Cyclosporine A-resistant human immunodeficiency virus type 1 mutants demonstrate that Gag encodes the functional target of cyclophilin A - PubMed (original) (raw)
Cyclosporine A-resistant human immunodeficiency virus type 1 mutants demonstrate that Gag encodes the functional target of cyclophilin A
D Braaten et al. J Virol. 1996 Aug.
Abstract
The cellular peptidyl-prolyl isomerase cyclophilin A is incorporated into human immunodeficiency virus type 1 virions via contacts with the proline-rich domain of the Gag polyprotein. Cyclosporine A and nonimmunosuppressive analogs bind with high affinity to cyclophilin A, compete with Gag for binding to cyclophilin A, and prevent incorporation of cyclophilin A into virions; in parallel with the disruption of cyclophilin A incorporation into virions, there is a linear reduction in the initiation of reverse transcription after infection of a T cell. Passage of human immunodeficiency virus type 1 in the presence of the drug selects one of two mutations, either of which alters the proline-rich domain of Gag and is sufficient to confer drug resistance on the cloned wild-type provirus. Neither mutation alters Gag's cyclophilin A-binding properties in vitro, and cyclophilin A incorporation into drug-resistant virions is effectively disrupted by cyclosporine A, indicating that the drug-resistant mutants do not require virion-associated cyclophilin A to initiate infection. That Gag's functional dependence on cyclophilin A can be differentiated genetically from its ability to bind cyclophilin A is further demonstrated by the rescue of a mutation precluding cyclophilin A packaging by a mutation conferring cyclosporine A resistance. These experiments demonstrate that, in addition to its ability to package cyclophilin A into virions, gag encodes the functional target of cyclophilin A.
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