The human immunodeficiency virus type 1 capsid p2 domain confers sensitivity to the cyclophilin-binding drug SDZ NIM 811.
Human immunodeficiency virus type 1 (HIV-1) specifically incorporates the host cell peptidyl-prolyl isomerase cyclophilin A into virions via contacts with the capsid (CA) domain of the Gag polyprotein Pr55gag. The immunosuppressant drug cyclosporin A and the nonimmunosuppressive cyclosporin A analog SDZ NIM 811 bind to cyclophilin A and inhibit its incorporation into HIV-1 virions. Both drugs inhibit the virion association of cyclophilin A and the replication of HIV-1 with a similar dose dependence. In contrast, these compounds are inactive against other primate lentiviruses which do not incorporate cyclophilin A, such as simian immunodeficiency virus (SIV). To locate determinants which confer sensitivity to SDZ NIM 811, we generated chimeric proviruses between HIV-1 and SIVmac. A hybrid SIVmac which has the CA-p2 domain of the Gag polyprotein replaced by the corresponding domain from HIV-1 replicated in an established CD4+ cell line and in human but not macaque peripheral blood mononuclear cells. The transfer of the HIV-1 CA-p2 domain to SIVmac led to the efficient incorporation of cyclophilin A, and SDZ NIM 811 effectively inhibited both the virion association of cyclophilin A and the spread of the hybrid virus in infected cultures. We conclude that the HIV-1 CA-p2 domain contains determinants which confer the necessity to interact with cyclophilin A for efficient virus replication. Furthermore, our data show that the CA-p2 domain can play a crucial role in species tropism.
Dorfman
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Division of Human Retrovirology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Göttlinger
H G
HG
D000591:Amino Acid Isomerases / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002678:Chimera; D003001:Cloning, Molecular; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D015683:Gene Products, gag / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D015750:Genes, gag; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D008251:Macaca; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009838:Oligodeoxyribonucleotides; D019696:Peptidylprolyl Isomerase; D011498:Protein Precursors / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011533:Proviruses / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014771:Virion / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology*
D000998:Antiviral Agents; D002352:Carrier Proteins; D015683:Gene Products, gag; D009838:Oligodeoxyribonucleotides; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D004706:Endodeoxyribonucleases; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase