TY - JOUR
T1 - Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7
AU - Lertjuthaporn, Sakaorat
AU - Cicala, Claudia
AU - Van Ryk, Donald
AU - Liu, Matthew
AU - Yolitz, Jason
AU - Wei, Danlan
AU - Nawaz, Fatima
AU - Doyle, Allison
AU - Horowitch, Brooke
AU - Park, Chung
AU - Lu, Shan
AU - Lou, Yang
AU - Wang, Shixia
AU - Pan, Ruimin
AU - Jiang, Xunqing
AU - Villinger, Francois
AU - Byrareddy, Siddappa N.
AU - Santangelo, Philip J.
AU - Morris, Lynn
AU - Wibmer, Constantinos Kurt
AU - Biris, Kristin
AU - Mason, Rosemarie D.
AU - Gorman, Jason
AU - Hiatt, Joseph
AU - Martinelli, Elena
AU - Roederer, Mario
AU - Fujikawa, Dai
AU - Gorini, Giacomo
AU - Franchini, Genoveffa
AU - Arakelyan, Anush
AU - Ansari, Aftab A.
AU - Pattanapanyasat, Kovit
AU - Kong, Xiang Peng
AU - Fauci, Anthony S.
AU - Arthos, James
N1 - Funding Information:
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. GG was supported by a fellowship from the Andrea and Libi Lorini Foundation. SL, YL, SW, XK, RDM, and XJ were supported by HIVRAD grant No. AI100151. KP is a recipient of a Thailand Research Fund-Distinguished Research Professor Grant (DPG5980001). SL was supported by a fellowship from the Thailand Research Fund, The Royal Golden Jubilee PhD Program (PHD/0111/2554). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank M. Rao, K. Peachman and L. Margolis for important advice, Dr. Paolo Lusso for providing the BG505 SOSIP trimer, Dr. Susan Zolla-Pazner for providing HIV V2 mAbs, Dr. K. Reimann and Mr. Adam Busby for the providing primatized α4 β7 mAb and the normal recombinant rhesus IgG, Drs. Faruk Sinangil and Lavon Riddle (GSID) for providing A244 gp120. Anti-α4 β7 mAb and rhesus IgG provided by the NIH Nonhuman Primate Reagents Resource. We also sincerely appreciate Mr. A. Weddle for assistance with graphics.
Publisher Copyright:
© 2018, Public Library of Science. All rights reserved.
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.ppat.1007278
DO - 10.1371/journal.ppat.1007278
M3 - Article
C2 - 30153309
AN - SCOPUS:85053086140
VL - 14
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 8
M1 - e1007278
ER -