS 2008, 22(18):2441-2450. doi: 10.1097/QAD.0b013e328319ea4e
• [34]Oxenius A, Price DA, Easterbrook PJ, O’Callaghan CA, Kelleher AD, Whelan JA, Sontag G, Sewell AK, Phillips RE: Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A 2000, 97(7):3382-3387.
• [35]Moir S, Buckner CM, Ho J, Wang W, Chen J, Waldner AJ, Posada JG, Kardava L, O’Shea MA, Kottilil S, Chun TW, Proschan MA, Fauci AS: B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy. Blood 2010, 116(25):5571-5579. doi: 10.1182/blood-2010-05-285528
• [36]Ngo-Giang-Huong N, Deveau C, Da Silva I, Pellegrin I, Venet A, Harzic M, Sinet M, Delfraissy JF, Meyer L, Goujard C, Rouzioux C, French PRIMO Cohort Study Group: Proviral HIV-1 DNA in subjects followed since primary HIV-1 infection who suppress plasma viral load after one year of highly active antiretroviral therapy. AIDS 2001, 15(6):665-673.
• [37]Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, Cohen MS, Coffin JM, Bosch RJ, Gay CL, Eron JJ, Margolis DM, Perelson AS: Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A 2012, 109(24):9523-9528. doi: 10.1073/pnas.1120248109
• [38]Jain V, Hartogensis W, Bacchetti P, Hunt PW, Hatano H, Sinclair E, Epling L, Lee TH, Busch MP, McCune JM, Pilcher CD, Hecht FM, Deeks SG: Antiretroviral therapy initiated within Six months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. J Infect Dis 2013, 208(8):1202-1211. doi: 10.1093/infdis/jit311
• [39]Chun TW, Justement JS, Murray D, Hallahan CW, Maenza J, Collier AC, Sheth PM, Kaul R, Ostrowski M, Moir S, Kovacs C, Fauci AS: Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS 2010, 24(18):2803-2808. doi: 10.1097/QAD.0b013e328340a239
• [40]Dybul M, Nies-Kraske E, Daucher M, Hertogs K, Hallahan CW, Csako G, Yoder C, Ehler L, Sklar PA, Belson M, Hidalgo B, Metcalf JA, Davey RT, Rock Kress DM, Powers A, Fauci AS: Long-cycle structured intermittent versus continuous highly active antiretroviral therapy for the treatment of chronic infection with human immunodeficiency virus: effects on drug toxicity and on immunologic and virologic parameters. J Infect Dis 2003, 188(3):388-396.
• [41]Alexander TH, Ortiz GM, Wellons MF, Allen A, Grace EJ 2nd, Schweighardt B, Brancato J, Sandberg JK, Furlan SN, Miralles GD, Nixon DF, Bartlett JA: Changes in CD4+ T-cell differentiation phenotype during structured treatment interruption in patients with chronic HIV-1 infection. J Acquir Immune Defic Syndr 2003, 34(5):475-481.
• [42]Papasavvas E, Kostman JR, Mounzer K, Grant RM, Gross R, Gallo C, Azzoni L, Foulkes A, Thiel B, Pistilli M, Mackiewicz A, Shull J, Montaner LJ: Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. PLoS Med 2004, 1(3):e64.
• [43]Pai NP, Tulsky JP, Lawrence J, Colford JM Jr, Reingold AL: Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults. Cochrane Database Syst Rev 2005, 2005(4):CD005482. Review
• [44]Hamer DH: Can HIV, be cured? Mechanisms of HIV persistence and strategies to combat it. Curr HIV Res 2004, 2(2):99-111. Review
• [45]Van Lint C, Bouchat S, Marcello A: HIV-1 transcription and latency: an update. Retrovirology 2013, 10:67. doi: 10.1186/1742-4690-10-67. Review BioMed Central Full Text
• [46]Sgarbanti M, Battistini A: Therapeutics for HIV-1 reactivation from latency. Curr Opin Virol 2013, 3(4):394-401. doi: 10.1016/j.coviro.2013.06.001. Review
• [47]Wightman F, Ellenberg P, Churchill M, Lewin SR: HDAC inhibitors in HIV. Immunol Cell Biol 2012, 90(1):47-54. doi: 10.1038/icb.2011.95. Review
• [48]Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM: Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 2012, 487(7408):482-485. doi: 10.1038/nature11286. Erratum in: Nature. 2012; 489(7416):460
• [49]Elliott J, Solomon A, Wightman F, Smith M, Palmer S, Prince M, Watson J, Hoy J, McMahon J, Lewin SR: The safety and effect of multiple doses of vorinostat on HIV transcription in HIV + patients receiving cART. In 20th Conference on Retroviruses and Opportunistic Infections (CROI). Atlanta, USA: Oral late breaker; 2013. abstract LB50
• [50]Monforte AD, Svicher V, Nozza S, Lazzarin A, Marchetti G, Perno CF: Highlights on HIV eradication in 2013. AIDS 2013. [Epub ahead of print]
• [51]Lifson J, Del Prete G, Kiser R, Trubey CM, Smedley J, Coalter V, Oswald K, Shoemaker R, Fast R, Li Y, Lara A, Wiles A, Wiles R, Macallister R, Sanchez R, Wai J, Tan C, Keele B, Estes J, Piatak M Jr, Hazuda DJ: Evaluation of treatment with the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid; SAHA) in antiretroviral drug treated, SIVmac239-infected Rhesus Macaques. In Towards a Cure: IAS pre-conference symposium. Washington D.C.: Oral presentation; 2012.
• [52]Lewis MG, DaFonseca S, Chomont N, Palamara AT, Tardugno M, Mai A, Collins M, Wagner WL, Yalley-Ogunro J, Greenhouse J, Chirullo B, Norelli S, Garaci E, Savarino A: Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS 2011, 25(11):1347-1356. doi: 10.1097/QAD.0b013e328347bd77
• [53]Savarino A, Mai A, Norelli S, El Daker S, Valente S, Rotili D, Altucci L, Palamara AT, Garaci E: “Shock and kill” effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence. Retrovirology 2009, 6:52. doi: 10.1186/1742-4690-6-52 BioMed Central Full Text
• [54]Rasmussen TA, Schmeltz Søgaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, Dinarello C, Ostergaard L, Tolstrup M: Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother 2013, 9(5):993-1001. doi: 10.4161/hv.23800
• [55]Shan L, Xing S, Yang HC, Zhang H, Margolick JB, Siliciano RF: Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ T cells. J Antimicrob Chemother 2013. [Epub ahead of print]
• [56]Vandergeeten C, Fromentin R, Chomont N: The role of cytokines in the establishment, persistence and eradication of the HIV reservoir. Cytokine Growth Factor Rev 2012, 23(4–5):143-149. doi: 10.1016/j.cytogfr.2012.05.001. Review
• [57]Imamichi H, Degray G, Asmuth DM, Fischl MA, Landay AL, Lederman MM, Sereti I: HIV-1 viruses detected during episodic blips following interleukin-7 administration are similar to the viruses present before and after interleukin-7 therapy. AIDS 2011, 25(2):159-164. doi: 10.1097/QAD.0b013e328340a270
• [58]Vandergeeten C, Fromentin R, DaFonseca S, Lawani MB, Sereti I, Lederman MM, Ramgopal M, Routy JP, Sékaly RP, Chomont N: Interleukin-7 promotes HIV persistence during antiretroviral therapy. Blood 2013, 121(21):4321-4329. doi: 10.1182/blood-2012-11-465625
• [59]Bosque A, Famiglietti M, Weyrich AS, Goulston C, Planelles V: Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells. PLoS Pathog 2011, 7(10):e1002288. doi: 10.1371/journal.ppat.1002288
• [60]Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E: Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009, 360(7):692-698. doi: 10.1056/NEJMoa0802905
• [61]Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T: Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 2011, 117(10):2791-2799. doi: 10.1182/blood-2010-09-309591
• [62]Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ: Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996, 273(5283):1856-62. Erratum in: Science 1996; 274(5290):1069
• [63]Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, Eisele E, Haase A, Ho YC, Hütter G, Justement JS, Keating S, Lee TH, Li P, Murray D, Palmer S, Pilcher C, Pillai S, Price RW, Rothenberger M, Schacker T, Siliciano J, Siliciano R, Sinclair E, Strain M, Wong J, Richman D, Deeks SG: Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog 2013, 9(5):e1003347. doi: 10.1371/journal.ppat.1003347
• [64]Hütter G, Zaia JA: Allogeneic haematopoietic stem cell transplantation in patients with human immunodeficiency virus: the experiences of more than 25 years. Clin Exp Immunol 2011, 163(3):284-295. doi: 10.1111/j.1365-2249.2010.04312.x. Review
• [65]Huzicka I: Could bone marrow transplantation cure AIDS?: review. Med Hypotheses 1999, 52(3):247-257.
• [66]Ando D, Lalezari J, Blick G, Rodriquez J, Hsu R, Hawkins T, Parks D, Zeidan J, Sekaly RP, Deeks S: Functional control of viremia in CCR5-Δ32 heterozygous (Δ32HZ) HIV+ subjects following adoptive transfer of zinc finger nuclease CCR5 modified autologous CD4 T-cells (SB-728-T). In 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Denver, USA; 2013.
• [67]Lee GK, Zeidan J, Lalezari J, Mitsuyasu R, Wang S, Giedlin M, Nichol G, Tang W, Ando D, Sekaly RP: Long Term CD4 Reconstitution in HIV Subjects Receiving ZFN CCR5 Modified CD4 T-Cells (SB-728-T) May Be Attributed to the Sustained Durability of the Central Memory T-Cell Subset. In 20th Conference on Retroviruses and Opportunistic Infections (CROI). Atlanta, USA; 2013. Abstract #126
• [68]Henrich TJ, Hu Z, Li JZ, Sciaranghella G, Busch MP, Keating SM, Gallien S, Lin NH, Giguel FF, Lavoie L, Ho VT, Armand P, Soiffer RJ, Sagar M, Lacasce AS, Kuritzkes DR: Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis 2013, 207(11):1694-1702. doi: 10.1093/infdis/jit086
• [69]Henrich T, Hanhauser E, Sirignano M, Davis B, Lee TH, Keating S, Busch M, Marty F, LaCasce A, Armand P, Soiffer R, Altfeld M, Kuritzkes D: In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specific cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation. In 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, Malaysia; 2013. Abstract WELBA05
• [70]Stewart GJ, Ashton LJ, Biti RA, Ffrench RA, Bennetts BH, Newcombe NR, Benson EM, Carr A, Cooper DA, Kaldor JM: Increased frequency of CCR-5 delta 32 heterozygotes among long-term non-progressors with HIV-1 infection. The Australian long-term Non-progressor study group. AIDS 1997, 11(15):1833-1838.
• [71]Paiardini M, Cervasi B, Reyes-Aviles E, Micci L, Ortiz AM, Chahroudi A, Vinton C, Gordon SN, Bosinger SE, Francella N, Hallberg PL, Cramer E, Schlub T, Chan ML, Riddick NE, Collman RG, Apetrei C, Pandrea I, Else J, Munch J, Kirchhoff F, Davenport MP, Brenchley JM, Silvestri G: Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression. Nat Med 2011, 17(7):830-836. doi: 10.1038/nm.2395
• [72]Jenq RR, van den Brink MR: Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer 2010, 10(3):213-221. doi: 10.1038/nrc2825. Review. Erratum in: Nat Rev Cancer. 2010;10(3)
• [73]Suarez-Almazor ME, Spooner CH, Belseck E, Shea B: Auranofin versus placebo in rheumatoid arthritis. Cochrane Database Syst Rev 2000, 2000(2):CD002048. Review
• [74]Shytaj IL, Norelli S, Chirullo B, Della Corte A, Collins M, Yalley-Ogunro J, Greenhouse J, Iraci N, Acosta EP, Barreca ML, Lewis MG, Savarino A: 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(6):e1002774. doi: 10.1371/journal.ppat.1002774
• [75]Vanham G, Van Gulck E: Can immunotherapy be useful as a “functional cure” for infection with Human Immunodeficiency Virus-1? Retrovirology 2012, 9:72. doi: 10.1186/1742-4690-9-72. Review BioMed Central Full Text
• [76]Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA: HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 2006, 107(12):4781-4789.
• [77]Almeida JR, Price DA, Papagno L, Arkoub ZA, Sauce D, Bornstein E, Asher TE, Samri A, Schnuriger A, Theodorou I, Costagliola D, Rouzioux C, Agut H, Marcelin AG, Douek D, Autran B, Appay V: Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med 2007, 204(10):2473-2485.
• [78]Hersperger AR, Pereyra F, Nason M, Demers K, Sheth P, Shin LY, Kovacs CM, Rodriguez B, Sieg SF, Teixeira-Johnson L, Gudonis D, Goepfert PA, Lederman MM, Frank I, Makedonas G, Kaul R, Walker BD, Betts MR: Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog 2010, 6(5):e1000917. doi: 10.1371/journal.ppat.1000917
• [79]Buckheit RW 3rd, Siliciano RF, Blankson JN: Primary CD8+ T cells from elite suppressors effectively eliminate non-productively HIV-1 infected resting and activated CD4+ T cells. Retrovirology 2013, 10:68. doi: 10.1186/1742-4690-10-68 BioMed Central Full Text
• [80]Bailey HH, Ripple G, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Mahvi D, Schink J, Pomplun M, Mulcahy RT, Wilding G: Phase I study of continuous-infusion L-S, R-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst 1997, 89(23):1789-1796.
• [81]Shytaj IL, Chirullo B, Wagner W, Ferrari MG, Sgarbanti R, Corte AD, LaBranche C, Lopalco L, Palamara AT, Montefiori D, Lewis MG, Garaci E, Savarino A: Investigational treatment suspension and enhanced cell-mediated immunity at rebound followed by drug-free remission of simian AIDS. Retrovirology 2013, 10:71. doi: 10.1186/1742-4690-10-71 BioMed Central Full Text
• [82]Stephenson KE, Li H, Walker BD, Michael NL, Barouch DH: Gag-specific cellular immunity determines in vitro viral inhibition and in vivo virologic control following simian immunodeficiency virus challenges of vaccinated rhesus monkeys. J Virol 2012, 86(18):9583-9589. doi: 10.1128/JVI.00996-12
• [83]Edwards BH, Bansal A, Sabbaj S, Bakari J, Mulligan MJ, Goepfert PA: Magnitude of functional CD8+ T-cell responses to the gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma. J Virol 2002, 76(5):2298-2305.
• [84]Zuñiga R, Lucchetti A, Galvan P, Sanchez S, Sanchez C, Hernandez A, Sanchez H, Frahm N, Linde CH, Hewitt HS, Hildebrand W, Altfeld M, Allen TM, Walker BD, Korber BT, Leitner T, Sanchez J, Brander C: Relative dominance of Gag p24-specific cytotoxic T lymphocytes is associated with human immunodeficiency virus control. J Virol 2006, 80(6):3122-3125.
• [85]Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, Reddy S, de Pierres C, Mncube Z, Mkhwanazi N, Bishop K, van der Stok M, Nair K, Khan N, Crawford H, Payne R, Leslie A, Prado J, Prendergast A, Frater J, McCarthy N, Brander C, Learn GH, Nickle D, Rousseau C, Coovadia H, Mullins JI, Heckerman D, Walker BD, Goulder P: CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 2007, 13(1):46-53.
• [86]Julg B, Williams KL, Reddy S, Bishop K, Qi Y, Carrington M, Goulder PJ, Ndung’u T, Walker BD: Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J Virol 2010, 84(11):5540-5549. doi: 10.1128/JVI.02031-09
• [87]Pace MJ, Graf EH, Agosto LM, Mexas AM, Male F, Brady T, Bushman FD, O’Doherty U: Directly infected resting CD4+T cells can produce HIV Gag without spreading infection in a model of HIV latency. PLoS Pathog 2012, 8(7):e1002818. doi: 10.1371/journal.ppat.1002818
• [88]Lu W, Wu X, Lu Y, Guo W, Andrieu JM: Therapeutic dendritic-cell vaccine for simian AIDS. Nat Med 2003, 9(1):27-32.
• [89]Lu W, Arraes LC, Ferreira WT, Andrieu JM: Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 2004, 10(12):1359-1365.
• [90]García F, Climent N, Assoumou L, Gil C, González N, Alcamí J, León A, Romeu J, Dalmau J, Martínez-Picado J, Lifson J, Autran B, Costagliola D, Clotet B, Gatell JM, Plana M, Gallart T, DCV2/MANON07- AIDS Vaccine Research Objective Study Group: A therapeutic dendritic cell-based vaccine for HIV-1 infection. J Infect Dis 2011, 203(4):473-478.
• [91]García F, Climent N, Guardo AC, Gil C, León A, Autran B, Lifson JD, Martínez-Picado J, Dalmau J, Clotet B, Gatell JM, Plana M, Gallart T, DCV2/MANON07-ORVACS Study Group: A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Sci Transl Med 2013, 5(166):166ra2. doi: 10.1126/scitranslmed.3004682
• [92]Hansen SG MP Jr, Ventura AB, Hughes CM, Gilbride RM, Ford JC, Oswald K, Shoemaker R, Li Y, Lewis MS, Gilliam AN, Xu G, Whizin N, Burwitz BJ, Planer SL, Turner JM, Legasse AW, Axthelm MK, Nelson JA, Früh K, Sacha JB, Estes JD, Keele BF, Edlefsen PT, Lifson JD, Picker LJ: Immune clearance of highly pathogenic SIV infection. Nature 2013, 502(7469):100-104. doi: 10.1038/nature12519
• [93]Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, Whizin N, Oswald K, Shoemaker R, Swanson T, Legasse AW, Chiuchiolo MJ, Parks CL, Axthelm MK, Nelson JA, Jarvis MA, Piatak M Jr, Lifson JD, Picker LJ: Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 2011, 473(7348):523-527. doi: 10.1038/nature10003
• [94]Vagenas P, Aravantinou M, Williams VG, Jasny E, Piatak M Jr, Lifson JD, Salazar AM, Blanchard JL, Gettie A, Robbiani M: A tonsillar PolyICLC/AT-2 SIV therapeutic vaccine maintains low viremia following antiretroviral therapy cessation. PLoS One 2010, 5(9):e12891. doi: 10.1371/journal.pone.0012891
• [95]Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J, Stephenson KE, Chang HW, Shekhar K, Gupta S, Nkolola JP, Seaman MS, Smith KM, Borducchi EN, Cabral C, Smith JY, Blackmore S, Sanisetty S, Perry JR, Beck M, Lewis MG, Rinaldi W, Chakraborty AK, Poignard P, Nussenzweig MC, Burton DR: Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 2013. doi: 10.1038/nature12744. [Epub ahead of print]
• [96]Villinger F, Brice GT, Mayne AE, Bostik P, Mori K, June CH, Ansari AA: Adoptive transfer of simian immunodeficiency virus (SIV) naïve autologous CD4(+) cells to macaques chronically infected with SIV is sufficient to induce long-term nonprogressor status. Blood 2002, 99(2):590-599.
• [97]Cillo AR, Krishnan A, Mitsuyasu RT, McMahon DK, Li S, Rossi JJ, Zaia JA, Mellors JW: Plasma viremia and cellular HIV-1 DNA persist despite autologous hematopoietic stem cell transplantation for HIV-related lymphoma. J Acquir Immune Defic Syndr 2013, 63(4):438-441. doi: 10.1097/QAI.0b013e31828e6163