The Role of Integrin α4ß7 Signaling in Human Immunodeficiency Virus-1 Pathogenesis and Viral Entry in Primary CD4+ T Cells As Revealed by Comparative Phosphoproteomic Signatures.

Integrin α4ß7, a CD4 independent receptor of human immunodeficiency virus-1 (HIV-1) gp120, defines a subset of CD4+T cells preferentially targeted by HIV. It is also considered as a promising therapeutic target for HIV-1 infection. Despite its role in HIV acquisition and disease progression, HIV-1-mediated integrin α4ß7 signaling has not been elucidated so far. In view of this, we determined phosphoproteomic signatures of HIV-1 gp120 signaling as well as signaling mediated by the integrin α4ß7 ligand, mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), in primary CD4+ T cells. This is the first comprehensive report on MAdCAM-1 signaling, which is believed to enhance HIV-1 replication. Importantly, we identified proteins associated with both classical and nonclassical integrin functions. We observed that HIV-1 gp120 signaling is associated with proteins that have previously not been associated with HIV-1 pathogenesis and thus, need to be explored further. There was a significant overlap in proteins identified by both MAdCAM-1 and HIV-1 gp120 signaling, which most likely represents cellular processes triggered upon interaction of HIV-1 gp120 with integrin α4ß7. Pathway analysis revealed enrichment of processes that could facilitate viral replication as well as viral entry through endocytosis. Although these results warrant independent replication and further validation, they suggest the presence of additional potential therapeutic targets. These results also suggest that combinatorial approaches for targeting both HIV-1 gp120 and MAdCAM-1 signaling may be necessary for efficient control of HIV-1 infection as well as novel innovation strategies in HIV therapeutics.