It is well-established that the most frequent route of HIV transmission occurs across mucosal tissues. Unfortunately, the earliest events in mucosal transmission are poorly defined. We regard a comprehensive understanding of these events as critically important information that can be utilized in the development of an effective HIV vaccine. A key feature of mucosal transmission of HIV is that it is typically inefficient. The virus must overcome multiple structural barriers and only achieves productive infection upon gaining access to metabolically active CD4+ T cells. This process requires that the HIV envelope protein first binds to the CD4 receptor and subsequently to a co-receptor (CCR5 or CXCR4). However, the CD4 receptor is expressed at high levels not just on metabolically activated cells, but also on resting cells, which are a poor substrate for productive infection. We have identified the integrin alpha4-beta7 as an additional HIV receptor on the surface of CD4+ T cells. Alpha4beta7 is not an entry receptor, however, unlike CD4, integrin alpha4-beta7 is preferentially expressed on a subset of cells in mucosal tissues that are activated. We are addressing the hypothesis that a direct interaction between gp120 and alpha4-beta7 provides important advantages that facilitate transmission across mucosal surfaces. By engaging alpha4-beta7 on a susceptible cell, a virion is able to target a relevant subset of CD4+ T cells that is relatively more susceptible to infection. In addition, alpha4-beta7+ CD4+ T cells migrate from genital mucosa into gut lymphoid tissues where an optimal cellular environment exists for viral replication. In this way, we hypothesize that the specific affinity of the HIV envelope for alpha4-beta7 provides a plausible explanation for the preferential establishment and/or maintenance of HIV replication in GALT. We continue to pursue the goal of better understanding the specific molecular events surrounding mucosal transmission because we regard this as critical information that will allow us to identify new strategies to prevent HIV transmission