HIV-1 triggers WAVE2 phosphorylation in primary CD4 T cells and macrophages, mediating Arp2/3-dependent nuclear migration.

[wiskott-aldrich syndrome]

The human immunodeficiency virus type 1 (HIV-1 ) initiates receptor signaling and early actin dynamics during viral entry . This process is required for viral infection of primary targets such as resting CD 4 T cells . WAVE 2 is a component of a multiprotein complex linking receptor signaling to dynamic remodeling of the actin cytoskeleton . WAVE 2 directly activates Arp 2 /3 , leading to actin nucleation and filament branching . Although several bacterial and viral pathogens target Arp 2 /3 for intracellular mobility , it remains unknown whether HIV-1 actively modulates the Arp 2 /3 complex through virus-mediated receptor signal transduction . Here we report that HIV-1 triggers WAVE 2 phosphorylation at serine 351 through gp 120 binding to the chemokine coreceptor CXCR 4 or CCR 5 during entry . This phosphorylation event involves both Gαi-dependent and -independent pathways , and is conserved both in X 4 and R 5 viral infection of resting CD 4 T cells and primary macrophages . We further demonstrate that inhibition of WAVE 2 -mediated Arp 2 /3 activity through stable shRNA knockdown of Arp 3 dramatically diminished HIV-1 infection of CD 4 T cells , preventing viral nuclear migration . Inhibition of Arp 2 /3 through a specific inhibitor , CK 548 , also drastically inhibited HIV-1 nuclear migration and infection of CD 4 T cells . Our results suggest that Arp 2 /3 and the upstream regulator , WAVE 2 , are essential co -factors hijacked by HIV for intracellular migration , and may serve as novel targets to prevent HIV transmission .