Significance Understanding the early events in HIV transmission will aid in the development of an efficacious HIV vaccine. Productive infection requires that virions access metabolically activated CD4 ⁺ T cells. These cells are, in general, limited in number, which contributes to inefficient viral transmission. This report describes a mechanism whereby the HIV gp120 envelope protein can deliver activating signals to CD4 ⁺ T cells. This activity may increase both productive infection in mucosal tissues around the time of transmission and the formation of viral reservoirs. gp120 mediates activating signals by binding to integrin α ₄ β ₇ . Antibodies specific to the V2 domain of gp120 block this interaction and may contribute to the efficacy of an HIV vaccine.