The mechanism of HIV-RNA transport/splicing control involves the action of a trans-acting viral protein (Rev) that binds to a cis-acting element in the viral RNA (the RRE). In contrast, the genome of Mason-Pfizer Monkey Virus (MPMV), a simpler retrovirus, contains a cis-acting element known as the constitutive transport element (CTE) that interacts directly with cellular factors to effectuate transport of intron-containing RNA. The investigator proposes to further study Rev/RRE and CTE regulation of nucleo-cytoplasmic RNA export.
The specific aims of this proposal are: 1) To isolate and functionally characterize cellular proteins that interact specifically with the MPMV CTE, 2) To identify and characterize novel cellular and viral CTEs and potential cellular RRE's, 3) To further analyze the pathways utilized for Rev/RRE and CTE mediated RNA export, and 4) To further characterize variants of HIV-1 that show resistance to RevM10 and to analyze the inhibition of HIV replication by different transdominant negative Rev proteins using Rev-dependent and Rev-independent viruses. The experiments proposed are designed to elucidate how the RNA export pathway utilized by Rev/RRE relates to that used by the CTE. They may also lead to an increased insight into pathways involved in export of cellular RNAs. An understanding of how retroviral RNA export relates to export of cellular RNAs may allow us to design novel inhibitors with selective effects.
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