Interaction between Nef and phosphatidylinositol-3-kinase leads to activation of p21-activated kinase and increased production of HIV

Virology. 2002 Mar 15;294(2):246-55. doi: 10.1006/viro.2002.1365.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • COS Cells
  • Chlorocebus aethiops
  • Enzyme Activation
  • Gene Products, nef / genetics
  • Gene Products, nef / metabolism*
  • HIV-1 / metabolism*
  • Humans
  • Jurkat Cells
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • nef Gene Products, Human Immunodeficiency Virus

Substances

  • Gene Products, nef
  • Recombinant Fusion Proteins
  • nef Gene Products, Human Immunodeficiency Virus
  • Protein Serine-Threonine Kinases