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 α ₄ β ₇ (α ₄ β ₇ ), the gut mucosal homing receptor. We find that α ₄ β ₇ ^high CD4 ⁺ T cells are more susceptible to productive infection than are α ₄ β ₇ ^low-neg CD4 ⁺ T cells in part because this cellular subset is enriched with metabolically active CD4 ⁺ T cells. α ₄ β ₇ ^high CD4 ⁺ T cells are CCR5 ^high and CXCR4 ^low ; on these cells, α ₄ β ₇ appears in a complex with CD4. The specific affinity of gp120 for α ₄ β ₇ provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.