We determined that HIV gp120 binds to an activated form of α4β. Because α4β is the principal integrin involved in lymphocyte homing to the lamina propria of gut associated lymphoid tissue (GALT), and HIV-infected CD4 T-cells preferentially localize to lymphoid tissues, particularly GALT, our finding suggests that a direct interaction between HIV gp120 and α4β may be necessary for preferential establishment and/or maintenance of HIV replication in GALT. The binding of gp120 to α4β is mediated by an LDV peptide sequence in the V2 loop that reiterates a structurally homologous binding motif present on MadCAM-1, VCAM-1 and fibronectin, the natural ligands for α4β. Removal of this sequence in the HIV envelope abrogates binding to α4β integrin. A prototypical α4β peptide antagonist based on the LDV sequence abrogates binding to gp120. Thus, HIV has acquired, through molecular mimicry, a mechanism to bind to the integrin receptor principally involved in directing lymphocytes to the lamina propria of the gut, the primary site of HIV replication. On CD4+ T cells, gp120 engagement of α4β results in a rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses. Activation of LFA-1 is known to increase HIV replication. 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. We find that α4β7high CD4+ T cells are more susceptible to productive infection than 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. We find that on these cells α4β7 appears in a complex with CD4. This is the first demonstration that these two receptors appear together in a complex on the surface of a CD4+ T cell. The delineation of the role of integrin α4β7 in HIV pathogenesis provides critical new information to understand the basic underlying mechanisms of HIV transmission and HIV-mediated immune dysfunction.
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