Integrin alpha(4)beta(7) expression on peripheral blood CD4(+) T cells predicts HIV acquisition and disease progression outcomes

• Type of Material: Article
• Authors: Aida Sivro, Centre for the AIDS Programme of Research in South Africa; Alexandra Schuetz, Armed Forces Research Institute of Medical Sciences; Daniel Sheward, University of Cape Town; Vineet Joag, University of Toronto; Sergev Yegorov, University of Toronto; Lenine J. Liebenberg, Centre for the AIDS Programme of Research in South Africa; Nonhlanhla Yende-Zuma, Centre for the AIDS Programme of Research in South Africa; Andrew Stalker, University of Manitoba; Ruth S. Mwatelah, University of Manitoba; Philippe Selhorst, University of Cape Town; Nigel Garrett, Centre for the AIDS Programme of Research in South Africa; Natasha Samsunder, Centre for the AIDS Programme of Research in South Africa; Anisha Balgobin, Centre for the AIDS Programme of Research in South Africa; Fatima Nawaz, National Institute of Allergy and Infectious Diseases; Claudia Cicala, National Institute of Allergy and Infectious Diseases; James Arthos, National Institute of Allergy and Infectious Diseases; Anthony S. Fauci, National Institute of Allergy and Infectious Diseases; A. Omu Anzala, Kenyan AIDS Vaccine Initiative; Joshua Kimani, University of Manitoba; Bernard S. Bagaya, Uganda Virus Research Institute; Aftab A Ansari, Emory University
• Language: English
• Date: 2018-01-24
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2018 The Authors, some rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aam6354
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 10
• Issue: 425
• Start Page: eaam6354
• End Page: eaam6354
• Grant/Funding Information: The CAPRISA 004 part of this project was funded by NIH R21 AI115978-01.; The original CAPRISA 004 Tenofovir gel trial was funded principally by the United States Agency for International Development (USAID) through FHI360 and CONRAD; with additional support provided by the South African Department of Science and Technology (DST).; RV254 is supported by cooperative agreements (W81XWH-07-2-0067, W81XWH-11-2-0174) between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of the Army and by an intramural grant from the Thai Red Cross AIDS Research Center.; The Majengo cohort in Nairobi has been funded by Gates Grand Challenges and US PEPFAR.; The ART in RV254 was supported by The Government Pharmaceutical Organization (GPO), Thailand, Gilead, Merck and ViiV Healthcare.
• Keywords: IMMUNODEFICIENCY-VIRUS TYPE-1; TRANSMISSION; LYMPHOID-TISSUE; ALPHA-4-BETA-7; INFECTION; Life Sciences & Biomedicine; DYSFUNCTION; Science & Technology; MARKER; Research & Experimental Medicine; Cell Biology; SUSCEPTIBILITY; BINDING; MAINTENANCE THERAPY; Medicine, Research & Experimental
• Research Categories: Health Sciences, Pathology; Biology, Virology

Abstract

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α4β7 binding. In addition, pre-HIV α4β7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α4β7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing α4β7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection.