title: Persistence of virus reservoirs in ART-treated SHIV-infected rhesus macaques after autologous hematopoietic stem cell transplant.
abstract: Despite many advances in AIDS research, a cure for HIV infection remains elusive. Here, we performed autologous hematopoietic stem cell transplantation (HSCT) in three Simian/Human Immunodeficiency Virus (SHIV)-infected, antiretroviral therapy (ART)-treated rhesus macaques (RMs) using HSCs collected prior to infection and compared them to three SHIV-infected, ART-treated, untransplanted control animals to assess the effect of conditioning and autologous HSCT on viral persistence. As expected, ART drastically reduced virus replication, below 100 SHIV-RNA copies per ml of plasma in all animals. After several weeks on ART, experimental RMs received myeloablative total body irradiation (1080 cGy), which resulted in the depletion of 94-99% of circulating CD4+ T-cells, and low to undetectable SHIV-DNA levels in peripheral blood mononuclear cells. Following HSC infusion and successful engraftment, ART was interrupted (40-75 days post-transplant). Despite the observed dramatic reduction of the peripheral blood viral reservoir, rapid rebound of plasma viremia was observed in two out of three transplanted RMs. In the third transplanted animal, plasma SHIV-RNA and SHIV DNA in bulk PBMCs remained undetectable at week two post-ART interruption. No further time-points could be assessed as this animal was euthanized for clinical reasons; however, SHIV-DNA could be detected in this animal at necropsy in sorted circulating CD4+ T-cells, spleen and lymph nodes but not in the gastro-intestinal tract or tonsils. Furthermore, SIV DNA levels post-ART interruption were equivalent in several tissues in transplanted and control animals. While persistence of virus reservoir was observed despite myeloablation and HSCT in the setting of short term ART, this experiment demonstrates that autologous HSCT can be successfully performed in SIV-infected ART-treated RMs offering a new experimental in vivo platform to test innovative interventions aimed at curing HIV infection in humans.
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Maud
authors.initials: M
authors.lastname: Mavigner
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Watkins
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Benton
authors.initials: B
authors.lastname: Lawson
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: S Thera
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America; Center for Immunology and Vaccines, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Chahroudi
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States of America; Center for Immunology and Vaccines, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Leslie
authors.initials: L
authors.lastname: Kean
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America; Center for Immunology and Vaccines, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D005434:Flow Cytometry; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology*; D008253:Macaca mulatta; D008297:Male; D012367:RNA, Viral / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000628:therapy / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics; D014182:Transplantation, Autologous; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication
chemical_list: D044966:Anti-Retroviral Agents; D012367:RNA, Viral; D054303:HIV Reverse Transcriptase