Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7

PLoS Pathogens
Sakaorat LertjuthapornJames Arthos

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 α4β7 and a soluble α4β7 heterodimer 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 α4β7 in 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, α4β7 antagonists 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 α4β7 binding 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 identif...Continue Reading

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Citations

Apr 18, 2019·Current Opinion in HIV and AIDS·Susan Zolla-PaznerSvenja Weiss
Jul 24, 2020·Human Vaccines & Immunotherapeutics·Miroslaw K Gorny
Oct 28, 2018·Nature Communications·Constantinos Kurt WibmerLynn Morris
May 15, 2019·PLoS Pathogens·Giulia CalendaElena Martinelli
Dec 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Livia R GoesJames Arthos
Dec 29, 2020·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Lucas GuilloLaurent Peyrin-Biroulet
Jan 24, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Widade ZianiHuanbin Xu
Feb 5, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ann J HessellMiroslaw K Gorny
Nov 16, 2020·Advanced Drug Delivery Reviews·Desiree SchützJanis A Müller

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Methods Mentioned

BETA
glycosylation
X-ray
surface-plasmon
resonance
biosensor
chips
ELISA
transfection
column chromatography
chip

Software Mentioned

PyMOL
BIAevaluation
Phenix
Imaris
Leica LAS AF
COOT

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