RNA Helicase A (RHA) is one of the cellular factors recruited into HIV-1 particles during virus assembly. The reduced infectivity of RHA-deficient virions demonstrates that the RHA molecules co-assembled with gRNA exert a continuous impact in early infection. However, it remains unclear how host RHA is specifically recruited during virus assembly, and how it supports the infectivity of progeny virions. Our laboratory has recently reported that the recruitment of RHA is mediated by the direct interactions between RHA and the PBS-segment of the viral genomic RNA during assembly. In addition, our preliminary studies indicate that the specific RHA:PBS-segment interaction may coordinate proper tRNA placement on the PBS-segment to initiate reverse transcription. We propose to employ an innovative integrated NMR/SAXS approach, in combination with cell-based functional assays, to determine the structural basis of the PBS-segment mediated recruitment of RHA during virus assembly, and to investigate the role of RHA during the early stage of viral replication.
HIV-1 infection is one of the leading causes of death globally, and will continue be one of the significant global causes for premature mortality in the coming decades. The overall goal of this proposed study is to investigate how HIV-1 specifically recruits host factors to bolster virion infectivity. The proposed structural and mechanistic studies of virus-host interactions will advance our understanding of important HIV-1 replication steps, and could help identify new antiviral targets for the development of drug-resistant strains of HIV.