Regulation of Human Retroviral Gene Expression 
Rev itself. The Rev protein therefore regulates its 
own expression via a negative feedback mecha- 
nism. It has been proposed that Rev achieves this 
effect by specifically regulating the export of 
viral RNAs from the cell nucleus to the cyto- 
plasm. This specificity is conferred by a cis-acting 
viral RNA target sequence, the Rev response ele- 
ment (RRE), which has been shown to form a 
complex RNA secondary structure. Recent data 
demonstrate that Rev specifically recognizes, and 
binds to, a short, approximately 13-nucleotide 
primary sequence within the context of the larger 
RRE structure. Rev function also appears to re- 
quire the subsequent binding of additional Rev 
protein monomers to secondary target sites 
within the RRE. 
Mutational analysis of the Rev protein has 
demonstrated the existence of two functional 
domains. The first is a sequence-specific RNA- 
binding domain required for binding to, and mul- 
timerization on, the RRE, while the second is be- 
lieved to interact with a currently unidentified 
cellular protein that may form part of the cellular 
RNA transport machinery. Mutations of this latter 
domain, the Rev activation domain, give rise to 
Rev proteins that act as competitive inhibitors of 
the wild-type Rev trans-activator. Mutant HIV-1 
proteins of this type (dominant negative mu- 
tants) may have future application in the gene 
therapy of HIV-1 -infected individuals. A major 
focus of this laboratory is the development of 
these trans-dominant Rev mutants and, in particu- 
lar, the further investigation of the role of cellu- 
lar proteins in the Rev response. 
Finally, we have begun to expand our research 
to other human retroviruses, including HIV-2 and 
the apparently nonpathogenic HFV, as well as to 
related animal retroviruses, such as visna virus. 
The elucidation of similarities and differences in 
the regulation of gene expression among these 
retroviruses should facilitate the identification 
and understanding of the cis- and trans-acting ele- 
ments required for their replication and 
pathology. 
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