HIV-1 Nef Interferes with Host Cell Motility by Deregulation of Cofilin

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HIV-1 Nef is a key factor in AIDS pathogenesis. Here, we report that Nef potently inhibits motility of fibroblasts and chemotaxis of HIV-1-infected primary human T lymphocytes toward the chemokines SDF-1α, CCL-19, and CCL-21 ex vivo. Furthermore, Nef inhibits guided motility of zebrafish primordial germ cells toward endogenous SDF-1a in vivo. These migration defects result from Nef-mediated inhibition of the actin remodeling normally triggered by migratory stimuli. Nef strongly induces phosphorylation of cofilin, inactivating this evolutionarily conserved actin-depolymerizing factor that promotes cell motility when unphosphorylated. Nef-dependent cofilin deregulation requires association of Nef with the cellular kinase Pak2. Disruption of Nef-Pak2 association restores the cofilin phosphorylation levels and actin remodeling that facilitate cell motility. We conclude that HIV-1 Nef alters Pak2 function, which directly or indirectly inactivates cofilin, thereby restricting migration of infected T lymphocytes as part of a strategy to optimize immune evasion and HIV-1 replication. © 2009 Elsevier Inc. All rights reserved.

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Stolp, B., Reichman-Fried, M., Abraham, L., Pan, X., Giese, S. I., Hannemann, S., … Fackler, O. T. (2009). HIV-1 Nef Interferes with Host Cell Motility by Deregulation of Cofilin. Cell Host and Microbe, 6(2), 174–186.

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