Regulation of Human Retroviral Gene Expression 
teins Gag and Env, while simultaneously repress- 
ing the expression of the fully spliced RNAs that 
encode the viral regulatory proteins, including 
Rev itself. The Rev protein therefore regulates its 
own expression via a negative feedback mecha- 
nism. Recent data suggest 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. Rev function 
appears to require the sequential binding of mul- 
tiple Rev protein monomers to the RRE sequence. 
Mutational analysis of the Rev protein has dem- 
onstrated the existence of two functional do- 
mains. The first is a sequence-specific RNA-bind- 
ing domain required for the interaction with the 
RRE, while the second appears to interact with a 
currently unidentified cellular protein that may 
be 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 mutants) may have future ap- 
plication in the gene therapy of HIV- 1 -infected 
individuals. A major focus of this laboratory is the 
development of these trans-dominant Rev mu- 
tants and, in particular, the further investigation 
of the role of cellular proteins in the Rev 
response. 
Finally, my laboratory has begun to expand our 
research to other human retroviruses, including 
HIV- 2 and the apparently nonpathogenic human 
foamy retrovirus, as well as to related animal ret- 
roviruses, 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 elements required for 
their replication and pathology. 
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