Signaling through Integrin α4β7 Promotes Replication of HIV in Sub-optimally Activated CD4+ T cells.

Mucosal transmission of HIV is inefficient. Viral infection of activated CD4⁺ T cells represents a key step in infection. α4β7/CD4⁺ T cells are targeted at an early stage of transmission. A recent study in rhesus macaques demonstrated that a primatized monoclonal anti- α4β7 antibody reduces the efficiency of mucosal transmission of SIV in a low-dose vaginal challenge model. α4β7 mediates homing to gut-associated lymphoid tissue through an interaction with MAdCAM-1, expressed on gut endothelial venules. MAdCAM binding to α4β7 delivers a potent costimulatory signal to CD4⁺ T cells. We hypothesized that the costimulatory activity of α4β7 could explain the enhanced susceptibility of α4β7/CD4⁺ T cells to HIV infection. We evaluated the capacity of α4β7-mediated costimulation to facilitate HIV replication, and the ability of the primatized anti- α4β7 mAb to inhibit viral replication.  Costimulation through α4β7 promotes viral replication in a way that is inhibitable by the primatized α4β7 mAb. CFSE dye analysis, upregulation of CD69, and shedding of CD62-L confirmed that α4β7 promotes activation.  These results provide a novel mechanism by which α4β7 can facilitate mucosal transmission that may aid in our understanding of the mechanism(s) by which a primatized anti-α4β7 mAb reduced the efficiency of mucosal transmission.