Absconding with the Chaperone: Essential Cyclophilin–Gag Interaction in HIV-1 Virions

Does CyP play a role in HIV-1 replication? CyPA, the member of the CyP family that colocalizes with Gag in College of Physicians and Surgeons 701 West 168th Street the cytoplasm, is specifically incorporated into HIV-1 virions via interaction with the Gag polyprotein Gag binding to CyPA requires a proline-rich region located in the center of the CA domain, and mutation of a single proline, P90, or of the residue immediately preceding Retroviral virion assembly and uncoating are orchestrated by gag-encoded proteins, including the Capsid it, G89, disrupts CyPA incorporation into virions and precludes viral replication. Furthermore, cyclosporine A protein (CA) which forms the mature virion core. New genetic and structural data demonstrate that cyclophilin inhibits the production of replication-competent HIV-1 virions by disrupting the Gag–CyPA interaction (Braaten A (CyPA), a cytoplasmic protein best known as the re-et al., 1996b; Thali et al., 1994). ceptor for the immunosuppressant cyclosporine A, Though CyPA is incorporated into HIV-1 virions it is forms a stable and essential complex with CA in HIV-1 not required for virion assembly per se: virions rendered virions. The most recent contribution to this evolving CyPA-deficient by gag mutation, or by production in the story, the solution of the three-dimensional structure of presence of cyclosporine A, are produced at normal the HIV-1 CA–CyPA complex, is described in a highly levels and are otherwise indistinguishable from wild-informative paper in this issue of Cell (Gamble et al., type virions by standard biochemical criteria (Braaten 1996). These data illuminate aspects of the retroviral life et al. cycle that had been relatively inaccessible to study and Nonetheless, disruption of CyPA incorporation causes a evoke questions about the function of the ubiquitous quantitative reduction in virion infectivity, with the block cyclophilin family of proteins. occuring early in the virus life cycle, after membrane The Many Faces of Gag fusion, but prior to the initiation of reverse transcription The myristylated Gag polyprotein of HIV-1 and other (Figure 1). Target cell CyPA is not required for these retroviruses is sufficient for the formation and release of early events and cannot rescue CyPA-deficient virions. enveloped virions. Gag recruits other viral components Two genetic approaches were used to demonstrate required for infectivity, including genomic RNA and Env that Gag not only packages CyPA into virions but that glycoprotein, via direct interactions during assembly. The protease product of the pol gene cleaves the Gag polyprotein into several mature proteins: …