Background: To complete its replication cycle, HIV-1 requires the nucleocytoplasmic
export of intron-containing viral mRNAs. This process is ordinarily restricted by the cell, but HIV
overcomes the block by means of a viral protein, Rev, and an RNA secondary structure found in all
unspliced and incompletely spliced viral mRNAs called the Rev Response Element (RRE). In vivo
activity of the Rev-RRE axis requires Rev binding to the RRE, oligomerization of Rev to form a
competent ribonucleoprotein complex, and recruitment of cellular factors including Crm1 and
RanGTP in order to export the targeted transcript. Sequence variability is observed among primary
isolates in both Rev and the RRE, and the activity of both can be modulated through relatively small
sequence changes. Primary isolates show differences in Rev-RRE activity and a few studies have
found a correlation between lower Rev-RRE activity and slower progression of clinical disease.
Lower Rev-RRE activity has also been associated with the evasion of cytotoxic T lymphocyte mediated
Conclusion: The HIV-1 Rev-RRE regulatory axis is an understudied mechanism by which viral adaptation
to diverse immune milieus may take place. There is evidence that this adaptation plays a
role in HIV pathogenesis, particularly in immune evasion and latency, but further studies with larger
sample sizes are warranted.