Characterization of a Cell Factor that Targets HIV-1 Rev

Souad Naji, The Scripps Research Institute
Mentor: Larry Gerace
Training in Basic Biomedical Sciences
Postdoctoral Fellowship Award

The Rev protein of the human immunodeficiency virus-1 (HIV-1) is critical for HIV replication. When Rev accumulates to sufficient levels, it binds to the cis-acting Rev-Response-Element (RRE) present in underspliced viral RNAs and mediates their export to the cytoplasm, to allow their translation and genome packaging.

In a proteomic screen for proteins that selectively interact with Rev complexed to the RRE, we identified an E3-ubiquitin-ligase, Huwe1. I found that Huwe1 silencing strongly suppresses gene expression mediated by the Rev/RRE pathway, but has no effect on gene expression by the pathway that is used for most cellular mRNAs. This phenotype is explained by my finding that Huwe1 silencing leads to loss of Rev protein although the expression and nuclear export of Rev mRNA is not disrupted. We hypothesize that Huwe1 negatively regulates the activity of previously unknown host cell restriction factor for Rev that affects Rev protein turnover or translation. We propose the following to test this hypothesis by 1) characterizing in detail the mechanism of Rev loss in Huwe1 depleted cells and 2) identifying the cellular target(s) of Huwe1 that negatively regulates Rev. Our long term objective is to contribute to an understanding of how host cell factors that bind the Rev/RRE promote HIV infection. This work is expected to identify new potential drug targets for blocking HIV replication.