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Open Access Publications from the University of California

Viral and host determinants for Crm1-mediated nuclear export of HIV RNA

  • Author(s): Booth, David Scott
  • Advisor(s): Frankel, Alan D
  • Cheng, Yifan
  • et al.
Abstract

The human immunodeficiency virus (HIV) protein Rev plays a central role in the viral lifecycle by post-transcriptionally regulating the expression of structural and envelope proteins and by providing genomic RNA for new virions. Rev accomplishes these tasks by interfacing with the host nuclear transport machinery to facilitate the nuclear export of unspliced and partially spliced viral RNAs. A cis-acting element within these RNAs, the Rev Response Element (RRE), directs the assembly of a Rev homoligomer that recruits the nuclear export adaptors Crm1 and Ran. In this dissertation, I share my efforts to understand this critical host-virus interaction. By providing the first structure of the entire complex with supporting biochemistry, this work reveals evolutionary changes in both the host and viral components that determine how HIV adapts the Rev-RRE complex to its human host. Specifically, these results highlight a novel attribute conserved in simian primates for Crm1 to form an ordered dimer that facilitates the cooperative recognition of the Rev-RRE complex and correlates to increased nuclear export of viral RNAs. Mutations in the RRE that augment nuclear export can change how Rev-RRE encounters this Crm1 dimer. These findings lay the groundwork for future studies to potentially develop novel therapeutics that antagonize Crm1 dimerization, to determine a high-resolution structure of the Rev-RRE complex bound to its host cofactors, and to investigate the fate of the virus-host complex during subsequent steps of virion biogenesis.

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