Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques.
BACKGROUND
The primate lentiviruses, human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus (SIV), encode a conserved accessory gene product, Nef. In vivo, Nef is important for the maintenance of high virus loads and progression to AIDS in SIV-infected adult rhesus macaques. In tissue culture cells expressing Nef, this viral protein interacts with a cellular serine kinase, designated Nef-associated kinase.


RESULTS
This study identifies the Nef-associated kinase as a member of the p21-activated kinase (PAK) family of kinases and investigates the role of this Nef-associated kinase in vivo. Mutants of Nef that do not associate with the cellular kinase are unable to activate the PAK-related kinase in infected cells. To determine the role of cellular kinase association in viral pathogenesis, macaques were infected with SIV containing point-mutations in Nef that block PAK activation. Virus recovered at early time points after inoculation with mutant virus was found to have reverted to prototype Nef function and sequence. Reversion of the kinase-negative mutant to a kinase-positive genotype in macaques infected with the mutant virus preceded the induction of high virus loads and disease progression.


CONCLUSIONS
Nef associates with and activates a PAK-related kinase in lymphocytes infected in vitro. Moreover, the Nef-mediated activation of a PAK-related kinase correlates with the induction of high virus loads and the development of AIDS in the infected host. These findings reveal that there is a strong selective pressure in vivo for the interaction between Nef and the PAK-related kinase.
Sawai
E T
ET
Department of Medical Pathology, University of California, Davis 95616, USA. etsawai@ucdavis.edu
Khan
I H
IH
Montbriand
P M
PM
Peterlin
B M
BM
Cheng-Mayer
C
C
Luciw
P A
PA
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation; D017353:Gene Deletion; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D015498:HIV-2 / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011817:Rabbits; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases
D015693:Gene Products, nef; D010748:Phosphopeptides; D054311:nef Gene Products, Human Immunodeficiency Virus; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases