MAdCAM costimulation through Integrin-alpha(4)beta(7) promotes HIV replication

• Type of Material: Article
• Authors: Fatima Nawaz, National Institute of Allergy and Infectious Diseases; Livia R. Goes, National Institute of Allergy and Infectious Diseases; Jocelyn C. Ray, National Institute of Allergy and Infectious Diseases; Ronke Olowojesiku, National Institute of Allergy and Infectious Diseases; Alia Sajani, National Institute of Allergy and Infectious Diseases; Aftab Ansari, Emory University; Ian Perrone, National Institute of Allergy and Infectious Diseases; Joseph Hiatt, National Institute of Allergy and Infectious Diseases; Donald Van Ryk, National Institute of Allergy and Infectious Diseases; Danlan Wei, National Institute of Allergy and Infectious Diseases; Mia Waliszewski, National Institute of Allergy and Infectious Diseases; Marcelo A. Soares, Instituto Nacional de Cancer; Katija Jelicic, National Institute of Allergy and Infectious Diseases; Mark Connors, National Institute of Allergy and Infectious Diseases; Stephen A. Migueles, National Institute of Allergy and Infectious Diseases; Elena Martinelli, Center of Biomedical Research; Francois Villinger, University of Louisiana Lafayette; Claudia Cicala, National Institute of Allergy and Infectious Diseases; Anthony S. Fauci, National Institute of Allergy and Infectious Diseases; James Arthos, National Institute of Allergy and Infectious Diseases
• Language: English
• Date: 2018-09-01
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, Society for Mucosal Immunology.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41385-018-0044-1
• Title of Journal or Parent Work: Mucosal Immunology
• ISSN: 1933-0219
• Volume: 11
• Issue: 5
• Start Page: 1342
• End Page: 1351
• Grant/Funding Information: The antibody used for staining of α4β7 (anti-α4β7 mAb) was obtained from Dr. Aftab Ansari but originates from the NIH Nonhuman Primate Reagents Resource supported by AI126683 and OD010976.; This work was supported by the Intramural Research Program of the US National Institutes of Health (National Institute of Allergy and Infectious Diseases).; Livia Ramos Goes was supported by a scholarship from National Council for Scientific and Technological Development (CNPq) – Brazil.
• Keywords: Immunology; L-SELECTIN; ADDRESSIN MADCAM-1; Life Sciences & Biomedicine; GASTROINTESTINAL-TRACT; T-CELL DEPLETION; TYPE-1 INFECTION; LYMPHOID-TISSUE; CO-STIMULATION; INTEGRIN ALPHA-4-BETA-7; ACUTE SIV INFECTION; Science & Technology; SIMIAN IMMUNODEFICIENCY VIRUS
• Research Categories: Health Sciences, Immunology

Abstract

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4β7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4β7. Such costimulation promotes high levels of HIV replication. An anti-α4β7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4β7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM–α4β7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4β7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.