title: Initiation of Antiretroviral Therapy Restores CD4+ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques.
abstract: Treatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4(+) T memory stem cells (TSCM) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4(+) TSCM are preserved in number but show (i) a decrease in the frequency of CCR5(+) cells, (ii) an expansion of the fraction of proliferating Ki-67(+) cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4(+) TSCM homeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4(+) CCR5(+) TSCM both in blood and in lymph nodes and a reduction in the fraction of proliferating CD4(+) Ki-67(+) TSCM in blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4(+) transitional memory (TTM) and effector memory (TEM) T cells declined ∼100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4(+) TSCM and central memory T cells (TCM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4(+) TSCM homeostasis, and the observed stable level of virus in TSCM supports the hypothesis that these cells are a critical contributor to SIV persistence.
  
  
  
  Understanding the roles of various CD4(+) T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (TSCM) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (TCM and TTM, respectively). CD4(+) TSCM are disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4(+) TSCM homeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as TTM and effector memory (TEM). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4(+) TSCM during suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir.
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Cartwright
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: David
authors.initials: D
authors.lastname: Palesch
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.|Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Maud
authors.initials: M
authors.lastname: Mavigner
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: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.|Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Chahroudi
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA gsilves@emory.edu.|Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D004279:DNA, Viral / Q000235:genetics; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D008253:Macaca mulatta; D018419:Primate Diseases / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000821:virology; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral