LIM kinase 1 modulates cortical actin and CXCR4 cycling and is activated by HIV-1 to initiate viral infection

J Biol Chem. 2011 Apr 8;286(14):12554-64. doi: 10.1074/jbc.M110.182238. Epub 2011 Feb 14.


Almost all viral pathogens utilize a cytoskeleton for their entry and intracellular transport. In HIV-1 infection, binding of the virus to blood resting CD4 T cells initiates a temporal course of cortical actin polymerization and depolymerization, a process mimicking the chemotactic response initiated from chemokine receptors. The actin depolymerization has been suggested to promote viral intracellular migration through cofilin-mediated actin treadmilling. However, the role of the virus-mediated actin polymerization in HIV infection is unknown, and the signaling molecules involved remain unidentified. Here we describe a pathogenic mechanism for triggering early actin polymerization through HIV-1 envelope-mediated transient activation of the LIM domain kinase (LIMK), a protein that phosphorylates cofilin. We demonstrate that HIV-mediated LIMK activation is through gp120-triggered transient activation of the Rack-PAK-LIMK pathway, and that knockdown of LIMK through siRNA decreases filamentous actin, increases CXCR4 trafficking, and diminishes viral DNA synthesis. These results suggest that HIV-mediated early actin polymerization may directly regulate the CXCR4 receptor during viral entry and is involved in viral DNA synthesis. Furthermore, we also demonstrate that in resting CD4 T cells, actin polymerization can be triggered through transient treatment with a pharmacological agent, okadaic acid, that activates LIMK and promotes HIV latent infection of resting CD4 T cells. Taken together, our results suggest that HIV hijacks LIMK to control the cortical actin dynamics for the initiation of viral infection of CD4 T cells.

Publication types

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

MeSH terms

  • Actins / metabolism*
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Chemotaxis, Leukocyte / genetics
  • Chemotaxis, Leukocyte / physiology
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • HIV Infections / metabolism*
  • HIV Infections / virology*
  • HIV-1 / pathogenicity*
  • HIV-1 / physiology*
  • Humans
  • Lim Kinases / genetics
  • Lim Kinases / metabolism*
  • Okadaic Acid / pharmacology
  • RNA, Small Interfering
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • Actins
  • RNA, Small Interfering
  • Receptors, CXCR4
  • Okadaic Acid
  • LIMK1 protein, human
  • Lim Kinases