CXCR4 Tropic HIV-1 gp120 Inhibition of SDF-1α-Induced Chemotaxis Requires Lck and is Associated with Cofilin Phosphorylation

OBJECTIVE: HIV gp120 is a pleiotropic protein present in the plasma and tissues of HIV-infected patients, which affects a variety of homeostatic functions. In this report, we examine the mechanism of how gp120 blocks CD4 T cells from migrating towards SDF-1α. METHODS: In vitro treatment of primary CD4 T cells with CXCR4 tropic gp120, SDF, and measurement of chemotaxis and cell signaling. RESULTS: gp120 signaling through CD4 receptor and Lck are required for its ability to inhibit chemotaxis induced by SDF, as demonstrated by CD4 receptor decoys, Lck inhibitors, as well as cells deficient in Lck, in which Lck expression is restored. Blocking Lck abrogates the ability of CXCR4 tropic gp120 to antagonize SDF-1α-induced chemotaxis. This inhibition is associated with cofilin phosphorylation, thereby providing a potential mechanism. CONCLUSION: We conclude that the ability of gp120 to inhibit SDF-1α-induced chemotaxis is mediated by the CD4 receptor and Lck signaling, potentially by promoting cofilin phosphorylation.