Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to alpha(4)beta(7)

• Type of Material: Article
• Authors: Sakaorat Lertjuthaporn, Mahidol University; Claudia Cicala, National Institute of Allergy and Infectious Diseases; Donald Van Ryk, National Institute of Allergy and Infectious Diseases; Matthew Liu, National Institute of Allergy and Infectious Diseases; Jason Yolitz, National Institute of Allergy and Infectious Diseases; Danlan Wei, National Institute of Allergy and Infectious Diseases; Fatima Nawaz, National Institute of Allergy and Infectious Diseases; Allison Doyle, National Institute of Allergy and Infectious Diseases; Brooke Horowitch, National Institute of Allergy and Infectious Diseases; Chung Park, National Institute of Allergy and Infectious Diseases; Shan Lu, University of Massachusetts; Yang Lou, University of Massachusetts; Shixia Wang, University of Massachusetts; Ruimin Pan, New York University; Xunqing Jiang, New York University; Francois Villinger, University of Louisiana Lafayette; Siddappa Byrareddy, Emory University; Philip Santangelo, Emory University; Lynn Morris, National Health Laboratory Service; Constantinos Kurt Wibmer, National Health Laboratory Service; Kristin Biris, National Institute of Allergy and Infectious Diseases; Rosemarie D. Mason, National Institute of Allergy and Infectious Diseases; Jason Gorman, National Institute of Allergy and Infectious Diseases; Joseph Hiatt, University of California San Francisco; Elena Martinelli, Population Council; Mario Roederer, National Institute of Allergy and Infectious Diseases; Dai Fujikawa, National Cancer Institute; Giacomo Gorini, National Cancer Institute; Genoveffa Franchini, National Cancer Institute; Anush Arakelyan, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Aftab Ansari, Emory University; Kovit Pattanapanyasat, Mahidol University; Xiang-Peng Kong, New York University; Anthony S. Fauci, National Institute of Allergy and Infectious Diseases; James Arthos, National Institute of Allergy and Infectious Diseases
• Language: English
• Date: 2018-08-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2018, Public Library of Science. All rights reserved.
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1007278
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 14
• Issue: 8
• Start Page: e1007278
• End Page: e1007278
• Grant/Funding Information: SL, YL, SW, XK, RDM, and XJ were supported by HIVRAD grant No. AI100151.; Support for this work was provided by the Intramural Program of the NIAID, NIH, Bethesda, MD, NIH R01 AI098628 to AAA, NIH R01 AI111907 to FV and PJS, NIH R01 AI104387 and the South African Medical Research Council to LM and CKW.; SL was supported by a fellowship from the Thailand Research Fund, The Royal Golden Jubilee PhD Program (PHD/0111/2554).; KP is a recipient of a Thailand Research Fund-Distinguished Research Professor Grant (DPG5980001).; GG was supported by a fellowship from the Andrea and Libi Lorini Foundation.
• Keywords: PERIPHERAL-BLOOD; ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODY; Virology; IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODY; Microbiology; LYMPHOID-TISSUE; Parasitology; HOMING RECEPTOR; Life Sciences & Biomedicine; INTEGRIN ALPHA(4)BETA(7); GASTROINTESTINAL-TRACT; Science & Technology; T-CELL DEPLETION
• Research Categories: Biology, Microbiology; Biology, Virology

Abstract

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4β7, a gut-homing receptor. Using both cell-surface expressed α4β7and a soluble α4β7heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4β7in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4β7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4β7antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4β7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4β7. It includes the canonical LDV/I α4β7binding site, a cryptic epitope that lies 7–9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4β7interactions. These mAbs recognize conformations absent from the β- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4β7interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.