Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+T cells from virally suppressed individuals

• Type of Material: Article
• Authors: Elizabeth R. Wonderlich, Southern Research Institute; Krupa Subramanian, Southern Research Institute; Bryan Cox, Emory University; Ann Wiegand, National Cancer Institute; Carol Lackman-Smith, Southern Research Institute; Michael J. Bale, National Cancer Institute; Mars Stone, Vitalant Research Institute; Rebecca Hoh, University of California San Francisco; Mary F. Kearney, National Cancer Institute; Frank Maldarelli, National Cancer Institute; Steven G. Deeks, University of California San Francisco; Michael P. Busch, Vitalant Research Institute; Roger G. Ptak, Southern Research Institute; Deanna Kulpa, Emory University
• Language: English
• Date: 2019-10-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1008074
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 15
• Issue: 10
• Start Page: e1008074
• End Page: e1008074
• Grant/Funding Information: A.W., M.J.B., M.F.K., F.M. National Cancer Institute.; S.G.D., R.H. The SCOPE cohort was supported the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763) and the CFAR Network of Integrated Systems (R24 AI067039).; E.R.W., K.S., C.L.S., R.G.P., D.A.K. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201500017C.; Additional support was provided by the Delaney AIDS Research Enterprise (DARE; AI096109, A127966).; M.S., M.P.B. Bill and Melinda Gates Foundation.
• Keywords: EXPRESSION; HUMAN-IMMUNODEFICIENCY-VIRUS; SUBSETS; Science & Technology; Microbiology; Life Sciences & Biomedicine; REACTIVATION; TRANSCRIPTION FACTOR; PROVIRUSES; Parasitology; DNA; CD4(+) T-CELLS; PERSISTENCE; LATENT RESERVOIR; Virology
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Biology, Virology

Abstract

Studies have demonstrated that intensive ART alone is not capable of eradicating HIV-1, as the virus rebounds within a few weeks upon treatment interruption. Viral rebound may be induced from several cellular subsets; however, the majority of proviral DNA has been found in antigen experienced resting CD4+ T cells. To achieve a cure for HIV-1, eradication strategies depend upon both understanding mechanisms that drive HIV-1 persistence as well as sensitive assays to measure the frequency of infected cells after therapeutic interventions. Assays such as the quantitative viral outgrowth assay (QVOA) measure HIV-1 persistence during ART by ex vivo activation of resting CD4+ T cells to induce latency reversal; however, recent studies have shown that only a fraction of replication-competent viruses are inducible by primary mitogen stimulation. Previous studies have shown a correlation between the acquisition of effector memory phenotype and HIV-1 latency reversal in quiescent CD4+ T cell subsets that harbor the reservoir. Here, we apply our mechanistic understanding that differentiation into effector memory CD4+ T cells more effectively promotes HIV-1 latency reversal to significantly improve proviral measurements in the QVOA, termed differentiation QVOA (dQVOA), which reveals a significantly higher frequency of the inducible HIV-1 replication-competent reservoir in resting CD4+ T cells.