Mechanistic independence of Nef and cyclophilin A enhancement of human immunodeficiency virus type 1 infectivity

Virology. 1998 Aug 15;248(1):139-47. doi: 10.1006/viro.1998.9254.

Abstract

Optimal HIV-1 infectivity requires the presence of both the viral factor Nef and the cellular protein cyclophilin A (CyPA) during virion assembly. These two proteins are integral components of HIV-1 particles. Both CyPA and Nef facilitate a step in the viral life cycle occurring between penetration and reverse transcription, suggesting a common mechanism of action. Experiments were performed to test the potential interplay of Nef- and CyPA-mediated enhancement of HIV-1 infectivity. In single-cycle infection assays, nef-defective virions were partially resistant to cyclosporin A (CsA), a drug that inhibits the binding of CyPA to the HIV-1 Gag precursor and CyPA incorporation into virions. Genetic dissection of the relative contributions of Nef and the cyclophilin A-Gag interaction to HIV-1 infectivity demonstrated the independence of these two effects. Nef was not required for incorporation of CyPA into HIV-1 virions and vice-versa. Surprisingly, CyPA-deficient virions remained sensitive to inhibition by CsA, in a manner that depended strongly on the presence of a functional nef gene. These results demonstrate that Nef and CyPA act independently to render HIV-1 particles fully infectious. They further suggest that in addition to blocking the CyPA-Gag interaction, CsA can also inhibit HIV-1 replication through a novel mechanism involving suppression of Nef-directed enhancement of virus infectivity.

Publication types

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

MeSH terms

  • Cell Line
  • Cyclosporine / pharmacology
  • Defective Viruses / pathogenicity
  • Defective Viruses / physiology
  • Gene Products, nef / metabolism*
  • Genes, nef*
  • HIV-1 / drug effects
  • HIV-1 / pathogenicity*
  • HIV-1 / physiology*
  • HeLa Cells
  • Humans
  • Peptidylprolyl Isomerase / metabolism*
  • T-Lymphocytes
  • Tumor Cells, Cultured
  • Virion / pathogenicity
  • Virion / physiology
  • Virus Replication*
  • nef Gene Products, Human Immunodeficiency Virus

Substances

  • Gene Products, nef
  • nef Gene Products, Human Immunodeficiency Virus
  • Cyclosporine
  • Peptidylprolyl Isomerase