Mechanistic independence of Nef and cyclophilin A enhancement of human immunodeficiency virus type 1 infectivity.
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.
Aiken
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Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232-2363, USA. chris.aiken@mcmail.vanderbilt.edu
D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D003673:Defective Viruses / Q000472:pathogenicity / Q000502:physiology; D015693:Gene Products, nef / Q000378:metabolism*; D015754:Genes, nef; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured; D014771:Virion / Q000472:pathogenicity / Q000502:physiology; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus; D016572:Cyclosporine; D019696:Peptidylprolyl Isomerase