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Title: Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α<inf>4</inf>β<inf>7</inf>
Authors: Sakaorat Lertjuthaporn
Claudia Cicala
Donald Van Ryk
Matthew Liu
Jason Yolitz
Danlan Wei
Fatima Nawaz
Allison Doyle
Brooke Horowitch
Chung Park
Shan Lu
Yang Lou
Shixia Wang
Ruimin Pan
Xunqing Jiang
Francois Villinger
Siddappa N. Byrareddy
Philip J. Santangelo
Lynn Morris
Constantinos Kurt Wibmer
Kristin Biris
Rosemarie D. Mason
Jason Gorman
Joseph Hiatt
Elena Martinelli
Mario Roederer
Dai Fujikawa
Giacomo Gorini
Genoveffa Franchini
Anush Arakelyan
Aftab A. Ansari
Kovit Pattanapanyasat
Xiang Peng Kong
Anthony S. Fauci
James Arthos
Centre for the AIDS Programme of Research in South Africa
National Institute for Communicable Diseases
NYU School of Medicine
University of California, San Francisco
Population Council Headquarters
New Iberia Research Center
Georgia Institute of Technology
National Institute of Child Health and Human Development
National Institute of Allergy and Infectious Diseases
University of Nebraska Medical Center
University of Witwatersrand
National Cancer Institute
Faculty of Medicine, Siriraj Hospital, Mahidol University
Emory University School of Medicine
University of Massachusetts Medical School
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 1-Aug-2018
Citation: PLoS Pathogens. Vol.14, No.8 (2018)
Abstract: © 2018, Public Library of Science. All rights reserved. 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.
ISSN: 15537374
Appears in Collections:Scopus 2018

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