The primary function of HIV-1 binding to its chemokine coreceptors is to mediate fusion and viral entry. However, it has been known that this interaction also triggers a variety of signaling cascades. It is likely that the virus-mediated signaling events may facilitate viral infection in various settings where the cellular conditions need to be primed. This has been exemplified recently in our findings that HIV-1 employs envelope-CXCR4 interaction to activate a cellular actin depolymerization factor, cofilin, to support viral latent infection of resting CD4 T cells. Activation of cofilin promotes the cortical actin dynamics that are critical for viral intracellular migration across the static cortical actin barrier in resting T cells.