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

J Biol Chem. 2014 Mar 7;289(10):6949-6959. doi: 10.1074/jbc.M113.492132. Epub 2014 Jan 10.


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 CD4 T cells. WAVE2 is a component of a multiprotein complex linking receptor signaling to dynamic remodeling of the actin cytoskeleton. WAVE2 directly activates Arp2/3, leading to actin nucleation and filament branching. Although several bacterial and viral pathogens target Arp2/3 for intracellular mobility, it remains unknown whether HIV-1 actively modulates the Arp2/3 complex through virus-mediated receptor signal transduction. Here we report that HIV-1 triggers WAVE2 phosphorylation at serine 351 through gp120 binding to the chemokine coreceptor CXCR4 or CCR5 during entry. This phosphorylation event involves both Gαi-dependent and -independent pathways, and is conserved both in X4 and R5 viral infection of resting CD4 T cells and primary macrophages. We further demonstrate that inhibition of WAVE2-mediated Arp2/3 activity through stable shRNA knockdown of Arp3 dramatically diminished HIV-1 infection of CD4 T cells, preventing viral nuclear migration. Inhibition of Arp2/3 through a specific inhibitor, CK548, also drastically inhibited HIV-1 nuclear migration and infection of CD4 T cells. Our results suggest that Arp2/3 and the upstream regulator, WAVE2, are essential co-factors hijacked by HIV for intracellular migration, and may serve as novel targets to prevent HIV transmission.

Keywords: Arp2/3; CCR5; CD4; HIV-1; Immunology; Microbiology; Signal Transduction; Virology; Wav2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin-Related Protein 2-3 Complex / antagonists & inhibitors
  • Actin-Related Protein 2-3 Complex / genetics
  • Actin-Related Protein 2-3 Complex / metabolism*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology*
  • Cell Nucleus / virology*
  • Gene Knockdown Techniques
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • HIV Infections / virology*
  • HIV-1 / physiology*
  • HeLa Cells
  • Humans
  • Macrophages / metabolism
  • Macrophages / virology*
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Virus Replication
  • Wiskott-Aldrich Syndrome Protein Family / metabolism*


  • Actin-Related Protein 2-3 Complex
  • RNA, Small Interfering
  • WASF2 protein, human
  • Wiskott-Aldrich Syndrome Protein Family