Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4^+ T cells to these sites is mediated by interactions between integrin α_4β_7, expressed on CD4^+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4^+ T cells following ligation with α_4β_7. Such costimulation promotes high levels of HIV replication. An anti-α_4β_7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α_4β_7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4^+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4^+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM–α_4β_7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α_4β_7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.