CD4 Depletion in SIV-Infected Macaques Results in Macrophage and Microglia Infection with Rapid Turnover of Infected Cells

• Type of Material: Article
• Authors: Luca Micci, Emory University; Xavier Alvarez, Tulane University; Robin I. Iriele, Emory University; Alexandra M. Ortiz, Emory University; Emily S. Ryan, Emory University; Colleen McGary, Emory University; Claire Deleage, Leidos Biomedical Research, Inc.; Brigitte B. McAtee, Tulane University; Tianyu He, University of Pittsburgh; Cristian Apetrei, University of Pittsburgh; Kirk Easley, Emory University; Savita Pahwa, University of Miami; Ronald G. Collman, University of Pennsylvania; Cynthia Derdeyn, Emory University; Miles P. Davenport, University of New South Wales; Jacob D. Estes, Leidos Biomedical Research, Inc.; Guido Silvestri, Emory University; Andrew A. Lackner, Tulane University; Mirko Paiardini, Emory University
• Language: English
• Date: 2014-10-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1004467
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 10
• Issue: 10
• Start Page: e1004467
• End Page: e1004467
• Grant/Funding Information: MPD is supported by the National Health and Medical Research Council (Australia).; Research reported in this publication was supported by the National Institute Of Allergy And Infectious Diseases of the National Institute of Health under Award Numbers R56AI087186 and R01AI084836 (to MP), as well as by grant OD011132 (to the Yerkes National Primate Research Center), P30AI50409 (to the Emory Center for AIDS Research) and RR000164/OD011104 (to Tulane National Primate Research Center).; This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E.
• Research Categories: Health Sciences, Pathology; Biology, Virology; Health Sciences, Immunology

Abstract

In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies.