Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells.
References
[1]
Yukl, S.A.; Shergill, A.; McQuaid, K.; Gianella, S.; Lampiris, H.; Hare, C.B.; Pandori, M.; Sinclair, E.; Günthard, H.F.; Fischer, M.; et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 2010, 24, 2451–2460, doi:10.1097/QAD.0b013e32833ef7bb.
[2]
Deeks, S.G. HIV infection, inflammation, immunosenescence, and aging. Medicine 2011, 62, 141–155, doi:10.1146/annurev-med-042909-093756.
[3]
Volberding, P.A.; Deeks, S.G. Antiretroviral therapy and management of HIV infection. Lancet 2010, 376, 49–62, doi:10.1016/S0140-6736(10)60676-9.
[4]
Yu, M.; Poeschla, E.; Wong-Staal, F. Progress towards gene therapy for HIV infection. Gene Ther. 1994, 1, 13–26.
[5]
Piché, A. Gene therapy for HIV infections: Intracellular immunization. Can. J. Infect. Dis. 1999, 10, 307–312.
[6]
Weiss, R.A. Thirty years on: HIV receptor gymnastics and the prevention of infection. BMC Biol. 2013, 11, e57, doi:10.1186/1741-7007-11-57.
[7]
Liu, R.; Paxton, W.A.; Choe, S.; Ceradini, D.; Martin, S.R.; Horuk, R.; MacDonald, M.E.; Stuhlmann, H.; Koup, R.A.; Landau, N.R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996, 86, 367–377, doi:10.1016/S0092-8674(00)80110-5.
[8]
De Roda Husman, A.M.; Koot, M.; Cornelissen, M.; Keet, I.P.; Brouwer, M.; Broersen, S.M.; Bakker, M.; Roos, M.T.; Prins, M.; de Wolf, F.; et al. Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann. Intern. Med. 1997, 127, 882–890, doi:10.7326/0003-4819-127-10-199711150-00004.
[9]
Gilliam, B.L.; Riedel, D.J.; Redfield, R.R. Clinical use of CCR5 inhibitors in HIV and beyond. J. Transl. Med. 2011, 9, S9, doi:10.1186/1479-5876-9-S1-S9.
[10]
Hütter, G.; Nowak, D.; Mossner, M.; Ganepola, S.; Mü？ig, A.; Allers, K.; Schneider, T.; Hofmann, J.; Kücherer, C.; Blau, O.; et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N. Engl. J. Med. 2009, 360, 692–698, doi:10.1056/NEJMoa0802905.
[11]
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, 2791–2799, doi:10.1182/blood-2010-09-309591.
[12]
Qin, X.-F.; An, D.S.; Chen, I.S.Y.; Baltimore, D. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc. Natl. Acad. Sci. USA 2003, 100, 183–188, doi:10.1073/pnas.232688199.
[13]
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, 244–254, doi:10.1006/mthe.2000.0038.
[14]
Swan, C.H.; Bühler, B.; Steinberger, P.; Tschan, M.P.; Barbas, C.F.; Torbett, B.E. T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery. Gene Ther. 2006, 13, 1480–1492, doi:10.1038/sj.gt.3302801.
[15]
Schroers, R.; Davis, C.M.; Wagner, H.-J.; Chen, S.-Y. Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection. Gene Ther. 2002, 9, 889–897, doi:10.1038/sj.gt.3301711.
[16]
Shimizu, S.; Hong, P.; Arumugam, B.; Pokomo, L.; Boyer, J.; Koizumi, N.; Kittipongdaja, P.; Chen, A.; Bristol, G.; Galic, Z.; et al. A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model. Blood 2010, 115, 1534–1544, doi:10.1182/blood-2009-04-215855.
[17]
Bobis-Wozowicz, S.; Osiak, A.; Rahman, S.H.; Cathomen, T. Targeted genome editing in pluripotent stem cells using zinc-finger nucleases. Methods 2011, 53, 339–346, doi:10.1016/j.ymeth.2010.12.019.
[18]
Perez, E.E.; Wang, J.; Miller, J.C.; Jouvenot, Y.; Kim, K.A.; Liu, O.; Wang, N.; Lee, G.; Bartsevich, V.V.; Lee, Y.-L.; et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat. Biotechnol. 2008, 26, 808–816, doi:10.1038/nbt1410.
[19]
Holt, N.; Wang, J.; Kim, K.; Friedman, G.; Wang, X.; Taupin, V.; Crooks, G.M.; Kohn, D.B.; Gregory, P.D.; Holmes, M.C.; et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat. Biotechnol. 2010, 28, 839–847, doi:10.1038/nbt.1663.
[20]
Li, L.; Krymskaya, L.; Wang, J.; Henley, J.; Rao, A.; Cao, L.-F.; Tran, C.-A.; Torres-Coronado, M.; Gardner, A.; Gonzalez, N.; et al. Genomic editing of the HIV-1 coreceptor CCR5 in adult hematopoietic stem and progenitor cells using zinc finger nucleases. Mol. Ther. 2013, 21, 1259–1269, doi:10.1038/mt.2013.65.
[21]
Wilen, C.B.; Wang, J.; Tilton, J.C.; Miller, J.C.; Kim, K.A.; Rebar, E.J.; Sherrill-Mix, S.A.; Patro, S.C.; Secreto, A.J.; Jordan, A.P.O.; et al. Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. PLoS Pathog. 2011, 7, e1002020, doi:10.1371/journal.ppat.1002020.
[22]
Kiem, H.-P.; Jerome, K.R.; Deeks, S.G.; McCune, J.M. Hematopoietic-stem-cell-based gene therapy for HIV disease. Stem Cell 2012, 10, 137–147.
[23]
Mitsuyasu, R.T.; Merigan, T.C.; Carr, A.; Zack, J.A.; Winters, M.A.; Workman, C.; Bloch, M.; Lalezari, J.; Becker, S.; Thornton, L.; et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat. Med. 2009, 15, 285–292, doi:10.1038/nm.1932.
[24]
Kang, E.M.; de Witte, M.; Malech, H.; Morgan, R.A.; Phang, S.; Carter, C.; Leitman, S.F.; Childs, R.; Barrett, A.J.; Little, R.; et al. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood 2002, 99, 698–701, doi:10.1182/blood.V99.2.698.
[25]
Bonyhadi, M.L.; Moss, K.; Voytovich, A.; Auten, J.; Kalfoglou, C.; Plavec, I.; Forestell, S.; Su, L.; B？hnlein, E.; Kaneshima, H. RevM10-expressing T cells derived in vivo from transduced human hematopoietic stem-progenitor cells inhibit human immunodeficiency virus replication. J. Virol. 1997, 71, 4707–4716.
[26]
Podsakoff, G.M.; Engel, B.C.; Carbonaro, D.A.; Choi, C.; Smogorzewska, E.M.; Bauer, G.; Selander, D.; Csik, S.; Wilson, K.; Betts, M.R.; et al. Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34+ cells. Mol. Ther. 2005, 12, 77–86, doi:10.1016/j.ymthe.2005.02.024.
[27]
Kohn, D.B.; Bauer, G.; Rice, C.R.; Rothschild, J.C.; Carbonaro, D.A.; Valdez, P.; Hao, Q.L.; Zhou, C.; Bahner, I.; Kearns, K.; et al. A clinical trial of retroviral-mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus-1-infected children. Blood 1999, 94, 368–371.
[28]
Jacque, J.-M.; Triques, K.; Stevenson, M. Modulation of HIV-1 replication by RNA interference. Nature 2002, 418, 435–438, doi:10.1038/nature00896.
[29]
Das, A.T.; Brummelkamp, T.R.; Westerhout, E.M.; Vink, M.; Madiredjo, M.; Bernards, R.; Berkhout, B. Human immunodeficiency virus type 1 escapes from RNA interference-mediated inhibition. J. Virol. 2004, 78, 2601–2605, doi:10.1128/JVI.78.5.2601-2605.2004.
[30]
Egelhofer, M.; Brandenburg, G.; Martinius, H.; Schult-Dietrich, P.; Melikyan, G.; Kunert, R.; Baum, C.; Choi, I.; Alexandrov, A.; von Laer, D. Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides. J. Virol. 2004, 78, 568–575, doi:10.1128/JVI.78.2.568-575.2004.
[31]
Van Lunzen, J.; Glaunsinger, T.; Stahmer, I.; von Baehr, V.; Baum, C.; Schilz, A.; Kuehlcke, K.; Naundorf, S.; Martinius, H.; Hermann, F.; et al. Transfer of autologous gene-modified T cells in HIV-infected patients with advanced immunodeficiency and drug-resistant virus. Mol. Ther. 2007, 15, 1024–1033.
[32]
Stremlau, M.; Owens, C.M.; Perron, M.J.; Kiessling, M.; Autissier, P.; Sodroski, J. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 2004, 427, 848–853, doi:10.1038/nature02343.
[33]
Li, Y.; Li, X.; Stremlau, M.; Lee, M.; Sodroski, J. Removal of arginine 332 allows human TRIM5alpha to bind human immunodeficiency virus capsids and to restrict infection. J. Virol. 2006, 80, 6738–6744, doi:10.1128/JVI.00270-06.
[34]
Anderson, J.; Akkina, R. Human immunodeficiency virus type 1 restriction by human-rhesus chimeric tripartite motif 5alpha (TRIM 5alpha) in CD34(+) cell-derived macrophages in vitro and in T cells in vivo in severe combined immunodeficient (SCID-hu) mice transplanted with human fetal tissue. Human Gene Ther. 2008, 19, 217–228, doi:10.1089/hum.2007.108.
[35]
Neagu, M.R.; Ziegler, P.; Pertel, T.; Strambio-De-Castillia, C.; Grütter, C.; Martinetti, G.; Mazzucchelli, L.; Grütter, M.; Manz, M.G.; Luban, J. Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. J. Clin. Invest. 2009, 119, 3035–3047, doi:10.1172/JCI39354.
[36]
Li, X.; Afif, H.; Cheng, S.; Martel-Pelletier, J.; Pelletier, J.-P.; Ranger, P.; Fahmi, H. Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes. J. Rheumatol. 2005, 32, 887–895.
[37]
Schr？felbauer, B.; Chen, D.; Landau, N.R. A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif). Proc. Natl. Acad. Sci. USA 2004, 101, 3927–3932, doi:10.1073/pnas.0307132101.
[38]
McNatt, M.W.; Zang, T.; Hatziioannou, T.; Bartlett, M.; Ben Fofana, I.; Johnson, W.E.; Neil, S.J.D.; Bieniasz, P.D.; Hope, T.J. Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. PLoS Pathog. 2009, 5, e1000300, doi:10.1371/journal.ppat.1000300.
[39]
DiGiusto, D.L.; Krishnan, A.; Li, L.; Li, H.; Li, S.; Rao, A.; Mi, S.; Yam, P.; Stinson, S.; Kalos, M.; et al. RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. Sci. Transl. Med. 2010, 2, 36ra43.
[40]
Kiem, H.-P.; Wu, R.A.; Sun, G.; von Laer, D.; Rossi, J.J.; Trobridge, G.D. Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo. Gene Ther. 2010, 17, 37–49, doi:10.1038/gt.2009.118.
[41]
ter Brake, O.; Konstantinova, P.; Ceylan, M.; Berkhout, B. Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol. Ther. 2006, 14, 883–892, doi:10.1016/j.ymthe.2006.07.007.
[42]
Chung, J.; Zhang, J.; Li, H.; Ouellet, D.L.; DiGiusto, D.L.; Rossi, J.J. Endogenous MCM7 MicroRNA cluster as a novel platform to multiplex small interfering and nucleolar RNAs for combinational HIV-1 gene therapy. Human Gene Ther. 2012, 23, 1200–1208, doi:10.1089/hum.2012.011.
[43]
Choudhary, R.; Baturin, D.; Fosmire, S.; Freed, B.; Porter, C.C. Knockdown of HPRT for selection of genetically modified human hematopoietic progenitor cells. PLoS One 2013, 8, e59594.
[44]
Hacke, K.; Treger, J.A.; Bogan, B.T.; Schiestl, R.H.; Kasahara, N. Genetic modification of mouse bone marrow by lentiviral vector-mediated delivery of hypoxanthine-Guanine phosphoribosyltransferase short hairpin RNA confers chemoprotection against 6-thioguanine cytotoxicity. Transplant. Proc. 2013, 45, 2040–2044, doi:10.1016/j.transproceed.2013.01.020.
[45]
Trono, D.; van Lint, C.; Rouzioux, C.; Verdin, E.; Barré-Sinoussi, F.; Chun, T.-W.; Chomont, N. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 2010, 329, 174–180, doi:10.1126/science.1191047.
[46]
Shan, L.; Deng, K.; Shroff, N.S.; Durand, C.M.; Rabi, S.A.; Yang, H.-C.; Zhang, H.; Margolick, J.B.; Blankson, J.N.; Siliciano, R.F. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 2012, 36, 491–501, doi:10.1016/j.immuni.2012.01.014.
[47]
Migueles, S.A.; Connors, M. Small molecules and big killers: The challenge of eliminating the latent HIV reservoir. Immunity 2012, 36, 320–321, doi:10.1016/j.immuni.2012.03.006.
[48]
Garcia, F.; León, A.; Gatell, J.; Plana, M.; Gallart, T. Therapeutic vaccines against HIV infection. Hum. Vaccines 2012, 8, 569–581.
[49]
Papagno, L.; Alter, G.; Assoumou, L.; Murphy, R.L.; Garcia, F.; Clotet, B.; Larsen, M.; Braibant, M.; Marcelin, A.-G.; 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, doi:10.1097/QAD.0b013e328340fe55.
[50]
Kinloch-de Loes, S.; Hoen, B.; Smith, D.E.; Autran, B.; Lampe, F.C.; Phillips, A.N.; Goh, L.-E.; 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, doi:10.1086/432002.
[51]
Bozzacco, L.; Trumpfheller, C.; Siegal, F.P.; Mehandru, S.; Markowitz, M.; Carrington, M.; Nussenzweig, M.C.; Piperno, A.G.; Steinman, R.M. DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes. Proc. Natl. Acad. Sci. USA 2007, 104, 1289–1294, doi:10.1073/pnas.0610383104.
[52]
García, F.; Climent, N.; Guardo, A.C.; Gil, C.; León, A.; Autran, B.; Lifson, J.D.; Martínez-Picado, J.; Dalmau, J.; Clotet, B.; et al. A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Sci. Transl. Med. 2013, 5, 166ra2.
[53]
Joseph, A.; Zheng, J.H.; Chen, K.; Dutta, M.; Chen, C. Inhibition of in vivo HIV infection in humanized mice by gene therapy of human hematopoietic stem cells with a lentiviral vector encoding a broadly neutralizing anti-HIV antibody. J. Virol. 2010, 84, 6645–6653, doi:10.1128/JVI.02339-09.
[54]
Cooper, L.J.; Kalos, M.; Lewinsohn, D.A.; Riddell, S.R.; Greenberg, P.D. Transfer of specificity for human immunodeficiency virus type 1 into primary human T lymphocytes by introduction of T-cell receptor genes. J. Virol. 2000, 74, 8207–8212, doi:10.1128/JVI.74.17.8207-8212.2000.
[55]
Varela-Rohena, A.; Molloy, P.E.; Dunn, S.M.; Li, Y.; Suhoski, M.M.; Carroll, R.G.; Milicic, A.; Mahon, T.; Sutton, D.H.; Laugel, B.; et al. Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat. Med. 2008, 14, 1390–1395, doi:10.1038/nm.1779.
[56]
Redirected High Affinity Gag-Specific Autologous T Cells for HIV Gene Therapy. Available online: http://clinicaltrials.gov/show/NCT00991224 (accessed on 19 December 2013).
[57]
Scholler, J.; Brady, T.L.; Binder-Scholl, G.; Hwang, W.-T.; Plesa, G.; Hege, K.M.; Vogel, A.N.; Kalos, M.; Riley, J.L.; Deeks, S.G.; et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 2012, 4, 132ra53.
[58]
Mitsuyasu, R.T.; Anton, P.A.; Deeks, S.G.; Scadden, D.T.; Connick, E.; Downs, M.T.; Bakker, A.; Roberts, M.R.; June, C.H.; Jalali, S.; et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood 2000, 96, 785–793.
[59]
Vatakis, D.N.; Arumugam, B.; Kim, S.G.; Bristol, G.; Yang, O.; Zack, J.A. Introduction of exogenous T-cell receptors into human hematopoietic progenitors results in exclusion of endogenous T-cell receptor expression. Mol. Ther. 2013, 21, 1055–1063, doi:10.1038/mt.2013.28.
[60]
Kitchen, S.G.; Levin, B.R.; Bristol, G.; Rezek, V.; Kim, S.; Aguilera-Sandoval, C.; Balamurugan, A.; Yang, O.O.; Zack, J.A. In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells. PLoS Pathog. 2012, 8, e1002649, doi:10.1371/journal.ppat.1002649.
[61]
Balamurugan, A.; Ng, H.L.; Yang, O.O. Rapid T cell receptor delineation reveals clonal expansion limitation of the magnitude of the HIV-1-specific CD8+ T cell response. J. Immunol. 2010, 185, 5935–5942, doi:10.4049/jimmunol.1002236.
[62]
Aiuti, A.; Cattaneo, F.; Galimberti, S.; Benninghoff, U.; Cassani, B.; Callegaro, L.; Scaramuzza, S.; Andolfi, G.; Mirolo, M.; Brigida, I.; et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 2009, 360, 447–458, doi:10.1056/NEJMoa0805817.
