title: Differential Impact of In Vivo CD8+ T Lymphocyte Depletion in Controller versus Progressor Simian Immunodeficiency Virus-Infected Macaques.
abstract: Numerous studies have demonstrated that CD8(+) T lymphocytes suppress virus replication during human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection. However, the mechanisms underlying this activity of T cells remain incompletely understood. Here, we conducted CD8(+) T lymphocyte depletion in 15 rhesus macaques (RMs) infected intravenously (i.v.) with SIVmac239. At day 70 postinfection, the animals (10 progressors with high viremia and 5 controllers with low viremia) were CD8 depleted by i.v. administration of the antibody M-T807R1. As expected, CD8 depletion resulted in increased virus replication, more prominently in controllers than progressors, which correlated inversely with predepletion viremia. Of note, the feature of CD8(+) T lymphocyte predepletion that correlated best with the increase in viremia postdepletion was the level of CD8(+) T-bet(+) lymphocytes. We next found that CD8 depletion resulted in a homogenous increase of SIV RNA in superficial and mesenteric lymph nodes, spleen, and the gastrointestinal tract of both controllers and progressors. Interestingly, the level of SIV DNA increased postdepletion in both CD4(+) central memory T lymphocytes (TCM) and CD4(+) effector memory T lymphocytes (TEM) in progressor RMs but decreased in the CD4(+) TCM of 4 out of 5 controllers. Finally, we found that CD8 depletion is associated with a greater increase in CD4(+) T lymphocyte activation (measured by Ki-67 expression) in controllers than in progressors. Overall, these data reveal a differential impact of CD8(+) T lymphocyte depletion between controller and progressor SIV-infected RMs, emphasizing the complexity of the in vivo antiviral role of CD8(+) T lymphocytes.
  
  
  OBJECTIVE
  In this study, we further dissect the impact of CD8(+) T lymphocytes on HIV/SIV replication during SIV infection. CD8(+) T lymphocyte depletion leads to a relatively homogenous increase in viral replication in peripheral blood and tissues. CD8(+) T lymphocyte depletion resulted in a more prominent increase in viral loads and CD4(+) T lymphocyte activation in controllers than in progressors. Interestingly, we found T-bet expression on CD8(+) T lymphocytes to be the best predictor of viral load increase following depletion. The levels of SIV DNA increase postdepletion in both CD4(+) TCM and TEM in progressor RMs but decrease in the CD4(+) TCM of controllers. The findings described in this study provide key insights into the differential functions of CD8(+) T lymphocytes in controller and progressor RMs.
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Hayes
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Benton O
authors.initials: BO
authors.lastname: Lawson
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanderford
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joern E
authors.initials: JE
authors.lastname: Schmitz
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
authors.affiliation: Institute for Immunology and Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Betts
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Chahroudi
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA gsilves@emory.edu.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D041981:Gastrointestinal Tract / Q000821:virology; D007156:Immunologic Memory / Q000276:immunology; D008198:Lymph Nodes / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D012367:RNA, Viral / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013154:Spleen / Q000821:virology; D019562:Viral Load; D014766:Viremia / Q000662:veterinary / Q000821:virology; D014779:Virus Replication / Q000276:immunology
chemical_list: D004279:DNA, Viral; D012367:RNA, Viral