Initiation of Antiretroviral Therapy Restores CD4(+) T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

• Type of Material: Article
• Authors: Emily K. Cartwright, Emory University; David Palesch, Emory University; Maud Mavigner, Emory University; Mirko Paiardini, Emory University; Ann Chahroudi, Emory University; Guido Silvestri, Emory University
• Language: English
• Date: 2016-08-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: t © 2016, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.00492-16
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 90
• Issue: 15
• Start Page: 6699
• End Page: 6708
• Grant/Funding Information: This work was funded in part by grant RR000165/OD011132 to the Yerkes National Primate Research Center and the Emory Center for AIDS Research, NIH grant P30-AI-504.
• Keywords: RESERVOIR; Virology; VIRAL SUPPRESSION; INTERRUPTION; SUBSET; PERSISTENCE; Life Sciences & Biomedicine; DYNAMICS; HIV-1 INFECTION; Science & Technology
• Research Categories: Health Sciences, Pathology; Biology, Virology

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.