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 α4β7high CD4+ T cells are more susceptible to productive infection than are α4β7low-neg CD4+ T cells in part because this cellular subset is enriched with metabolically active CD4+ T cells. α4β7high CD4+ T cells are CCR5high and CXCR4low; 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.