The V2 loop of HIV gp120 delivers costimulatory signals to CD4 T cells through Integrin αβ and promotes cellular activation and infection.

Acute HIV infection is characterized by rapid viral seeding of immunologic inductive sites in the gut followed by the severe depletion of gut CD4 T cells. Trafficking of αβ-expressing lymphocytes to the gut is mediated by MAdCAM, the natural ligand of αβ that is expressed on gut endothelial cells. MAdCAM signaling through αβ costimulates CD4 T cells and promotes HIV replication. Similar to MAdCAM, the V2 domain of the gp120 HIV envelope protein binds to αβ In this study, we report that gp120 V2 shares with MAdCAM the capacity to signal through αβ resulting in CD4 T cell activation and proliferation. As with MAdCAM-mediated costimulation, cellular activation induced by gp120 V2 is inhibited by anti-αβ monoclonal antibodies (mAbs). It is also inhibited by anti-V2 domain antibodies including nonneutralizing mAbs that recognize an epitope in V2 that has been linked to reduced risk of acquisition in the RV144 vaccine trial. The capacity of the V2 domain of gp120 to mediate signaling through αβ likely impacts early events in HIV infection. The capacity of nonneutralizing V2 antibodies to block this activity reveals a previously unrecognized mechanism whereby such antibodies might impact HIV transmission and pathogenesis.