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Our studies are focused on the molecular biology of HIV-1 and, in particular, on the synthesis and processing of HIV RNA. HIV-1 RNA is synthesized as a single primary transcript that is differentially processed by RNA splicing into more than 40 different mRNAs. It is necessary that splicing is regulated since both unspliced and spliced viral RNA are required for replication. Some of the primary transcripts are packaged into virions. Also, the spliced mRNAs are produced with significantly different efficiencies. We have found that there are sequences within the HIV genome that act as splicing silencers (exon splicing silencers or ESS elements) and we have characterized these sites as high affinity binding sites for cellular proteins of the hnRNP A/B family. We are investigating the mechanism by which these proteins cause splicing inhibition and the importance of these splicing silencers for virus replication. There are also sequences within the HIV-1 genome that act as splicing enhancers (ESE elements) and these are also under investigation. We are also investigating strain and virus group-specific differences in the sequence of the splicing elements and the effect of these differences on the relative replication efficiency. Viral and host factors that regulate retrovirus splicing are potential targets for antiviral drugs.
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