Both activated and resting CD4⁺ T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin α₄β₇ (α₄β₇), the gut mucosal homing receptor. We find that α₄β₇^high CD4⁺ T cells are more susceptible to productive infection than are α₄β₇^low-neg CD4⁺ T cells in part because this cellular subset is enriched with metabolically active CD4⁺ T cells. α₄β₇^high CD4⁺ T cells are CCR5^high and CXCR4^low; on these cells, α₄β₇ appears in a complex with CD4. The specific affinity of gp120 for α₄β₇ provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.