Functional domain analysis of HIV accessory proteins

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In this study, we have done functional domain analyses on Vif and Nef of HIV-1, and also on Vpx and Vpr of HIV-2. Results obtained can be summarized as follows. (1) HIV-1 Vif. By comparing the activities of Vif from long term nonprogressors and progressors for AIDS, we found that Vif could influence HIV-1 infectivity and disease progression in infected individuals. We have constructed a series of HIV-1 Vif mutants in vitro, and have characterized them biologically and biochemically. During the course of this mutational analysis, we noticed that HIV-1 Vif is extremely and uniquely sensitive to proteasome-degradation among HIV accessory proteins. We identified the lysine residues responsible for this degradation, and showed that it is critically important for the optimal infectivity of HIV-1. (2) HIV-1 Nef. By using a point mutant of Nef which is defective only for MHC-I down-regulation, we have demonstrated that HIV-1 Nef suppresses the cytokine production by CTL cells only partially, while completely their cytocydial activity. (3) HIV-2 Vpx and Vpr. In additoin to Vpr, which is also encoded by the genome of HIV, HIV-2 carries Vpx in its genome. By homology modeling, it has been clearly and strongly suggested that HIV-1 Vpr, HIV-2 Vpx and HIV-2 Vpr are structurally very similar, having three or four major helices. In our functional mutational study, HIV-2 Vpx and Vpr were found to have more functions than HIV-1 Vpr such as enhancing reverse transcription of viral genome and augmenting virion release.