CYCLOPHILIN-A IS REQUIRED FOR THE REPLICATION OF GROUP-M HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) AND SIMIAN IMMUNODEFICIENCY VIRUS SIV(CPZ)GAB BUT NOT GROUP-O HIV-1 OR OTHER PRIMATE IMMUNODEFICIENCY VIRUSES

The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein binds to cyclophilin A and incorporates this cellular peptidyl prolyl-isomer ase into virions. Disruption of cyclophilin A incorporation, either by gag mutations or by cyclosporine A, inhibits virion infectivity, indi cating that cyclophilin A plays an essential role in the HIV-1 life cy cle, Using assays for packaging of cyclophilin A into virions and for viral replication sensitivity to cyclosporine A, as well as informatio n gleaned from the alignment of Gag residues encoded by representative viral isolates, we demonstrate that of the five lineages of primate i mmunodeficiency viruses, only HIV-1 requires cyclophilin A for replica tion, Cloned viral isolates from clades A, B, and D of HIV-1 group M, as well as a phylogenetically related isolate from chimpanzee, all req uire cyclophilin A for replication. In contrast, the replication of tw o outlier (group 0) HIV-1 isolates is unaffected by concentrations of cyclosporine A which disrupt cyclophilin A incorporation into virions, indicating that these viruses are capable of replicating independentl y of cyclophilin A, These studies identify the first phenotypic differ ence between HIV-1 group M and group 0 and are consistent with phyloge netic studies suggesting that the two HIV-1 groups were introduced int o human populations via separate zoonotic transmission events.