title: Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates.
abstract: Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34(+) cells expressing the mC46 anti-HIV fusion protein. We show that SHIV(+), ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34(+) cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV(+), ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4(+) T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4(+)CCR5(+)T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Patrick M
authors: PM
authors: Younan
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Christopher W
authors: CW
authors: Peterson
authors: Washington National Primate Research Center, Seattle, Washington, USA.
authors: Patricia
authors: P
authors: Polacino
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: John P
authors: JP
authors: Kowalski
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Willimark
authors: W
authors: Obenza
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Hannah W
authors: HW
authors: Miller
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Brian P
authors: BP
authors: Milless
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Phil
authors: P
authors: Gafken
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Stephen C
authors: SC
authors: DeRosa
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
authors: Shiu-Lok
authors: SL
authors: Hu
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Medicine, University of Washington, Seattle, Washington, USA. Electronic address: hkiem@fhcrc.org.
authors: Hans-Peter
authors: HP
authors: Kiem
mesh_terms: D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D016130:Immunophenotyping; D016086:Lentivirus / Q000235:genetics*; D018655:Lymphocyte Count; D008254:Macaca nemestrina; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000628:therapy / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000528:radiation effects / Q000821:virology; D014161:Transduction, Genetic; D019076:Transgenes; D019172:Transplantation Conditioning; D019562:Viral Load
references: Clin Exp Immunol. 2011 Mar;163(3):284-95
references: 21303358
references: Hematology Am Soc Hematol Educ Program. 2013;2013:382-8
references: 24319208
references: N Engl J Med. 2014 Mar 6;370(10):901-10
references: 24597865
references: Cell Mol Life Sci. 2014 Jul;71(14):2641-9
references: 24509823
references: Sci Transl Med. 2010 Jun 16;2(36):36ra43
references: 20555022
references: Viruses. 2013 Dec;5(12):2946-62
references: 24287598
references: AIDS. 2011 Jan 14;25(2):273-4
references: 21173593
references: J Acquir Immune Defic Syndr. 2013 Aug 1;63(4):438-41
references: 23493152
references: J Clin Oncol. 2014 Aug 1;32(22):2344-50
references: 24982448
references: Antimicrob Agents Chemother. 1998 Mar;42(3):612-7
references: 9517941
references: Adv Hematol. 2012;2012:507257
references: 22272202
references: Mol Ther. 2014 Feb;22(2):257-64
references: 24220323
references: Curr Pharm Biotechnol. 2013;14(5):488-500
references: 22429132
references: Mol Ther. 2012 Apr;20(4):849-59
references: 22273578
references: Mol Ther. 2007 Jul;15(7):1356-65
references: 17440443
references: Anal Chem. 2012 Oct 16;84(20):8614-21
references: 23030780
references: Hum Gene Ther. 2009 May;20(5):519-23
references: 19199822
references: J Med Primatol. 2007 Aug;36(4-5):254-65
references: 17669214
references: Methods Mol Biol. 2014;1185:321-44
references: 25062639
references: Clin Infect Dis. 2004 Mar 1;38(5):743-53
references: 14986261
references: N Engl J Med. 2009 Feb 12;360(7):692-8
references: 19213682
references: Nat Biotechnol. 2008 Jul;26(7):808-16
references: 18587387
references: J Med Primatol. 2013 Oct;42(5):237-46
references: 24025078
references: Viruses. 2012 Dec;4(12):3572-88
references: 23223198
references: J Clin Invest. 2010 Jul;120(7):2345-54
references: 20551514
references: Retrovirology. 2009;6:65
references: 19602283
references: Blood. 2013 Jul 11;122(2):179-87
references: 23719296
references: AIDS. 2010 Jul 17;24(11):1765-70
references: 20453630
references: Blood. 2008 Jun 15;111(12):5537-43
references: 18388180
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Nov 7;843(2):147-56
references: 16828350
references: Methods Mol Biol. 2011;737:1-25
references: 21590391
references: PLoS Biol. 2004 Aug;2(8):E234
references: 15314653
references: J Virol. 2008 Dec;82(24):12449-63
references: 18842730
references: Exp Hematol. 2014 Jul;42(7):497-504
references: 24704161
references: Science. 2014 Aug 1;345(6196):570-3
references: 25011556
references: PLoS One. 2009;4(11):e7693
references: 19888329
references: Cell Stem Cell. 2012 Feb 3;10(2):137-47
references: 22305563
references: J Exp Med. 2002 Mar 18;195(6):737-45
references: 11901199
references: J Infect Dis. 2010 Dec 1;202(11):1738-48
references: 20979453
references: Science. 2014 Jul 11;345(6193):179-83
references: 24968937
references: J Virol. 2002 Apr;76(8):3739-47
references: 11907213
references: J Infect Dis. 2013 Jun 1;207(11):1694-702
references: 23460751
references: J Virol. 2008 Jan;82(2):638-51
references: 17959660
references: Gene Ther. 2010 Jan;17(1):37-49
references: 19741733
references: PLoS Pathog. 2014 Sep;10(9):e1004406
references: 25254512
references: ScientificWorldJournal. 2011;11:1068-76
references: 21552772
references: Viruses. 2013 Nov;5(11):2898-919
references: 24284880
references: Hematology Am Soc Hematol Educ Program. 2013;2013:389-93
references: 24319209