Interaction between Nef and phosphatidylinositol-3-kinase leads to activation of p21-activated kinase and increased production of HIV.
The negative factor (Nef) is one of six accessory proteins from primate lentiviruses (HIV-1, HIV-2, and SIV). It leads to high levels of viremia and the progression to AIDS in monkeys and humans. In this study, we demonstrated that Nef from HIV-1 binds to the regulatory subunit (p85) of phosphatidylinositol-3-kinase (PI3K). This interaction depended on the C-terminus of p85 and Nef. Moreover, PI3K was required to activate the Nef-associated p21-activated kinase (PAK). Finally, inhibition of PI3K blocked the activation of PAK and decreased the production of viral particles to levels observed with the Nef-deleted provirus. We conclude that Nef assembles a multiprotein signaling complex which is required for the optimal replication of HIV-1.
Linnemann
Thomas
T
Howard Hughes Medical Institute, University of California at San Francisco, 94143, USA.
Zheng
Yong-Hui
YH
Mandic
Robert
R
Peterlin
B Matija
BM
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus