Regulation of HIV-1 Alternative RNA Splicing and Its Role in Virus Replication

Over 40 different human immunodeficiency virus type 1 (HIV-1) mRNA species, both completely and incompletely spliced, are produced by alternative splicing of the primary viral RNA transcript. In addition, about half of the viral RNA remains unspliced and is transported to the cytoplasm where it is used both as mRNA and as genomic RNA. In general, the identities of the completely and incompletely spliced HIV-1 mRNA species are determined by the proximity of the open reading frames to the 5'-end of the mRNAs. The relative abundance of the mRNAs encoding the HIV-1 gene products is determined by the frequency of splicing at the different alternative 3'-splice sites. This chapter will highlight studies showing how HIV-1 uses exon definition to control the level of splicing at each of its 3'-splice sites through a combination of positively acting exonic splicing enhancer (ESE) elements, negatively acting exonic and intronic splicing silencer elements (ESS and ISS elements, respectively), and the 5'-splice sites of the regulated exons. Each of these splicing elements represent binding sites for cellular factors whose levels in the infected cell can determine the dominance of the positive or negative elements on HIV-1 alternative splicing. Both mutations of HIV-1 splicing elements and overexpression or inhibition of cellular splicing factors that bind to these elements have been used to show that disruption of regulated splicing inhibits HIV-1 replication. These studies have provided strong rationale for the investigation and development of antiviral drugs that specifically inhibit HIV-1 RNA splicing.