Can immunotherapy be useful as a “functional cure” for infection with Human Immunodeficiency Virus-1?

Retrovirology

Ellen Van Gulck²  Guido Vanham¹ 

[1] Department of Biomedical Sciences, University of Antwerpen, Antwerpen, Belgium;Present address: Community of Research Excellence and Advanced Technology (C.R.E.A.Te), Division of Janssen, Beerse, Belgium

关键词: Human trials;    Macaque trials;    CD8 T cells;    Therapeutic vaccine;    Functional cure;    Immune therapy;    SIV;    HIV;   

Others  :  1209270
DOI  :  10.1186/1742-4690-9-72

 received in 2012-06-12, accepted in 2012-08-07,  发布年份 2012

【 摘 要 】

Immunotherapy aims to assist the natural immune system in achieving control over viral infection. Various immunotherapy formats have been evaluated in either therapy-naive or therapy-experienced HIV-infected patients over the last 20 years. These formats included non-antigen specific strategies such as cytokines that stimulate immunity or suppress the viral replication, as well as antibodies that block negative regulatory pathways. A number of HIV-specific therapeutic vaccinations have also been proposed, using in vivo injection of inactivated virus, plasmid DNA encoding HIV antigens, or recombinant viral vectors containing HIV genes. A specific format of therapeutic vaccines consists of ex vivo loading of autologous dendritic cells with one of the above mentioned antigenic formats or mRNA encoding HIV antigens.

This review provides an extensive overview of the background and rationale of these different therapeutic attempts and discusses the results of trials in the SIV macaque model and in patients. To date success has been limited, which could be explained by insufficient quality or strength of the induced immune responses, incomplete coverage of HIV variability and/or inappropriate immune activation, with ensuing increased susceptibility of target cells.

Future attempts at therapeutic vaccination should ideally be performed under the protection of highly active antiretroviral drugs in patients with a recovered immune system. Risks for immune escape should be limited by a better coverage of the HIV variability, using either conserved or mosaic sequences. Appropriate molecular adjuvants should be included to enhance the quality and strength of the responses, without inducing inappropriate immune activation. Finally, to achieve a long-lasting effect on viral control (i.e. a “functional cure”) it is likely that these immune interventions should be combined with anti-latency drugs and/or gene therapy.

【 授权许可】

   
2012 Vanham and Van Gulck; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]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, 12:607-614.
• [2]Hutter G, Thiel E: Allogeneic transplantation of CCR5-deficient progenitor cells in a patient with HIV infection: an update after 3 years and the search for patient no. 2. AIDS 2011, 25:273-274.
• [3]Lafeuillade A, Stevenson M: The Search for a Cure for Persistent HIV Reservoirs. AIDS Rev 2011, 13:63-66.
• [4]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, 28:839-847.
• [5]Kiem HP, Jerome KR, Deeks SG, McCune JM: Hematopoietic-Stem-Cell-Based Gene Therapy for HIV Disease. Cell Stem Cell 2012, 10:137-147.
• [6]Chakrabarti LA, Simon V: Immune mechanisms of HIV control. Curr Opin Immunol 2010, 22:488-496.
• [7]Koup RA, Douek DC: Vaccine design for CD8 T lymphocyte responses. Cold Spring Harb Perspect Med 2011, 1:a007252.
• [8]Koup RA, Graham BS, Douek DC: The quest for a T cell-based immune correlate of protection against HIV: a story of trials and errors. NatRevImmunol 2011, 11:65-70.
• [9]Alter G, Heckerman D, Schneidewind A, Fadda L, Kadie CM, Carlson JM, Oniangue-Ndza C, Martin M, Li B, Khakoo SI, et al.: HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 2011, 476:96-100.
• [10]Romani L, Puccetti P, Bistoni F: Interleukin-12 in infectious diseases. Clin Microbiol Rev 1997, 10:611-636.
• [11]Autran B, Descours B, Avettand-Fenoel V, Rouzioux C: Elite controllers as a model of functional cure. Curr Opin HIV AIDS 2011, 6:181-187.
• [12]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, 24:1598-1601.
• [13]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, 23:1-4.
• [14]Van Gulck E, Heyndrickx L, Bracke L, Coppens S, Florence E, Buve A, Lewi P, Vanham G: Control of viral replication after cessation of HAART. AIDS Res Ther 2011, 8:6. BioMed Central Full Text
• [15]Van Gulck E, Bracke L, Heyndrickx L, Coppens S, Atkinson D, Merlin C, Pasternak A, Florence E, Vanham G: Immune and Viral Correlates of "Secondary Viral Control" after Treatment Interruption in Chronically HIV-1 Infected Patients. PLoS One 2012, 7:e37792.
• [16]Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, Reddy S, de Pierres C, Mncube Z, Mkhwanazi N, et al.: CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 2007, 13:46-53.
• [17]Rolland M, Heckerman D, Deng W, Rousseau CM, Coovadia H, Bishop K, Goulder PJ, Walker BD, Brander C, Mullins JI: Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads. PLoS One 2008, 3:e1424.
• [18]Hersperger AR, Migueles SA, Betts MR, Connors M: Qualitative features of the HIV-specific CD8+ T-cell response associated with immunologic control. Curr Opin HIV AIDS 2011, 6:169-173.
• [19]Saez-Cirion A, Shin SY, Versmisse P, Barre-Sinoussi F, Pancino G: Ex vivo T cell-based HIV suppression assay to evaluate HIV-specific CD8+ T-cell responses. Nat Protoc 2010, 5:1033-1041.
• [20]Spentzou A, Bergin P, Gill D, Cheeseman H, Ashraf A, Kaltsidis H, Cashin-Cox M, Anjarwalla I, Steel A, Higgs C, et al.: Viral inhibition assay: a CD8 T cell neutralization assay for use in clinical trials of HIV-1 vaccine candidates. J Infect Dis 2010, 201:720-729.
• [21]Theze J, Chakrabarti LA, Vingert B, Porichis F, Kaufmann DE: HIV controllers: A multifactorial phenotype of spontaneous viral suppression. Clin Immunol 2011, 4:4.
• [22]Steinman RM, Granelli-Piperno A, Pope M, Trumpfheller C, Ignatius R, Arrode G, Racz P, Tenner-Racz K: The interaction of immunodeficiency viruses with dendritic cells. Curr Top Microbiol Immunol 2003, 276:1-30.
• [23]Porichis F, Kaufmann DE: HIV-specific CD4 T cells and immune control of viral replication. Curr Opin HIV AIDS 2011, 6:174-180.
• [24]Rinaldo CR: Dendritic cell-based human immunodeficiency virus vaccine. J Intern Med 2009, 265:138-158.
• [25]Van Gulck E, Van Tendeloo VF, Berneman ZN, Vanham G: Role of dendritic cells in HIV-immunotherapy. CurrHIV Res 2010, 8:310-322.
• [26]Sodora DL, Silvestri G: Immune activation and AIDS pathogenesis. AIDS 2008, 22:439-446.
• [27]Lichtfuss GF, Hoy J, Rajasuriar R, Kramski M, Crowe SM, Lewin SR: Biomarkers of immune dysfunction following combination antiretroviral therapy for HIV infection. Biomark Med 2011, 5:171-186.
• [28]De Keersmaecker B, Thielemans K, Aerts JL: Fighting with the enemy's weapons? the role of costimulatory molecules in HIV. Curr Mol Med 2011, 11:172-196.
• [29]Paton NI: Treatment interruption strategies: how great are the risks? Curr Opin Infect Dis 2008, 21:25-30.
• [30]Palmer S, Josefsson L, Coffin JM: HIV reservoirs and the possibility of a cure for HIV infection. J Intern Med 2011, 19:1365-2796.
• [31]Hakre S, Chavez L, Shirakawa K, Verdin E: HIV latency: experimental systems and molecular models. FEMS Microbiol Rev 2012, 28:1574-6976.
• [32]Matalon S, Rasmussen TA, Dinarello CA: Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med 2011, 17:466-472.
• [33]Lewin SR, Evans VA, Elliott JH, Spire B, Chomont N: Finding a cure for HIV: will it ever be achievable? J Int AIDS Soc 2011, 14:4. BioMed Central Full Text
• [34]Shete A, Thakar M, Singh DP, Gangakhedkar R, Gaikwad A, Pawar J, Paranjape R: HIV Antigen-Specific Reactivation of HIV Infection from Cellular Reservoirs: Implications in the Settings of Therapeutic Vaccinations. AIDS Res Hum Retroviruses 2011, 21:21.
• [35]Jacobson MA, Hardy D, Connick E, Watson J, DeBruin M: Phase 1 trial of a single dose of recombinant human interleukin-12 in human immunodeficiency virus-infected patients with 100–500 CD4 cells/microL. J Infect Dis 2000, 182:1070-1076.
• [36]Jacobson MA, Spritzler J, Landay A, Chan E, Katzenstein D, Schock B, Fox L, Roe J, Kundu S, Pollard R: A Phase I, placebo-controlled trial of multi-dose recombinant human interleukin-12 in patients with HIV infection. AIDS 2002, 16:1147-1154.
• [37]Emery S, Capra WB, Cooper DA, Mitsuyasu RT, Kovacs JA, Vig P, Smolskis M, Saravolatz LD, Lane HC, Fyfe GA, Curtin PT: Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease. J Infect Dis 2000, 182:428-434.
• [38]Abrams D, Levy Y, Losso MH, Babiker A, Collins G, Cooper DA, Darbyshire J, Emery S, Fox L, Gordin F, et al.: Interleukin-2 therapy in patients with HIV infection. N Engl J Med 2009, 361:1548-1559.
• [39]Molina JM, Levy Y, Fournier I, Hamonic S, Bentata M, Beck-Wirth G, Gougeon ML, Venet A, Madelaine I, Sereni D, et al.: Interleukin-2 before antiretroviral therapy in patients with HIV infection: a randomized trial (ANRS 119). J Infect Dis 2009, 200:206-215.
• [40]Levy Y, Thiebaut R, Gougeon ML, Molina JM, Weiss L, Girard PM, Venet A, Morlat P, Poirier B, Lascaux AS, et al.: Effect of Intermittent Interleukin-2 Therapy on CD4+ T cell counts following antiretroviral cessation in patients with HIV (ANRS 118/NIH 04-I-0018 ILIADE Trial). AIDS 2012, 1:1.
• [41]Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K, Battaglia CA, Landay AL, Pahwa S, Fischl MA, et al.: IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood 2009, 113:6304-6314.
• [42]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, 25:159-164.
• [43]Parker R, Dutrieux J, Beq S, Lemercier B, Rozlan S, Fabre-Mersseman V, Rancez M, Gommet C, Assouline B, Rance I, et al.: Interleukin-7 treatment counteracts IFN-alpha therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques. Blood 2010, 116:5589-5599.
• [44]Lugli E, Mueller YM, Lewis MG, Villinger F, Katsikis PD, Roederer M: Interleukin-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques. Blood 2011, 14:14.
• [45]Pallikkuth S, Rogers K, Villinger F, Dosterii M, Vaccari M, Franchini G, Pahwa R, Pahwa S: Interleukin-21 administration to rhesus macaques chronically infected with simian immunodeficiency virus increases cytotoxic effector molecules in T cells and NK cells and enhances B cell function without increasing immune activation or viral replication. Vaccine 2011, 29:9229-9238.
• [46]Simone R, Piatti G, Saverino D: The inhibitory co-receptors: a way to save from anergy the HIV-specific T cells. Curr HIV Res 2009, 7:266-272.
• [47]Hryniewicz A, Boasso A, Edghill-Smith Y, Vaccari M, Fuchs D, Venzon D, Nacsa J, Betts MR, Tsai WP, Heraud JM, et al.: CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood 2006, 108:3834-3842.
• [48]Cecchinato V, Tryniszewska E, Ma ZM, Vaccari M, Boasso A, Tsai WP, Petrovas C, Fuchs D, Heraud JM, Venzon D, et al.: Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. J Immunol 2008, 180:5439-5447.
• [49]Valdez H, Lederman MM: Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev 1998, 187-228.
• [50]Lane HC, Davey V, Kovacs JA, Feinberg J, Metcalf JA, Herpin B, Walker R, Deyton L, Davey RT, Falloon J, et al.: Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med 1990, 112:805-811.
• [51]Gringeri A, Musicco M, Hermans P, Bentwich Z, Cusini M, Bergamasco A, Santagostino E, Burny A, Bizzini B, Zagury D: Active anti-interferon-alpha immunization: a European-Israeli, randomized, double-blind, placebo-controlled clinical trial in 242 HIV-1-infected patients (the EURIS study). J Acquir Immune Defic Syndr Hum Retrovirol 1999, 20:358-370.
• [52]Ries M, Pritschet K, Schmidt B: Blocking Type I Interferon Production: A New Therapeutic Option to Reduce the HIV-1-Induced Immune Activation. Clin Dev Immunol 2012, 2012:534929.
• [53]Paton NI, Goodall RL, Dunn DT, Franzen S, Collaco-Moraes Y, Gazzard BG, Williams IG, Fisher MJ, Winston A, Fox J, et al.: Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial. JAMA 2012, 308:353-361.
• [54]Clerici M, Shearer GM: A TH1– > TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 1993, 14:107-111.
• [55]Clerici M, Lucey DR, Berzofsky JA, Pinto LA, Wynn TA, Blatt SP, Dolan MJ, Hendrix CW, Wolf SF, Shearer GM: Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science 1993, 262:1721-1724.
• [56]Landay AL, Clerici M, Hashemi F, Kessler H, Berzofsky JA, Shearer GM: In vitro restoration of T cell immune function in human immunodeficiency virus-positive persons: effects of interleukin (IL)-12 and anti-IL-10. J Infect Dis 1996, 173:1085-1091.
• [57]Koblish HK, Hunter CA, Wysocka M, Trinchieri G, Lee WM: Immune suppression by recombinant interleukin (rIL)-12 involves interferon gamma induction of nitric oxide synthase 2 (iNOS) activity: inhibitors of NO generation reveal the extent of rIL-12 vaccine adjuvant effect. J Exp Med 1998, 188:1603-1610.
• [58]Gherardi MM, Ramirez JC, Esteban M: Interleukin-12 (IL-12) enhancement of the cellular immune response against human immunodeficiency virus type 1 env antigen in a DNA prime/vaccinia virus boost vaccine regimen is time and dose dependent: suppressive effects of IL-12 boost are mediated by nitric oxide. J Virol 2000, 74:6278-6286.
• [59]Rochman Y, Spolski R, Leonard WJ: New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 2009, 9:480-490.
• [60]Sirskyj D, Theze J, Kumar A, Kryworuchko M: Disruption of the gamma c cytokine network in T cells during HIV infection. Cytokine 2008, 43:1-14.
• [61]Cheng G, Yu A, Malek TR: T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells. Immunol Rev 2011, 241:63-76.
• [62]Kirkpatrick CH, Davis KC, Horsburgh CR, Cohn DL, Penley K, Judson FN: Interleukin-2 production by persons with the generalized lymphadenopathy syndrome or the acquired immune deficiency syndrome. J Clin Immunol 1985, 5:31-37.
• [63]Fahey JL, Giorgi J, Martinez-Maza O, Detels R, Mitsuyasu R, Taylor J: Immune pathogenesis of AIDS and related syndromes. Ann Inst Pasteur Immunol 1987, 138:245-252.
• [64]Gougeon ML, Chiodi F: Impact of gamma-chain cytokines on T cell homeostasis in HIV-1 infection: therapeutic implications. J Intern Med 2010, 267:502-514.
• [65]Ahmad A, Ahmad R, Iannello A, Toma E, Morisset R, Sindhu ST: IL-15 and HIV infection: lessons for immunotherapy and vaccination. Curr HIV Res 2005, 3:261-270.
• [66]Iannello A, Tremblay C, Routy JP, Boulassel MR, Toma E, Ahmad A: Decreased levels of circulating IL-21 in HIV-infected AIDS patients: correlation with CD4+ T-cell counts. Viral Immunol 2008, 21:385-388.
• [67]Mueller YM, Katsikis PD: IL-15 in HIV infection: pathogenic or therapeutic potential? Eur Cytokine Netw 2010, 21:219-221. Epub 2010 Aug 2019
• [68]Li S, Qi X, Gao Y, Hao Y, Cui L, Ruan L, He W: IL-15 increases the frequency of effector memory CD8+ T cells in rhesus monkeys immunized with HIV vaccine. Cell Mol Immunol 2010, 7:491-494.
• [69]Parmigiani A, Pallin MF, Schmidtmayerova H, Lichtenheld MG, Pahwa S: Interleukin-21 and cellular activation concurrently induce potent cytotoxic function and promote antiviral activity in human CD8 T cells. Hum Immunol 2011, 72:115-123.
• [70]Iannello A, Boulassel MR, Samarani S, Tremblay C, Toma E, Routy JP, Ahmad A: IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication. J Leukoc Biol 2010, 87:857-867.
• [71]White L, Krishnan S, Strbo N, Liu H, Kolber MA, Lichtenheld MG, Pahwa RN, Pahwa S: Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV). Blood 2007, 109:3873-3880.
• [72]Strbo N, de Armas L, Liu H, Kolber MA, Lichtenheld M, Pahwa S: IL-21 augments natural killer effector functions in chronically HIV-infected individuals. AIDS 2008, 22:1551-1560.
• [73]Chevalier MF, Julg B, Pyo A, Flanders M, Ranasinghe S, Soghoian DZ, Kwon DS, Rychert J, Lian J, Muller MI, et al.: HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J Virol 2011, 85:733-741.
• [74]Shankar EM, Che KF, Messmer D, Lifson JD, Larsson M: Expression of a Broad Array of Negative Costimulatory Molecules and Blimp-1 in T-cells Following Priming by HIV-1 Pulsed Dendritic Cells. MolMed 2010, 17:229-240.
• [75]Kaufmann DE, Walker BD: PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol 2009, 182:5891-5897.
• [76]Porichis F, Kaufmann DE: Role of PD-1 in HIV Pathogenesis and as Target for Therapy. Curr HIV/AIDS Rep 2011, 24:24.
• [77]Dyavar Shetty R, Velu V, Titanji K, Bosinger SE, Freeman GJ, Silvestri G, Amara RR: PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques. J Clin Invest 2012, 122:1712-1716.
• [78]Fernandez-Cruz E, Navarro J, Rodriguez-Sainz C, Gil J, Moreno S, Gonzalez-Lahoz J, Carbone J: The potential role of the HIV-1 immunogen (Remune) as a therapeutic vaccine in the treatment of HIV infection. Expert Rev Vaccines 2003, 2:739-752.
• [79]Chantratita W, Sukeepaisarncharoen W, Chandeying V, Kulpradist S, Israngkura Na Ayudhtaya B, Rugpao S, Sirawaraporn W, Boonshuyar C, Churdboonchart V: Delayed progression to AIDS in volunteers treated with long-term HIV-1 Immunogen (REMUNE) therapy in Thailand. HIV Med 2004, 5:317-325.
• [80]Kinloch-de Loes S, Hoen B, Smith DE, Autran B, Lampe FC, Phillips AN, Goh LE, Andersson J, Tsoukas C, Sonnerborg A, et al.: Impact of therapeutic immunization on HIV-1 viremia after discontinuation of antiretroviral therapy initiated during acute infection. J Infect Dis 2005, 192:607-617.
• [81]Rosati M, von Gegerfelt A, Roth P, Alicea C, Valentin A, Robert-Guroff M, Venzon D, Montefiori DC, Markham P, Felber BK, Pavlakis GN: DNA vaccines expressing different forms of simian immunodeficiency virus antigens decrease viremia upon SIVmac251 challenge. J Virol 2005, 79:8480-8492.
• [82]Rosati M, Bergamaschi C, Valentin A, Kulkarni V, Jalah R, Alicea C, Patel V, von Gegerfelt AS, Montefiori DC, Venzon DJ, et al.: DNA vaccination in rhesus macaques induces potent immune responses and decreases acute and chronic viremia after SIVmac251 challenge. Proc Natl Acad Sci U S A 2009, 106:15831-15836.
• [83]Wilson CC, Newman MJ, Livingston BD, MaWhinney S, Forster JE, Scott J, Schooley RT, Benson CA: Clinical phase 1 testing of the safety and immunogenicity of an epitope-based DNA vaccine in human immunodeficiency virus type 1-infected subjects receiving highly active antiretroviral therapy. Clin Vaccine Immunol 2008, 15:986-994.
• [84]Rosenberg ES, Graham BS, Chan ES, Bosch RJ, Stocker V, Maenza J, Markowitz M, Little S, Sax PE, Collier AC, et al.: Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection. PLoS One 2010, 5:e10555.
• [85]Gudmundsdotter L, Wahren B, Haller BK, Boberg A, Edback U, Bernasconi D, Butto S, Gaines H, Imami N, Gotch F, et al.: Amplified antigen-specific immune responses in HIV-1 infected individuals in a double blind DNA immunization and therapy interruption trial. Vaccine 2011, 29:5558-5566.
• [86]Tubiana R, Carcelain G, Vray M, Gourlain K, Dalban C, Chermak A, Rabian C, Vittecoq D, Simon A, Bouvet E, et al.: Therapeutic immunization with a human immunodeficiency virus (HIV) type 1-recombinant canarypox vaccine in chronically HIV-infected patients: The Vacciter Study (ANRS 094). Vaccine 2005, 23:4292-4301.
• [87]Levy Y, Gahery-Segard H, Durier C, Lascaux AS, Goujard C, Meiffredy V, Rouzioux C, El Habib R, Beumont-Mauviel M, Guillet JG, et al.: Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS 2005, 19:279-286.
• [88]Kilby JM, Bucy RP, Mildvan D, Fischl M, Santana-Bagur J, Lennox J, Pilcher C, Zolopa A, Lawrence J, Pollard RB, et al.: A randomized, partially blinded phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024). J Infect Dis 2006, 194:1672-1676.
• [89]Angel JB, Routy JP, Tremblay C, Ayers D, Woods R, Singer J, Bernard N, Kovacs C, Smaill F, Gurunathan S, Sekaly RP: A randomized controlled trial of HIV therapeutic vaccination using ALVAC with or without Remune. AIDS 2011, 25:731-739.
• [90]Autran B, Murphy RL, Costagliola D, Tubiana R, Clotet B, Gatell J, Staszewski S, Wincker N, Assoumou L, El-Habib R, et al.: Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic immunization with the ALVAC-HIV vaccine (vCP1452). AIDS 2008, 22:1313-1322.
• [91]Emery S, Workman C, Puls RL, Bloch M, Baker D, Bodsworth N, Anderson J, Crowe SM, French MA, Hoy J, et al.: Randomized, placebo-controlled, phase I/IIa evaluation of the safety and immunogenicity of fowlpox virus expressing HIV gag-pol and interferon-gamma in HIV-1 infected subjects. Hum Vaccin 2005, 1:232-238.
• [92]Emery S, Kelleher AD, Workman C, Puls RL, Bloch M, Baker D, Anderson J, Hoy J, Ip S, Nalliah K, et al.: Influence of IFNgamma co-expression on the safety and antiviral efficacy of recombinant fowlpox virus HIV therapeutic vaccines following interruption of antiretroviral therapy. Hum Vaccin 2007, 3:260-267.
• [93]Uberla K, Rosenwirth B, Ten Haaft P, Heeney J, Sutter G, Erfle V: Therapeutic immunization with Modified Vaccinia Virus Ankara (MVA) vaccines in SIV-infected rhesus monkeys undergoing antiretroviral therapy. J Med Primatol 2007, 36:2-9.
• [94]Shimada M, Wang HB, Kondo A, Xu XP, Yoshida A, Shinoda K, Ura T, Mizuguchi H, Klinman D, Luo JL, et al.: Effect of therapeutic immunization using Ad5/35 and MVA vectors on SIV infection of rhesus monkeys undergoing antiretroviral therapy. Gene Ther 2009, 16:218-228.
• [95]Harrer E, Bauerle M, Ferstl B, Chaplin P, Petzold B, Mateo L, Handley A, Tzatzaris M, Vollmar J, Bergmann S, et al.: Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption. Antivir Ther 2005, 10:285-300.
• [96]Dorrell L, Yang H, Ondondo B, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P, Bowness P, et al.: Expansion and diversification of virus-specific T cells following immunization of human immunodeficiency virus type 1 (HIV-1)-infected individuals with a recombinant modified vaccinia virus Ankara/HIV-1 Gag vaccine. J Virol 2006, 80:4705-4716.
• [97]Dorrell L, Williams P, Suttill A, Brown D, Roberts J, Conlon C, Hanke T, McMichael A: Safety and tolerability of recombinant modified vaccinia virus Ankara expressing an HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected persons receiving combination antiretroviral therapy. Vaccine 2007, 25:3277-3283.
• [98]Soloff AC, Liu X, Gao W, Day RD, Gambotto A, Barratt-Boyes SM: Adenovirus 5- and 35-based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection. Eur J Immunol 2009, 39:2437-2449.
• [99]Schooley RT, Spritzler J, Wang H, Lederman MM, Havlir D, Kuritzkes DR, Pollard R, Battaglia C, Robertson M, Mehrotra D, et al.: AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein. J Infect Dis 2010, 202:705-716.
• [100]Kundu SK, Engleman E, Benike C, Shapero MH, Dupuis M, van Schooten WC, Eibl M, Merigan TC: A pilot clinical trial of HIV antigen-pulsed allogeneic and autologous dendritic cell therapy in HIV-infected patients. AIDS Res Hum Retroviruses 1998, 14:551-560.
• [101]Ide F, Nakamura T, Tomizawa M, Kawana-Tachikawa A, Odawara T, Hosoya N, Iwamoto A: Peptide-loaded dendritic-cell vaccination followed by treatment interruption for chronic HIV-1 infection: a phase 1 trial. J Med Virol 2006, 78:711-718.
• [102]De Rose R, Fernandez CS, Smith MZ, Batten CJ, Alcantara S, Peut V, Rollman E, Loh L, Mason RD, Wilson K, et al.: Control of viremia and prevention of AIDS following immunotherapy of SIV-infected macaques with peptide-pulsed blood. PLoS Pathog 2008, 4:e1000055.
• [103]Lu W, Wu X, Lu Y, Guo W, Andrieu JM: Therapeutic dendritic-cell vaccine for simian AIDS. Nat Med 2003, 9:27-32.
• [104]Lu W, Arraes LC, Ferreira WT, Andrieu JM: Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 2004, 10:1359-1365.
• [105]Garcia F, Ruiz L, de Quiros JC L-B, Moreno S, Domingo P: Immunotherapy and therapeutic vaccines in HIV infection. Enferm Infecc Microbiol Clin 2005, 23(Suppl 2):84-104.
• [106]Garcia F, Climent N, Assoumou L, Gil C, Gonzalez N, Alcami J, Leon A, Romeu J, Dalmau J, Martinez-Picado J, et al.: A Therapeutic Dendritic Cell-Based Vaccine for HIV-1 Infection. J Infect Dis 2010, 203:473-478.
• [107]Gandhi RT, O'Neill D, Bosch RJ, Chan ES, Bucy RP, Shopis J, Baglyos L, Adams E, Fox L, Purdue L, et al.: A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy. Vaccine 2009, 27:6088-6094.
• [108]Routy JP, Boulassel MR, Yassine-Diab B, Nicolette C, Healey D, Jain R, Landry C, Yegorov O, Tcherepanova I, Monesmith T, et al.: Immunologic activity and safety of autologous HIV RNA-electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin Immunol 2010, 134:140-147.
• [109]Routy JP, Nicolette C: Arcelis AGS-004 dendritic cell-based immunotherapy for HIV infection. Immunotherapy 2010, 2:467-476.
• [110]Allard SD, De Keersmaecker B, de Goede AL, Verschuren EJ, Koetsveld J, Reedijk ML, Wylock C, De Bel AV, Vandeloo J, Pistoor F, et al.: A Phase I/IIa Immunotherapy Trial of HIV-1-Infected Patients with Tat, Rev and Nef expressing dendritic cells followed by treatment interruption. Clin Immunol 2012, 142:252-268.
• [111]Van Gulck E, Vlieghe E, Vekemans M, Van Tendeloo VF, Van De Velde A, Smits E, Anguille S, Cools N, Goossens H, Mertens L, et al.: mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients. AIDS 2012, 26:F1-F12.
• [112]Limsuwan A, Churdboonchart V, Moss RB, Sirawaraporn W, Sutthent R, Smutharaks B, Glidden D, Trauger R, Theofan G, Carlo D: Safety and immunogenicity of REMUNE in HIV-infected Thai subjects. Vaccine 1998, 16:142-149.
• [113]von Gegerfelt AS, Rosati M, Alicea C, Valentin A, Roth P, Bear J, Franchini G, Albert PS, Bischofberger N, Boyer JD, et al.: Long-lasting decrease in viremia in macaques chronically infected with simian immunodeficiency virus SIVmac251 after therapeutic DNA immunization. J Virol 2007, 81:1972-1979.
• [114]Valentin A, von Gegerfelt A, Rosati M, Miteloudis G, Alicea C, Bergamaschi C, Jalah R, Patel V, Khan AS, Draghia-Akli R, et al.: Repeated DNA therapeutic vaccination of chronically SIV-infected macaques provides additional virological benefit. Vaccine 2010, 28:1962-1974.
• [115]Lori F: DermaVir: a plasmid DNA-based nanomedicine therapeutic vaccine for the treatment of HIV/AIDS. Expert Rev Vaccines 2011, 10:1371-1384.
• [116]Lisziewicz J, Bakare N, Calarota SA, Banhegyi D, Szlavik J, Ujhelyi E, Toke ER, Molnar L, Lisziewicz Z, Autran B, Lori F: Single DermaVir Immunization: Dose-Dependent Expansion of Precursor/Memory T Cells against All HIV Antigens in HIV-1 Infected Individuals. PLoS One 2012, 7:e35416.
• [117]Kim JJ, Nottingham LK, Tsai A, Lee DJ, Maguire HC, Oh J, Dentchev T, Manson KH, Wyand MS, Agadjanyan MG, et al.: Antigen-specific humoral and cellular immune responses can be modulated in rhesus macaques through the use of IFN-gamma, IL-12, or IL-18 gene adjuvants. J Med Primatol 1999, 28:214-223.
• [118]Halwani R, Boyer JD, Yassine-Diab B, Haddad EK, Robinson TM, Kumar S, Parkinson R, Wu L, Sidhu MK, Phillipson-Weiner R, et al.: Therapeutic vaccination with simian immunodeficiency virus (SIV)-DNA + IL-12 or IL-15 induces distinct CD8 memory subsets in SIV-infected macaques. J Immunol 2008, 180:7969-7979.
• [119]Boyer JD, Cohen AD, Ugen KE, Edgeworth RL, Bennett M, Shah A, Schumann K, Nath B, Javadian A, Bagarazzi ML, et al.: Therapeutic immunization of HIV-infected chimpanzees using HIV-1 plasmid antigens and interleukin-12 expressing plasmids. AIDS 2000, 14:1515-1522.
• [120]Hirao LA, Wu L, Khan AS, Hokey DA, Yan J, Dai A, Betts MR, Draghia-Akli R, Weiner DB: Combined effects of IL-12 and electroporation enhances the potency of DNA vaccination in macaques. Vaccine 2008, 26:3112-3120.
• [121]Kalams SA, Parker S, Jin X, Elizaga M, Metch B, Wang M, Hural J, Lubeck M, Eldridge J, Cardinali M, et al.: Safety and Immunogenicity of an HIV-1 Gag DNA Vaccine with or without IL-12 and/or IL-15 Plasmid Cytokine Adjuvant in Healthy, HIV-1 Uninfected Adults. PLoS One 2012, 7:e29231.
• [122]Vasan S, Hurley A, Schlesinger SJ, Hannaman D, Gardiner DF, Dugin DP, Boente-Carrera M, Vittorino R, Caskey M, Andersen J, et al.: In Vivo Electroporation Enhances the Immunogenicity of an HIV-1 DNA Vaccine Candidate in Healthy Volunteers. PLoS One 2011, 6:e19252.
• [123]Hallengard D, Haller BK, Maltais AK, Gelius E, Nihlmark K, Wahren B, Brave A: Comparison of plasmid vaccine immunization schedules using intradermal in vivo electroporation. Clin Vaccine Immunol 2011, 18:1577-1581.
• [124]Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, et al.: Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009, 361:2209-2220.
• [125]Papagno L, Alter G, Assoumou L, Murphy RL, Garcia F, Clotet B, Larsen M, Braibant M, Marcelin AG, Costagliola D, et al.: Comprehensive analysis of virus-specific T-cells provides clues for the failure of therapeutic immunization with ALVAC-HIV vaccine. AIDS 2011, 25:27-36.
• [126]Frahm N, Decamp AC, Friedrich DP, Carter DK, Defawe OD, Kublin JG, Casimiro DR, Duerr A, Robertson MN, Buchbinder SP, et al.: Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine. J Clin Invest 2012, 122:359-367.
• [127]French MA, Tanaskovic S, Law MG, Lim A, Fernandez S, Ward LD, Kelleher AD, Emery S: Vaccine-induced IgG2 anti-HIV p24 is associated with control of HIV in patients with a 'high-affinity' FcgammaRIIa genotype. AIDS 2010, 24:1983-1990.
• [128]Wang SW, Bertley FM, Kozlowski PA, Herrmann L, Manson K, Mazzara G, Piatak M, Johnson RP, Carville A, Mansfield K, Aldovini A: An SHIV DNA/MVA rectal vaccination in macaques provides systemic and mucosal virus-specific responses and protection against AIDS. AIDS Res Hum Retroviruses 2004, 20:846-859.
• [129]Bertley FM, Kozlowski PA, Wang SW, Chappelle J, Patel J, Sonuyi O, Mazzara G, Montefiori D, Carville A, Mansfield KG, Aldovini A: Control of simian/human immunodeficiency virus viremia and disease progression after IL-2-augmented DNA-modified vaccinia virus Ankara nasal vaccination in nonhuman primates. J Immunol 2004, 172:3745-3757.
• [130]Makitalo B, Lundholm P, Hinkula J, Nilsson C, Karlen K, Morner A, Sutter G, Erfle V, Heeney JL, Wahren B, et al.: Enhanced cellular immunity and systemic control of SHIV infection by combined parenteral and mucosal administration of a DNA prime MVA boost vaccine regimen. J Gen Virol 2004, 85:2407-2419.
• [131]Amara RR, Ibegbu C, Villinger F, Montefiori DC, Sharma S, Nigam P, Xu Y, McClure HM, Robinson HL: Studies using a viral challenge and CD8 T cell depletions on the roles of cellular and humoral immunity in the control of an SHIV-89.6P challenge in DNA/MVA-vaccinated macaques. Virology 2005, 343:246-255.
• [132]Precopio ML, Betts MR, Parrino J, Price DA, Gostick E, Ambrozak DR, Asher TE, Douek DC, Harari A, Pantaleo G, et al.: Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8(+) T cell responses. J Exp Med 2007, 204:1405-1416.
• [133]Greenough TC, Cunningham CK, Muresan P, McManus M, Persaud D, Fenton T, Barker P, Gaur A, Panicali D, Sullivan JL, Luzuriaga K: Safety and immunogenicity of recombinant poxvirus HIV-1 vaccines in young adults on highly active antiretroviral therapy. Vaccine 2008, 26:6883-6893.
• [134]Climent N, Guerra S, Garcia F, Rovira C, Miralles L, Gomez CE, Pique N, Gil C, Gatell JM, Esteban M, Gallart T: Dendritic Cells Exposed to MVA-Based HIV-1 Vaccine Induce Highly Functional HIV-1-Specific CD8 T Cell Responses in HIV-1-Infected Individuals. PLoS One 2011, 6:e19644.
• [135]Gray G, Buchbinder S, Duerr A: Overview of STEP and Phambili trial results: two phase IIb test-of-concept studies investigating the efficacy of MRK adenovirus type 5 gag/pol/nef subtype B HIV vaccine. Curr Opin HIV AIDS 2010, 5:357-361.
• [136]Benlahrech A, Harris J, Meiser A, Papagatsias T, Hornig J, Hayes P, Lieber A, Athanasopoulos T, Bachy V, Csomor E, et al.: Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1. Proc Natl Acad Sci U S A 2009, 106:19940-19945.
• [137]Michael NL: Rare serotype adenoviral vectors for HIV vaccine development. J Clin Invest 2012, 122:25-27.
• [138]Koup RA, Roederer M, Lamoreaux L, Fischer J, Novik L, Nason MC, Larkin BD, Enama ME, Ledgerwood JE, Bailer RT, et al.: Priming immunization with DNA augments immunogenicity of recombinant adenoviral vectors for both HIV-1 specific antibody and T-cell responses. PLoS One 2010, 5:e9015.
• [139]Freel SA, Lamoreaux L, Chattopadhyay PK, Saunders K, Zarkowsky D, Overman RG, Ochsenbauer C, Edmonds TG, Kappes JC, Cunningham CK, et al.: Phenotypic and functional profile of HIV-inhibitory CD8 T cells elicited by natural infection and heterologous prime/boost vaccination. J Virol 2010, 84:4998-5006.
• [140]Pillai VK, Kannanganat S, Penaloza-Macmaster P, Chennareddi L, Robinson HL, Blackwell J, Amara RR: Different patterns of expansion, contraction and memory differentiation of HIV-1 Gag-specific CD8 T cells elicited by adenovirus type 5 and modified vaccinia Ankara vaccines. Vaccine 2011, 29:5399-5406.
• [141]Lapenta C, Santini SM, Logozzi M, Spada M, Andreotti M, Di Pucchio T, Parlato S, Belardelli F: Potent immune response against HIV-1 and protection from virus challenge in hu-PBL-SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-alpha. J Exp Med 2003, 198:361-367.
• [142]Yoshida A, Tanaka R, Murakami T, Takahashi Y, Koyanagi Y, Nakamura M, Ito M, Yamamoto N, Tanaka Y: Induction of protective immune responses against R5 human immunodeficiency virus type 1 (HIV-1) infection in hu-PBL-SCID mice by intrasplenic immunization with HIV-1-pulsed dendritic cells: possible involvement of a novel factor of human CD4(+) T-cell origin. J Virol 2003, 77:8719-8728.
• [143]Jonuleit H, Wiedemann K, Muller G, Degwert J, Hoppe U, Knop J, Enk AH: Induction of IL-15 messenger RNA and protein in human blood-derived dendritic cells: a role for IL-15 in attraction of T cells. J Immunol 1997, 158:2610-2615.
• [144]Van Tendeloo VF, Ponsaerts P, Lardon F, Nijs G, Lenjou M, Van Broeckhoven C, Van Bockstaele DR, Berneman ZN: Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 2001, 98:49-56.
• [145]Garcia F: 'Functional cure' of HIV infection: the role of immunotherapy. Immunotherapy 2012, 4:245-248.
• [146]Ahlers JD, Belyakov IM: Strategies for recruiting and targeting dendritic cells for optimizing HIV vaccines. Trends Mol Med 2009, 15:263-274.
• [147]Trumpfheller C, Longhi MP, Caskey M, Idoyaga J, Bozzacco L, Keler T, Schlesinger SJ, Steinman RM: Dendritic cell-targeted protein vaccines: a novel approach to induce T cell immunity. J Intern Med 2011, 29:1365-2796.
• [148]Hutnick NA, Myles DJ, Bian CB, Muthumani K, Weiner DB: Selected approaches for increasing HIV DNA vaccine immunogenicity in vivo. Curr Opin Virol 2011, 1:233-240.
• [149]Weide B, Garbe C, Rammensee HG, Pascolo S: Plasmid DNA- and messenger RNA-based anti-cancer vaccination. Immunol Lett 2008, 115:33-42.
• [150]Letourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, Dorrell L, Dong T, Korber B, McMichael AJ, Hanke T: Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One 2007, 2:e984.
• [151]Knudsen ML, Mbewe-Mvula A, Rosario M, Johansson DX, Kakoulidou M, Bridgeman A, Reyes-Sandoval A, Nicosia A, Ljungberg K, Hanke T, Liljestrom P: Superior Induction of T Cell Responses to Conserved HIV-1 Regions by Electroporated Alphavirus Replicon DNA Compared to That with Conventional Plasmid DNA Vaccine. J Virol 2012, 86:4082-4090.
• [152]Mothe B, Llano A, Ibarrondo J, Daniels M, Miranda C, Zamarreno J, Bach V, Zuniga R, Perez-Alvarez S, Berger CT, et al.: Definition of the viral targets of protective HIV-1-specific T cell responses. J Transl Med 2011, 9:208. BioMed Central Full Text
• [153]Fischer W, Perkins S, Theiler J, Bhattacharya T, Yusim K, Funkhouser R, Kuiken C, Haynes B, Letvin NL, Walker BD, et al.: Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat Med 2007, 13:100-106.
• [154]Thurmond J, Yoon H, Kuiken C, Yusim K, Perkins S, Theiler J, Bhattacharya T, Korber B, Fischer W: Web-based design and evaluation of T-cell vaccine candidates. Bioinformatics 2008, 24:1639-1640.
• [155]Barouch DH, O'Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun YH, La Porte A, Riggs AM, Lynch DM, et al.: Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med 2010, 16:319-323.
• [156]Santra S, Liao HX, Zhang R, Muldoon M, Watson S, Fischer W, Theiler J, Szinger J, Balachandran H, Buzby A, et al.: Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys. Nat Med 2010, 16:324-328.
• [157]Ndhlovu ZM, Piechocka-Trocha A, Vine S, McMullen A, Koofhethile KC, Goulder PJ, Ndung'u T, Barouch DH, Walker BD: Mosaic HIV-1 Gag Antigens Can Be Processed and Presented to Human HIV-Specific CD8+ T Cells. J Immunol 2011, 186:6914-6924.
• [158]Van Lint S, Goyvaerts C, Maenhout S, Goethals L, Disy A, Benteyn D, Pen J, Bonehill A, Heirman C, Breckpot K, Thielemans K: Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy. Cancer Res 2012, 72:1661-1671.
• [159]Pascolo S: Vaccination with messenger RNA (mRNA). Handb Exp Pharmacol 2008, 221-235.
• [160]Fotin-Mleczek M, Duchardt KM, Lorenz C, Pfeiffer R, Ojkic-Zrna S, Probst J, Kallen KJ: Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J Immunother 2011, 34:1-15.
• [161]Dai B, Xiao L, Bryson PD, Fang J, Wang P: PD-1/PD-L1 Blockade Can Enhance HIV-1 Gag-specific T Cell Immunity Elicited by Dendritic Cell-Directed Lentiviral Vaccines. Mol Ther 2012, 15:98.
• [162]Li F, Malhotra U, Gilbert PB, Hawkins NR, Duerr AC, McElrath JM, Corey L, Self SG: Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation. Vaccine 2006, 24:6893-6904.
• [163]Routy JP, Boulassel MR, Nicolette CA, Jacobson JM: Assessing risk of a short-term antiretroviral therapy discontinuation as a read-out of viral control in immune-based therapy. J Med Virol 2012, 84:885-889.