HIV-1 Nef interferes with host cell motility by deregulation of Cofilin.
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-1alpha, 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.
Stolp
Bettina
B
Department of Virology, Im Neuenheimer Feld 324, University of Heidelberg, Heidelberg 69120, Germany.
Reichman-Fried
Michal
M
Abraham
Libin
L
Pan
Xiaoyu
X
Giese
Simone I
SI
Hannemann
Sebastian
S
Goulimari
Polyxeni
P
Raz
Erez
E
Grosse
Robert
R
Fackler
Oliver T
OT
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D005347:Fibroblasts / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D013601:T-Lymphocytes / Q000821:virology; D037521:Virulence Factors / Q000502:physiology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000502:physiology*; D054462:p21-Activated Kinases / Q000378:metabolism
D051339:Actin Depolymerizing Factors; D037521:Virulence Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C515907:PAK2 protein, human; D054462:p21-Activated Kinases