Limited impact of fingolimod treatment during the initial weeks of ART in SIV-infected rhesus macaques

• Type of Material: Article
• Authors: Maria Pino, Emory University; Amélie Pagliuzza, Université de Montréal; Betina M Pampena, University of Pennsylvania; Claire Deleage, Leidos Biomedical Research, Inc.; Elise G Viox, Emory University; Kevin Nguyen, Emory University; Inbo Shim, Emory University; Adam Zhang, Emory University; Justin L Harper, Emory University; Sadia Samer, Emory University; Colin T King, Emory University; Barbara Cervasi, Emory University; Kiran P Gill, Emory University; Stephanie Ehnert, Emory University; Sherrie Jean, Emory University; Michael L Freeman, Case Western Reserve University; Jeffrey D Lifson, Leidos Biomedical Research, Inc.; Deanna Kulpa, Emory University; Michael R Betts, University of Pennsylvania; Nicolas Chomont, Université de Montréal; Michael M Lederman, Case Western Reserve University; Mirko Paiardini, Emory University
• Language: English
• Date: 2022-08-27
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-32698-y
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 5055
• End Page: 5055
• Grant/Funding Information: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This research is supported by NIH R33AI116171 (to M.M.L. and M.P.); NIH P01AI131338 (to M.R.B.); ERASE HIV UM1AI164562 (to M.P.), co-funded by National Heart, Lung and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases; NIH Office of the Director, Office of Research Infrastructure Programs, P51OD011132 and U42OD011023 to EPC, and Center for AIDS Research at Emory University P30AI050409 and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract Nos. 75N91019D00024 and HHSN261201500003I.
• Keywords: HIV-1 REPLICATION; SPHINGOSINE-1-PHOSPHATE; SECONDARY LYMPHOID-TISSUES; MUCOSAL; FOLLICLES; Multidisciplinary Sciences; HELPER T-CELLS; EGRESS; Science & Technology - Other Topics; RESPONSES; DYNAMICS; Science & Technology; FTY720
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology; Biology, Microbiology

Abstract

Antiretroviral therapy (ART) is not curative due to the persistence of a reservoir of HIV-infected cells, particularly in tissues such as lymph nodes, with the potential to cause viral rebound after treatment cessation. In this study, fingolimod (FTY720), a lysophospholipid sphingosine-1-phosphate receptor modulator is administered to SIV-infected rhesus macaques at initiation of ART to block the egress from lymphoid tissues of natural killer and T-cells, thereby promoting proximity between cytolytic cells and infected CD4+ T-cells. When compared with the ART-only controls, FTY720 treatment during the initial weeks of ART induces a profound lymphopenia and increases frequencies of CD8+ T-cells expressing perforin in lymph nodes, but not their killing capacity; FTY720 also increases frequencies of cytolytic NK cells in lymph nodes. This increase of cytolytic cells, however, does not limit measures of viral persistence during ART, including intact proviral genomes. After ART interruption, a subset of animals that initially receives FTY720 displays a modest delay in viral rebound, with reduced plasma viremia and frequencies of infected T follicular helper cells. Further research is needed to optimize the potential utility of FTY720 when coupled with strategies that boost the antiviral function of T-cells in lymphoid tissues.