CD4 and HIV infectious disease: Together with previous reports of WAVE2 regulation in HIV infection, these results support HIV Nef as a major disruptor of cortical actin through WAVE2-ARP2/3 inhibition at the lamellipodia, providing a novel mechanism of HIV-mediated CD4+ T-cell dysfunction and depletion.<h4>Importance</h4>CD4<sup>+</sup> T cells migrate throughout the body and form immune synapses to carry out their functions.