Novel gene and cellular therapy approaches for treating HIV

Discovery Medicine

Volumn 21, Issue 116, 2016, Pages 283-292

  Bhoj, Vijay G ^a   Thibodeaux, Suzanne R ^a   Levine, Bruce L ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOVIRUS VECTOR; APOLIPOPROTEIN B MESSENGER RNA EDITING ENZYME CATALYTIC POLYPEPTIDE 3G; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; CHIMERIC ANTIGEN RECEPTOR; GLYCOPROTEIN GP 160; GLYCOPROTEIN GP 41; INTEGRASE; LENTIVIRUS VECTOR; MARAVIROC; RETROVIRUS VECTOR; RIBOZYME; RNA DIRECTED DNA POLYMERASE; TRANSCRIPTION ACTIVATOR LIKE EFFECTOR NUCLEASE; ZINC FINGER NUCLEASE; ANTIRETROVIRUS AGENT; CCR5 PROTEIN, HUMAN; DNA BINDING PROTEIN; ESCHERICHIA COLI PROTEIN; MAZF PROTEIN, E COLI; REV PROTEIN; RIBONUCLEASE;

ADOPTIVE IMMUNOTHERAPY; ANTIVIRAL RESISTANCE; ARTICLE; CD4+ T LYMPHOCYTE; CELL BASED GENE THERAPY; CRISPR CAS SYSTEM; GENE DELIVERY SYSTEM; HEMATOPOIETIC STEM CELL; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LEUKAPHERESIS; NONHUMAN; PATIENT COMPLIANCE; PERSONALIZED MEDICINE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROVIRUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVERSE TRANSCRIPTION; RNA STABILITY; RNA TRANSCRIPTION; VIRAL GENE THERAPY; VIRUS ENTRY; AUTOTRANSPLANTATION; BIOLOGICAL THERAPY; DRUG EFFECTS; GENE THERAPY; GENE TRANSFER; GENETICS; HIV INFECTIONS; IMMUNOLOGY; PHYSIOLOGY; PROCEDURES; QUALITY OF LIFE; T LYMPHOCYTE; TRANSPLANTATION;

ANTI-RETROVIRAL AGENTS; CELL- AND TISSUE-BASED THERAPY; CRISPR-CAS SYSTEMS; DNA-BINDING PROTEINS; DRUG RESISTANCE, VIRAL; ENDORIBONUCLEASES; ESCHERICHIA COLI PROTEINS; GENE TRANSFER TECHNIQUES; GENETIC THERAPY; HIV INFECTIONS; HIV-1; HUMANS; QUALITY OF LIFE; RECEPTORS, CCR5; REV GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; T-LYMPHOCYTES; TRANSCRIPTION ACTIVATOR-LIKE EFFECTOR NUCLEASES; TRANSPLANTATION, AUTOLOGOUS;

EID: 85007409905     PISSN: 15396509     EISSN: 19447930     Source Type: Journal    
DOI: None     Document Type: Article

References (70)

1. 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 117(10):2791-2799, 2011.
2. Amado RG, Mitsuyasu RT, Rosenblatt JD, Ngok FK, Bakker A, Cole S, Chorn N, Lin LS, Bristol G, Boyd MP, Macpherson JL, Fanning GC, Todd AV, Ely JA, Zack JA, Symonds GP. Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients. Hum Gene Ther 15(3):251-262, 2004.
3. Amado RG, Mitsuyasu RT, Symonds G, Rosenblatt JD, Zack J, Sun LQ, Miller M, Ely J, Gerlach W. A phase I trial of autologous CD34+ hematopoietic progenitor cells transduced with an anti-HIV ribozyme. Hum Gene Ther 10(13):2255-2270, 1999.
4. Anderson J, Li MJ, Palmer B, Remling L, Li S, Yam P, Yee JK, Rossi J, Zaia J, Akkina R. Safety and efficacy of a lentiviral vector containing three anti-HIV genes-CCR5 ribozyme, tat-rev siRNA, and TAR decoy-in SCID-hu mouse-derived T cells. Mol Ther 15(6):1182-1188, 2007.
5. Archin NM, Margolis DM. Attacking latent HIV provirus: from mechanism to therapeutic strategies. Curr Opin HIV AIDS 1(2):134-140, 2006.
6. Bogerd HP, Kornepati AVR, Marshall JB, Kennedy EM, Cullen BR. Specific induction of endogenous viral restriction factors using CRISPR/Cas-derived transcriptional activators. Proc Natl Acad Sci 112(52):E7249-E7256, 2015.
7. Bouhamdan M, Duan LX, Pomerantz RJ, Strayer DS. Inhibition of HIV-1 by an anti-integrase single-chain variable fragment (SFv): delivery by SV40 provides durable protection against HIV-1 and does not require selection. Gene Ther 6(4):660-666, 1999.
8. Chono H, Matsumoto K, Tsuda H, Saito N, Lee K, Kim S, Shibata H, Ageyama N, Terao K, Yasutomi Y, Mineno J, Kim S, Inouye M, Kato I. Acquisition of HIV-1 resistance in T lymphocytes using an ACA-specific E. coli mRNA interferase. Hum Gene Ther 22(1):35-43, 2011a.
9. Chono H, Saito N, Tsuda H, Shibata H, Ageyama N, Terao K, Yasutomi Y, Mineno J, Kato I. In vivo safety and persistence of endoribonuclease gene-transduced CD4+ T cells in cynomolgus macaques for HIV-1 gene therapy model. PLoS One 6(8):e23585, 2011b.
10. Cooper D, Penny R, Symonds G, Carr A, Gerlach W, Sun LQ, Ely J. A marker study of therapeutically transduced CD4+ peripheral blood lymphocytes in HIV discordant identical twins. Hum Gene Ther 10(8):1401-1421, 1999.
11. Da Silva FA, Li M, Rato S, Maia S, Malho R, Warren K, Harrich D, Craigie R, Barbas C, 3rd, Goncalves J. Recombinant rabbit single-chain antibodies bind to the catalytic and C-terminal domains of HIV-1 integrase protein and strongly inhibit HIV-1 replication. Biotechnol Appl Biochem 59(5):353-366, 2012.
12. Dampier W, Nonnemacher MR, Sullivan NT, Jacobson JM, Wigdahl B. HIV Excision Utilizing CRISPR/Cas9 Technology: Attacking the Proviral Quasispecies in Reservoirs to Achieve a Cure. MOJ Immunol 1(4), 2014.
13. Didigu CA, Wilen CB, Wang J, Duong J, Secreto AJ, Danet-Desnoyers GA, Riley JL, Gregory PD, June CH, Holmes MC, Doms RW. Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. Blood 123(1):61-69, 2014.
14. Digiusto DL, Krishnan A, Li L, Li H, Li S, Rao A, Mi S, Yam P, Stinson S, Kalos M, Alvarnas J, Lacey SF, Yee JK, Li M, Couture L, Hsu D, Forman SJ, Rossi JJ, Zaia JA. RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. Sci Transl Med 2(36):36ra43, 2010.
15. Ebina H, Kanemura Y, Misawa N, Sakuma T, Kobayashi T, Yamamoto T, Koyanagi Y. A high excision potential of TALENs for integrated DNA of HIV-based lentiviral vector. PLoS One 10(3):e0120047, 2015.
16. Hao YZ, Teng ZP, Yang YS, Sun XN, Ma J, Jin XH, Zeng Y. [Inhibition of HIV-1 in vitro by combination of vpr and tat specific short hairpin RNA via lentiviral vectors]. Bing Du Xue Bao 29(2):126-131, 2013.
17. Herschhorn A, Admon A, Hizi A. Recombinant human antibodies against the reverse transcriptase of human immunodeficiency virus type-1. Biochim Biophys Acta 1648(1-2):154-163, 2003.
18. Hou P, Chen S, Wang S, Yu X, Chen Y, Jiang M, Zhuang K, Ho W, Hou W, Huang J, Guo D. Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection. Sci Rep 5:15577, 2015.
19. Hu W, Kaminski R, Yang F, Zhang Y, Cosentino L, Li F, Luo B, Alvarez-Carbonell D, Garcia-Mesa Y, Karn J, Mo X, Khalili K. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc Natl Acad Sci U S A 111(31):11461-11466, 2014.
20. Hu Z, Luo Z, Wan Z, Wu H, Li W, Zhang T, Jiang W. HIV-associated memory B cell perturbations. Vaccine 33(22):2524-2529, 2015.
21. Hütter G, Ganepola S. Eradication of HIV by Transplantation of CCR5-Deficient Hematopoietic Stem Cells. Sci World J 11:1068-1076, 2011.
22. Ji H, Jiang Z, Lu P, Ma L, Li C, Pan H, Fu Z, Qu X, Wang P, Deng J, Yang X, Wang J, Zhu H. Specific reactivation of latent HIV-1 by dCas9-SunTag-VP64-mediated guide RNA targeting the HIV-1 promoter. Mol Ther 24(3):508-521, 2016.
23. Joseph A, Zheng JH, Follenzi A, Dilorenzo T, Sango K, Hyman J, Chen K, Piechocka-Trocha A, Brander C, Hooijberg E, Vignali DA, Walker BD, Goldstein H. 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 82(6):3078-3089, 2008.
24. Kang EM, De Witte M, Malech H, Morgan RA, Phang S, Carter C, Leitman SF, Childs R, Barrett AJ, Little R, Tisdale JF. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood 99(2):698-701, 2002.
25. Kang H, Minder P, Park MA, Mesquitta W-T, Torbett BE, Slukvin II. CCR5 Disruption in Induced Pluripotent Stem Cells Using CRISPR/Cas9 Provides Selective Resistance of Immune Cells to CCR5-tropic HIV-1 Virus. Mol Ther Nucleic Acids 4:e268, 2015.
26. Kershaw MH, Westwood JA, Slaney CY, Darcy PK. Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunol 3(5):e16, 2014.
27. Kitchen SG, Levin BR, Bristol G, Rezek V, Kim S, Aguilera-Sandoval C, Balamurugan A, Yang OO, Zack JA. In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells. PLoS Pathog 8(4):e1002649, 2012.
28. Kohn DB, Bauer G, Rice CR, Rothschild JC, Carbonaro DA, Valdez P, Hao Q, Zhou C, Bahner I, Kearns K, Brody K, Fox S, Haden E, Wilson K, Salata C, Dolan C, Wetter C, Aguilar-Cordova E, Church J. 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 94(1):368-371, 1999.
29. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol 119:51-83, 2013.
30. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967):517-528, 2015.
31. Levine BL, Humeau LM, Boyer J, Macgregor RR, Rebello T, Lu X, Binder GK, Slepushkin V, Lemiale F, Mascola JR, Bushman FD, Dropulic B, June CH. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A 103(46):17372-17377, 2006.
32. Levy-Mintz P, Duan L, Zhang H, Hu B, Dornadula G, Zhu M, Kulkosky J, Bizub-Bender D, Skalka AM, Pomerantz RJ. Intracellular expression of single-chain variable fragments to inhibit early stages of the viral life cycle by targeting human immunodeficiency virus type 1 integrase. J Virol 70(12):8821-8832, 1996.
33. Li C, Guan X, Du T, Jin W, Wu B, Liu Y, Wang P, Hu B, Griffin GE, Shattock RJ, Hu Q. Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9. J Gen Virol 96(8):2381-2393, 2015.
34. Liu L, Patel B, Ghanem MH, Bundoc V, Zheng Z, Morgan RA, Rosenberg SA, Dey B, Berger EA. Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity. J Virol 89(13):6685-6694, 2015.
35. Lu X, Yu Q, Binder GK, Chen Z, Slepushkina T, Rossi J, Dropulic B. Antisense-mediated inhibition of human immunodeficiency virus (HIV) replication by use of an HIV type 1-based vector results in severely attenuated mutants incapable of developing resistance. J Virol 78(13):7079-7088, 2004.
36. Maciejewski JP, Weichold FF, Young NS, Cara A, Zella D, Reitz MS, Jr., Gallo RC. Intracellular expression of antibody fragments directed against HIV reverse transcriptase prevents HIV infection in vitro. Nat Med 1(7):667-673, 1995.
37. Macpherson JL, Boyd MP, Arndt AJ, Todd AV, Fanning GC, Ely JA, Elliott F, Knop A, Raponi M, Murray J, Gerlach W, Sun LQ, Penny R, Symonds GP, Carr A, Cooper DA. Long-term survival and concomitant gene expression of ribozyme-transduced CD4+ T-lymphocytes in HIV-infected patients. J Gene Med 7(5):552-564, 2005.
38. Maeder ML, Gersbach CA. Genome-editing technologies for gene and cell therapy. Mol Ther 24(3):430-446, 2016.
39. Maier DA, Brennan AL, Jiang S, Binder-Scholl GK, Lee G, Plesa G, Zheng Z, Cotte J, Carpenito C, Wood T, Spratt SK, Ando D, Gregory P, Holmes MC, Perez EE, Riley JL, Carroll RG, June CH, Levine BL. Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. Hum Gene Ther 24(3):245-258, 2013.
40. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507-1517, 2014.
41. Michienzi A, Li S, Zaia JA, Rossi JJ. A nucleolar TAR decoy inhibitor of HIV-1 replication. Proc Natl Acad Sci U S A 99(22):14047-14052, 2002.
42. Mitsuyasu RT, Merigan TC, Carr A, Zack JA, Winters MA, Workman C, Bloch M, Lalezari J, Becker S, Thornton L, Akil B, Khanlou H, Finlayson R, Mcfarlane R, Smith DE, Garsia R, Ma D, Law M, Murray JM, Von Kalle C, et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med 15(3):285-292, 2009.
43. Mock U, Machowicz R, Hauber I, Horn S, Abramowski P, Berdien B, Hauber J, Fehse B. mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5. Nucleic Acids Res 43(11):5560-5571, 2015.
44. Morgan RA, Kakarla S. Genetic modification of T cells. Cancer J 20(2):145-150, 2014.
45. Morgan RA, Walker R, Carter CS, Natarajan V, Tavel JA, Bechtel C, Herpin B, Muul L, Zheng Z, Jagannatha S, Bunnell BA, Fellowes V, Metcalf JA, Stevens R, Baseler M, Leitman SF, Read EJ, Blaese RM, Lane HC. Preferential survival of CD4+ T lymphocytes engineered with anti-human immunodeficiency virus (HIV) genes in HIV-infected individuals. Hum Gene Ther 16(9):1065-1074, 2005.
46. Oz Gleenberg I, Avidan O, Goldgur Y, Herschhorn A, Hizi A. Peptides derived from the reverse transcriptase of human immunodeficiency virus type 1 as novel inhibitors of the viral integrase. J Biol Chem 280(23):21987-21996, 2005.
47. Oz Gleenberg I, Herschhorn A, Goldgur Y, Hizi A. Inhibition of human immunodeficiency virus type-1 reverse transcriptase by a novel peptide derived from the viral integrase. Arch Biochem Biophys 458(2):202-212, 2007.
48. Pham QT, Bouchard A, Grutter MG, Berthoux L. Generation of human TRIM5alpha mutants with high HIV-1 restriction activity. Gene Ther 17(7):859-871, 2010.
49. Pierson T, Mcarthur J, Siliciano RF. Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol 18:665-708, 2000.
50. Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7(303):303ra139, 2015.
51. Qu X, Wang P, Ding D, Wang X, Zhang G, Zhou X, Liu L, Zhu X, Zeng H, Zhu H. Zinc finger nuclease: a new approach for excising HIV-1 proviral DNA from infected human T cells. Mol Biol Rep 41(9):5819-5827, 2014.
52. Ranga U, Woffendin C, Verma S, Xu L, June CH, Bishop DK, Nabel GJ. Enhanced T cell engraftment after retroviral delivery of an antiviral gene in HIV-infected individuals. Proc Natl Acad Sci U S A 95(3):1201-1206, 1998.
53. Richardson MW, Guo L, Xin F, Yang X, Riley JL. Stabilized human TRIM5alpha protects human T cells from HIV-1 infection. Mol Ther 22(6):1084-1095, 2014.
54. Ross EL, Weinstein MC, Schackman BR, Sax PE, Paltiel AD, Walensky RP, Freedberg KA, Losina E. The clinical role and cost-effectiveness of long-acting antiretroviral therapy. Clin Infect Dis 60(7):1102-1110, 2015.
55. Sahu GK, Sango K, Selliah N, Ma Q, Skowron G, Junghans RP. Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells. Virology 446(1-2):268-275, 2013.
56. Sather BD, Romano Ibarra GS, Sommer K, Curinga G, Hale M, Khan IF, Singh S, Song Y, Gwiazda K, Sahni J, Jarjour J, Astrakhan A, Wagner TA, Scharenberg AM, Rawlings DJ. Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template. Sci Transl Med 7(307):307ra156-307ra156, 2015.
57. Setiawan LC, Kootstra NA. Adaptation of HIV-1 to rhTrim5alpha-mediated restriction in vitro. Virology 486:239-247, 2015.
58. Spivak AM, Planelles V. HIV-1 eradication: early trials (and tribulations). Trends Mol Med 22(1):10-27, 2016.
59. Tebas P, Stein D, Binder-Scholl G, Mukherjee R, Brady T, Rebello T, Humeau L, Kalos M, Papasavvas E, Montaner LJ, Schullery D, Shaheen F, Brennan AL, Zheng Z, Cotte J, Slepushkin V, Veloso E, Mackley A, Hwang WT, Aberra F, et al. Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV. Blood 121(9):1524-1533, 2013.
60. Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang W-T, Levine BL, June CH. Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. N Engl J Med 370(10):901-910, 2014.
61. Unwalla H, Chakraborti S, Sood V, Gupta N, Banerjea AC. Potent inhibition of HIV-1 gene expression and TAT-mediated apoptosis in human T cells by novel mono-and multitarget anti-TAT/Rev/Env ribozymes and a general purpose RNA-cleaving DNA-enzyme. Antiviral Res 72(2):134-144, 2006.
62. Van Lunzen J, Glaunsinger T, Stahmer I, Von Baehr V, Baum C, Schilz A, Kuehlcke K, Naundorf S, Martinius H, Hermann F, Giroglou T, Newrzela S, Muller I, Brauer F, Brandenburg G, Alexandrov A, Von Laer D. Transfer of autologous gene-modified T cells in HIV-infected patients with advanced immunodeficiency and drug-resistant virus. Mol Ther 15(5):1024-1033, 2007.
63. Varela-Rohena A, Molloy PE, Dunn SM, Li Y, Suhoski MM, Carroll RG, Milicic A, Mahon T, Sutton DH, Laugel B, Moysey R, Cameron BJ, Vuidepot A, Purbhoo MA, Cole DK, Phillips RE, June CH, Jakobsen BK, Sewell AK, Riley JL. Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med 14(12):1390-1395, 2008.
64. Voit RA, Mcmahon MA, Sawyer SL, Porteus MH. Generation of an HIV resistant T-cell line by targeted "stacking" of restriction factors. Mol Ther 21(4):786-795, 2013.
65. Wagner TB, Hale A, Romano M, Khan G, Sahni I, Scharenberg J, Rawlings AD. Anti-HIV CAR+ lymphocytes protected from HIV-infection by CCR5 disruption as a strategy to cure HIV. Vancouver, Canada, International Aids Society: Towards an HIV Cure Symposium. 2015.
66. Walli R, Reinhart B, Luckow B, Lederer E, Loch O, Malo A, Wank R, Schlondorff D, Goebel FD. HIV-1-infected long-term slow progressors heterozygous for delta32-CCR5 show significantly lower plasma viral load than wild-type slow progressors. J Acquir Immune Defic Syndr Hum Retrovirol 18(3):229-233, 1998.
67. Wong-Staal F, Poeschla EM, Looney DJ. A controlled, Phase 1 clinical trial to evaluate the safety and effects in HIV-1 infected humans of autologous lymphocytes transduced with a ribozyme that cleaves HIV-1 RNA. Hum Gene Ther 9(16):2407-2425, 1998.
68. Younan PM, Polacino P, Kowalski JP, Hu SL, Kiem HP. Combinatorial hematopoietic stem cell transplantation and vaccination reduces viral pathogenesis following SHIV89.6P-challenge. Gene Ther 22(12):1007-1012, 2015.
69. Younan PM, Polacino P, Kowalski JP, Peterson CW, Maurice NJ, Williams NP, Ho O, Trobridge GD, Von Laer D, Prlic M, Beard BC, Derosa S, Hu SL, Kiem HP. Positive selection of mC46-expressing CD4+ T cells and maintenance of virus specific immunity in a primate AIDS model. Blood 122(2):179-187, 2013.
70. Zhu W, Lei R, Le Duff Y, Li J, Guo F, Wainberg MA, Liang C. The CRISPR/Cas9 system inactivates latent HIV-1 proviral DNA. Retrovirology 12:22, 2015.