HIV-1 functional cure: will the dream come true?

BMC Medicine

Hui Zhang¹  Cancan Chen¹  Bingfeng Liu¹  Xiancai Ma¹  Chao Liu¹ 

[1] Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China

关键词: Sterilizing cure;    Permanent silencing;    Shock and kill;    Latency reservoir;    HIV-1;    Genetic engineering;    Functional cure;    cART;   

Others  :  1234100
DOI  :  10.1186/s12916-015-0517-y

 received in 2015-07-25, accepted in 2015-11-03,  发布年份 2015

【 摘 要 】

The reservoir of human immunodeficiency virus type 1 (HIV-1), a long-lived pool of latently infected cells harboring replication-competent viruses, is the major obstacle to curing acquired immune deficiency syndrome (AIDS). Although the combination antiretroviral therapy (cART) can successfully suppress HIV-1 viremia and significantly delay the progression of the disease, it cannot eliminate the viral reservoir and the patient must continue to take anti-viral medicines for life. Currently, the appearance of the ‘Berlin patient’, the ‘Boston patients’, and the ‘Mississippi baby’ have inspired many therapeutic strategies for HIV-1 aimed at curing efforts. However, the specific eradication of viral latency and the recovery and optimization of the HIV-1-specific immune surveillance are major challenges to achieving such a cure. Here, we summarize recent studies addressing the mechanisms underlying the viral latency and define two categories of viral reservoir: ‘shallow’ and ‘deep’. We also present the current strategies and recent advances in the development of a functional cure for HIV-1, focusing on full/partial replacement of the immune system, ‘shock and kill’, and ‘permanent silencing’ approaches.

【 授权许可】

   
2015 Liu et al.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K et al.. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009; 360(7):692-8.
• [2]Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E et al.. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood. 2011; 117(10):2791-9.
• [3]Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH et al.. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014; 161(5):319-27.
• [4]Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M, Chun TW et al.. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013; 369(19):1828-35.
• [5]Siliciano JD, Siliciano RF. AIDS/HIV. Rekindled HIV infection. Science. 2014; 345(6200):1005-6.
• [6]Katlama C, Deeks SG, Autran B, Martinez-Picado J, van Lunzen J, Rouzioux C et al.. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013; 381(9883):2109-17.
• [7]Abdel-Mohsen M, Raposo RA, Deng X, Li M, Liegler T, Sinclair E et al.. Expression profile of host restriction factors in HIV-1 elite controllers. Retrovirology. 2013; 10:106.
• [8]Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PI et al.. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 2010; 330(6010):1551-7.
• [9]Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L et al.. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci U S A. 2000; 97(6):2709-14.
• [10]Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J et al.. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood. 2006; 107(12):4781-9.
• [11]Hersperger AR, Pereyra F, Nason M, Demers K, Sheth P, Shin LY et al.. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog. 2010; 6(5):e1000917.
• [12]Jiang Y, Chen O, Cui C, Zhao B, Han X, Zhang Z et al.. KIR3DS1/L1 and HLA-Bw4-80I are associated with HIV disease progression among HIV typical progressors and long-term nonprogressors. BMC Infect Dis. 2013; 13:405.
• [13]Lambotte O, Ferrari G, Moog C, Yates NL, Liao HX, Parks RJ et al.. Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers. AIDS. 2009; 23(8):897-906.
• [14]Smalls-Mantey A, Doria-Rose N, Klein R, Patamawenu A, Migueles SA, Ko SY et al.. Antibody-dependent cellular cytotoxicity against primary HIV-infected CD4+ T cells is directly associated with the magnitude of surface IgG binding. J Virol. 2012; 86(16):8672-80.
• [15]Palacios JA, Perez-Pinar T, Toro C, Sanz-Minguela B, Moreno V, Valencia E et al.. Long-term nonprogressor and elite controller patients who control viremia have a higher percentage of methylation in their HIV-1 proviral promoters than aviremic patients receiving highly active antiretroviral therapy. J Virol. 2012; 86(23):13081-4.
• [16]Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus KA, Reimann KA et al.. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science. 1999; 286(5443):1353-7.
• [17]Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med. 1995; 1(12):1284-90.
• [18]Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB et al.. 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):727-8.
• [19]Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z et al.. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med. 2014; 20(2):139-42.
• [20]Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J, Bixby D, Savona MR et al.. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010; 16(4):446-51.
• [21]Kumar A, Abbas W, Herbein G. HIV-1 latency in monocytes/macrophages. Viruses. 2014; 6(4):1837-60.
• [22]Lassen K, Han Y, Zhou Y, Siliciano J, Siliciano RF. The multifactorial nature of HIV-1 latency. Trends Mol Med. 2004; 10(11):525-31.
• [23]Van Lint C, Bouchat S, Marcello A. HIV-1 transcription and latency: an update. Retrovirology. 2013; 10:67.
• [24]Hakre S, Chavez L, Shirakawa K, Verdin E. Epigenetic regulation of HIV latency. Curr Opin HIV AIDS. 2011; 6(1):19-24.
• [25]du Chene I, Basyuk E, Lin YL, Triboulet R, Knezevich A, Chable-Bessia C et al.. Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J. 2007; 26(2):424-35.
• [26]Marban C, Suzanne S, Dequiedt F, de Walque S, Redel L, Van Lint C et al.. Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J. 2007; 26(2):412-23.
• [27]Imai K, Togami H, Okamoto T. Involvement of histone H3 lysine 9 (H3K9) methyltransferase G9a in the maintenance of HIV-1 latency and its reactivation by BIX01294. J Biol Chem. 2010; 285(22):16538-45.
• [28]Friedman J, Cho WK, Chu CK, Keedy KS, Archin NM, Margolis DM et al.. Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol. 2011; 85(17):9078-89.
• [29]Ding D, Qu X, Li L, Zhou X, Liu S, Lin S et al.. Involvement of histone methyltransferase GLP in HIV-1 latency through catalysis of H3K9 dimethylation. Virology. 2013; 440(2):182-9.
• [30]Blazkova J, Murray D, Justement JS, Funk EK, Nelson AK, Moir S et al.. Paucity of HIV DNA methylation in latently infected, resting CD4+ T cells from infected individuals receiving antiretroviral therapy. J Virol. 2012; 86(9):5390-2.
• [31]Blazkova J, Trejbalova K, Gondois-Rey F, Halfon P, Philibert P, Guiguen A et al.. CpG methylation controls reactivation of HIV from latency. PLoS Pathog. 2009; 5(8):e1000554.
• [32]Matsuda Y, Kobayashi-Ishihara M, Fujikawa D, Ishida T, Watanabe T, Yamagishi M. Epigenetic heterogeneity in HIV-1 latency establishment. Sci Rep. 2015; 5:7701.
• [33]Han Y, Lin YB, An W, Xu J, Yang HC, O'Connell K et al.. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe. 2008; 4(2):134-46.
• [34]Lenasi T, Contreras X, Peterlin BM. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe. 2008; 4(2):123-33.
• [35]Zhang Y, Fan M, Geng G, Liu B, Huang Z, Luo H et al.. A novel HIV-1-encoded microRNA enhances its viral replication by targeting the TATA box region. Retrovirology. 2014; 11:23.
• [36]Huang J, Wang F, Argyris E, Chen K, Liang Z, Tian H et al.. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med. 2007; 13(10):1241-7.
• [37]Ahluwalia JK, Khan SZ, Soni K, Rawat P, Gupta A, Hariharan M et al.. Human cellular microRNA hsa-miR-29a interferes with viral nef protein expression and HIV-1 replication. Retrovirology. 2008; 5:117.
• [38]Triboulet R, Mari B, Lin YL, Chable-Bessia C, Bennasser Y, Lebrigand K et al.. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science. 2007; 315(5818):1579-82.
• [39]Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, Hill S et al.. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science. 2014; 345(6193):179-83.
• [40]Wagner TA, McLaughlin S, Garg K, Cheung CY, Larsen BB, Styrchak S et al.. HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science. 2014; 345(6196):570-3.
• [41]Cohn LB, Silva IT, Oliveira TY, Rosales RA, Parrish EH, Learn GH et al.. HIV-1 integration landscape during latent and active infection. Cell. 2015; 160(3):420-32.
• [42]Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B et al.. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009; 15(8):893-900.
• [43]Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES et al.. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 2013; 9(2):e1003174.
• [44]Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI et al.. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013; 155(3):540-51.
• [45]Ott M, Schnolzer M, Garnica J, Fischle W, Emiliani S, Rackwitz HR et al.. Acetylation of the HIV-1 Tat protein by p300 is important for its transcriptional activity. Curr Biol. 1999; 9(24):1489-92.
• [46]Zhang HS, Wu MR. SIRT1 regulates Tat-induced HIV-1 transactivation through activating AMP-activated protein kinase. Virus Res. 2009; 146(1–2):51-7.
• [47]Pagans S, Kauder SE, Kaehlcke K, Sakane N, Schroeder S, Dormeyer W et al.. The Cellular lysine methyltransferase Set7/9-KMT7 binds HIV-1 TAR RNA, monomethylates the viral transactivator Tat, and enhances HIV transcription. Cell Host Microbe. 2010; 7(3):234-44.
• [48]Sakane N, Kwon HS, Pagans S, Kaehlcke K, Mizusawa Y, Kamada M et al.. Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog. 2011; 7(8):e1002184.
• [49]Razooky BS, Pai A, Aull K, Rouzine IM, Weinberger LS. A hardwired HIV latency program. Cell. 2015; 160(5):990-1001.
• [50]Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T et al.. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996; 2(11):1240-3.
• [51]Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R et al.. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996; 86(3):367-77.
• [52]Bai J, Gorantla S, Banda N, Cagnon L, Rossi J, Akkina R. Characterization of anti-CCR5 ribozyme-transduced CD34+ hematopoietic progenitor cells in vitro and in a SCID-hu mouse model in vivo. Mol Ther. 2000; 1(3):244-54.
• [53]Swan CH, Buhler B, Steinberger P, Tschan MP, Barbas CF, Torbett BE. T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery. Gene Ther. 2006; 13(20):1480-92.
• [54]Luis Abad J, Gonzalez MA, del Real G, Mira E, Manes S, Serrano F et al.. Novel interfering bifunctional molecules against the CCR5 coreceptor are efficient inhibitors of HIV-1 infection. Mol Ther. 2003; 8(3):475-84.
• [55]Anderson J, Banerjea A, Akkina R. Bispecific short hairpin siRNA constructs targeted to CD4, CXCR4, and CCR5 confer HIV-1 resistance. Oligonucleotides. 2003; 13(5):303-12.
• [56]Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O et al.. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008; 26(7):808-16.
• [57]Nerys-Junior A, Costa LC, Braga-Dias LP, Oliveira M, Rossi AD, da Cunha RD et al.. Use of the heteroduplex mobility assay and cell sorting to select genome sequences of the CCR5 gene in HEK 293T cells edited by transcription activator-like effector nucleases. Genet Mol Biol. 2014; 37(1):120-6.
• [58]Wilen CB, Wang J, Tilton JC, Miller JC, Kim KA, Rebar EJ et al.. Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. PLoS Pathog. 2011; 7(4):e1002020.
• [59]Scarlatti G, Tresoldi E, Bjorndal A, Fredriksson R, Colognesi C, Deng HK et al.. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nat Med. 1997; 3(11):1259-65.
• [60]Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. Change in coreceptor use correlates with disease progression in HIV-1--infected individuals. J Exp Med. 1997; 185(4):621-8.
• [61]Anderson J, Banerjea A, Planelles V, Akkina R. Potent suppression of HIV type 1 infection by a short hairpin anti-CXCR4 siRNA. AIDS Res Hum Retroviruses. 2003; 19(8):699-706.
• [62]Didigu CA, Wilen CB, Wang J, Duong J, Secreto AJ, Danet-Desnoyers GA et al.. Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. Blood. 2014; 123(1):61-9.
• [63]Li C, Guan X, Du T, Jin W, Wu B, Liu Y et al.. Inhibition of HIV-1 infection of primary CD4+ T cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9. J Gen Virol. 2015; 96(8):2381-93.
• [64]Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z et al.. Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Delta32 mutation confers resistance to HIV infection. Proc Natl Acad Sci U S A. 2014; 111(26):9591-6.
• [65]Wang W, Ye C, Liu J, Zhang D, Kimata JT, Zhou P. CCR5 gene disruption via lentiviral vectors expressing Cas9 and single guided RNA renders cells resistant to HIV-1 infection. PLoS One. 2014; 9(12):e115987.
• [66]Liao HK, Gu Y, Diaz A, Marlett J, Takahashi Y, Li M et al.. Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells. Nat Commun. 2015; 6:6413.
• [67]Hu W, Kaminski R, Yang F, Zhang Y, Cosentino L, Li F et al.. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc Natl Acad Sci U S A. 2014; 111(31):11461-6.
• [68]Wang FX, Xu Y, Sullivan J, Souder E, Argyris EG, Acheampong EA et al.. IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J Clin Invest. 2005; 115(1):128-37.
• [69]Vandergeeten C, Fromentin R, DaFonseca S, Lawani MB, Sereti I, Lederman MM et al.. Interleukin-7 promotes HIV persistence during antiretroviral therapy. Blood. 2013; 121(21):4321-9.
• [70]Perez M, de Vinuesa AG, Sanchez-Duffhues G, Marquez N, Bellido ML, Munoz-Fernandez MA et al.. Bryostatin-1 synergizes with histone deacetylase inhibitors to reactivate HIV-1 from latency. Curr HIV Res. 2010; 8(6):418-29.
• [71]Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, Boyd MR et al.. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood. 2001; 98(10):3006-15.
• [72]Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS. 2004; 18(8):1101-8.
• [73]Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A et al.. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005; 366(9485):549-55.
• [74]Siliciano JD, Lai J, Callender M, Pitt E, Zhang H, Margolick JB et al.. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J Infect Dis. 2007; 195(6):833-6.
• [75]Sagot-Lerolle N, Lamine A, Chaix ML, Boufassa F, Aboulker JP, Costagliola D et al.. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS. 2008; 22(10):1125-9.
• [76]Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM et al.. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One. 2010; 5(2):e9390.
• [77]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. 2014; 69(1):28-33.
• [78]Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM et al.. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012; 487(7408):482-5.
• [79]Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A et al.. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014; 1(1):e13-21.
• [80]Søgaard OS, Graversen ME, Leth S, Olesen R, Brinkmann CR, Nissen SK et al.. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015; 11(9):e1005142.
• [81]Bouchat S, Gatot JS, Kabeya K, Cardona C, Colin L, Herbein G et al.. Histone methyltransferase inhibitors induce HIV-1 recovery in resting CD4(+) T cells from HIV-1-infected HAART-treated patients. AIDS. 2012; 26(12):1473-82.
• [82]Xing S, Bullen CK, Shroff NS, Shan L, Yang HC, Manucci JL et al.. Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation. J Virol. 2011; 85(12):6060-4.
• [83]Spivak AM, Andrade A, Eisele E, Hoh R, Bacchetti P, Bumpus NN et al.. A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin Infect Dis. 2014; 58(6):883-90.
• [84]Doyon G, Zerbato J, Mellors JW, Sluis-Cremer N. Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog. AIDS. 2013; 27(2):F7-11.
• [85]Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014; 20(4):425-9.
• [86]Mothe B, Climent N, Plana M, Rosas M, Jimenez JL, Munoz-Fernandez MA et al.. Safety and immunogenicity of a modified vaccinia Ankara-based HIV-1 vaccine (MVA-B) in HIV-1-infected patients alone or in combination with a drug to reactivate latent HIV-1. J Antimicrob Chemother. 2015; 70(6):1833-42.
• [87]Itzen F, Greifenberg AK, Bosken CA, Geyer M. Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic Acids Res. 2014; 42(12):7577-90.
• [88]Yang Z, Yik JH, Chen R, He N, Jang MK, Ozato K et al.. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005; 19(4):535-45.
• [89]Li Z, Guo J, Wu Y, Zhou Q. The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. Nucleic Acids Res. 2013; 41(1):277-87.
• [90]Boehm D, Calvanese V, Dar RD, Xing S, Schroeder S, Martins L et al.. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle. 2013; 12(3):452-62.
• [91]Darcis G, Kula A, Bouchat S, Fujinaga K, Corazza F, Ait-Ammar A et al.. An in-depth comparison of latency-reversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified bryostatin-1+JQ1 and ingenol-B+JQ1 to potently reactivate viral gene expression. PLoS Pathog. 2015; 11(7):e1005063.
• [92]Laird GM, Bullen CK, Rosenbloom DI, Martin AR, Hill AL, Durand CM et al.. Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J Clin Invest. 2015; 125(5):1901-12.
• [93]Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC et al.. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012; 36(3):491-501.
• [94]Portales P, Reynes J, Pinet V, Rouzier-Panis R, Baillat V, Clot J et al.. Interferon-alpha restores HIV-induced alteration of natural killer cell perforin expression in vivo. AIDS. 2003; 17(4):495-504.
• [95]Guillot B, Portales P, Thanh AD, Merlet S, Dereure O, Clot J et al.. The expression of cytotoxic mediators is altered in mononuclear cells of patients with melanoma and increased by interferon-alpha treatment. Br J Dermatol. 2005; 152(4):690-6.
• [96]Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM, Mounzer K et al.. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis. 2013; 207(2):213-22.
• [97]Porichis F, Hart MG, Zupkosky J, Barblu L, Kwon DS, McMullen A et al.. Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions. J Virol. 2014; 88(5):2508-18.
• [98]Grabmeier-Pfistershammer K, Steinberger P, Rieger A, Leitner J, Kohrgruber N. Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. J Acquir Immune Defic Syndr. 2011; 56(2):118-24.
• [99]Nakanjako D, Ssewanyana I, Mayanja-Kizza H, Kiragga A, Colebunders R, Manabe YC et al.. High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort. BMC Infect Dis. 2011; 11:43.
• [100]Seung E, Dudek TE, Allen TM, Freeman GJ, Luster AD, Tager AM. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads. PLoS One. 2013; 8(10):e77780.
• [101]Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B et al.. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006; 12(10):1198-202.
• [102]Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L et al.. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009; 458(7235):206-10.
• [103]Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E et al.. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U S A. 2002; 99(25):16168-73.
• [104]Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015; 348(6230):62-8.
• [105]Chandran SS, Paria BC, Srivastava AK, Rothermel LD, Stephens DJ, Dudley ME et al.. Persistence of CTL clones targeting melanocyte differentiation antigens was insufficient to mediate significant melanoma regression in humans. Clin Cancer Res. 2015; 21(3):534-43.
• [106]Chapuis AG, Casper C, Kuntz S, Zhu J, Tjernlund A, Diem K et al.. HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo. Blood. 2011; 117(20):5391-402.
• [107]Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G et al.. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015; 517(7534):381-5.
• [108]Li Y, Moysey R, Molloy PE, Vuidepot AL, Mahon T, Baston E et al.. Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat Biotechnol. 2005; 23(3):349-54.
• [109]Joseph A, Zheng JH, Follenzi A, Dilorenzo T, Sango K, Hyman J et al.. Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity. J Virol. 2008; 82(6):3078-89.
• [110]Varela-Rohena A, Molloy PE, Dunn SM, Li Y, Suhoski MM, Carroll RG et al.. Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med. 2008; 14(12):1390-5.
• [111]Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L et al.. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013; 122(6):863-71.
• [112]Leibman RS, Riley JL. Engineering T cells to functionally cure HIV-1 infection. Mol Ther. 2015; 23(7):1149-59.
• [113]Jensen MC, Riddell SR. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev. 2014; 257(1):127-44.
• [114]Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014; 123(17):2625-35.
• [115]Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM et al.. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012; 4(132):132ra153.
• [116]Masiero S, Del Vecchio C, Gavioli R, Mattiuzzo G, Cusi MG, Micheli L et al.. T-cell engineering by a chimeric T-cell receptor with antibody-type specificity for the HIV-1 gp120. Gene Ther. 2005; 12(4):299-310.
• [117]Roberts MR, Qin L, Zhang D, Smith DH, Tran AC, Dull TJ et al.. Targeting of human immunodeficiency virus-infected cells by CD8+ T lymphocytes armed with universal T-cell receptors. Blood. 1994; 84(9):2878-89.
• [118]Dey B, Berger EA. Towards an HIV cure based on targeted killing of infected cells: different approaches against acute versus chronic infection. Curr Opin HIV AIDS. 2015; 10(3):207-13.
• [119]Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM et al.. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009; 106(9):3360-5.
• [120]Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N et al.. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006; 66(22):10995-1004.
• [121]Casucci M, Bondanza A. Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes. J Cancer. 2011; 2:378-82.
• [122]MacLean AG, Walker E, Sahu GK, Skowron G, Marx P, von Laer D et al.. A novel real-time CTL assay to measure designer T-cell function against HIV Env(+) cells. J Med Primatol. 2014; 43(5):341-8.
• [123]Liu L, Patel B, Ghanem MH, Bundoc V, Zheng Z, Morgan RA et al.. Novel CD4-based bispecific chimeric antigen receptor designed for enhanced Anti-HIV potency and absence of HIV entry receptor activity. J Virol. 2015; 89(13):6685-94.
• [124]Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S et al.. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature. 2012; 492(7427):118-22.
• [125]Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J et al.. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature. 2013; 503(7475):224-8.
• [126]Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, Tretiakova A, Eisenreich TR et al.. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A. 2013; 110(41):16538-43.
• [127]Chun TW, Murray D, Justement JS, Blazkova J, Hallahan CW, Fankuchen O et al.. Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir. Proc Natl Acad Sci U S A. 2014; 111(36):13151-6.
• [128]Malbec M, Porrot F, Rua R, Horwitz J, Klein F, Halper-Stromberg A et al.. Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission. J Exp Med. 2013; 210(13):2813-21.
• [129]Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP, Buckley N et al.. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015; 522(7557):487-91.
• [130]Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S, Nogueira L et al.. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell. 2014; 158(5):989-99.
• [131]Suzuki K, Shijuuku T, Fukamachi T, Zaunders J, Guillemin G, Cooper D et al.. Prolonged transcriptional silencing and CpG methylation induced by siRNAs targeted to the HIV-1 promoter region. J RNAi Gene Silencing. 2005; 1(2):66-78.
• [132]Yamagishi M, Ishida T, Miyake A, Cooper DA, Kelleher AD, Suzuki K et al.. Retroviral delivery of promoter-targeted shRNA induces long-term silencing of HIV-1 transcription. Microbes Infect. 2009; 11(4):500-8.
• [133]Suzuki K, Hattori S, Marks K, Ahlenstiel C, Maeda Y, Ishida T et al.. Promoter targeting shRNA suppresses HIV-1 infection in vivo through transcriptional gene silencing. Mol Ther Nucleic Acids. 2013; 2:e137.
• [134]Turner AM, De La Cruz J, Morris KV. Mobilization-competent lentiviral vector-mediated sustained transcriptional modulation of HIV-1 expression. Mol Ther. 2009; 17(2):360-8.
• [135]Turner AM, Ackley AM, Matrone MA, Morris KV. Characterization of an HIV-targeted transcriptional gene-silencing RNA in primary cells. Hum Gene Ther. 2012; 23(5):473-83.
• [136]Saayman S, Ali SA, Morris KV, Weinberg MS. The therapeutic application of CRISPR/Cas9 technologies for HIV. Expert Opin Biol Ther. 2015; 15(6):819-30.
• [137]Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013; 3:2510.
• [138]Murry JP, Godoy J, Mukim A, Swann J, Bruce JW, Ahlquist P et al.. Sulfonation pathway inhibitors block reactivation of latent HIV-1. Virology. 2014; 471–3:1-12.
• [139]Mantelingu K, Reddy BA, Swaminathan V, Kishore AH, Siddappa NB, Kumar GV et al.. Specific inhibition of p300-HAT alters global gene expression and represses HIV replication. Chem Biol. 2007; 14(6):645-57.
• [140]Mousseau G, Clementz MA, Bakeman WN, Nagarsheth N, Cameron M, Shi J et al.. An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription. Cell Host Microbe. 2012; 12(1):97-108.
• [141]Mousseau G, Kessing CF, Fromentin R, Trautmann L, Chomont N, Valente ST. The Tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from latency. MBio. 2015; 6(4):e00465.
• [142]Heredia A, Le N, Gartenhaus RB, Sausville E, Medina-Moreno S, Zapata JC et al.. Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice. Proc Natl Acad Sci U S A. 2015; 112(30):9412-7.
• [143]Fenaux P. Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol. 2005; 2 Suppl 1:S36-44.
• [144]Reuse S, Calao M, Kabeya K, Guiguen A, Gatot JS, Quivy V et al.. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One. 2009; 4(6):e6093.
• [145]Burnett JC, Lim KI, Calafi A, Rossi JJ, Schaffer DV, Arkin AP. Combinatorial latency reactivation for HIV–1 subtypes and variants. J Virol. 2010; 84(12):5958-74.