Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to ?4?7.

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 ?4?7, a gut-homing receptor. Using both cell-surface expressed ?4?7 and a soluble ?4?7 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 ?4?7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to ?4?7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, ?4?7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to ?4?7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to ?4?7. It includes the canonical LDV/I ?4?7 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 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-?4?7 interactions. These mAbs recognize conformations absent from the ?- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-?4?7 interactions 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.

SUBMITTER: Lertjuthaporn S 

PROVIDER: S-EPMC6130882 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature