Rev–Rev Response Element Activity Selection Bias at the Human Immunodeficiency Virus Transmission Bottleneck

BACKGROUND: Sexual transmission of human immunodeficiency virus (HIV) is inefficient and results in selection of viral variants based on incompletely understood factors. Functional variation in the Rev–Rev response element (RRE) regulatory axis of HIV affect replication kinetics and relative expression of viral proteins. We explored whether differences in this axis among viral isolates affect transmission fitness. METHODS: HIV sequences were identified from nine female-to-male transmission pairs. Using a rapid flow cytometric assay, we analyzed Rev-RRE functional activity of primary isolates. RESULTS: Rev-RRE activity was significantly lower in recipient viruses compared with corresponding donor viruses. In most transmission events, recipient virus Rev-RRE activity clustered at the extreme low end of the range of donor virus activity. CONCLUSIONS: These data indicate selection pressure on the Rev-RRE axis during female-to-male sexual transmission. Variation in Rev-RRE activity may permit viral adaptation to different fitness landscapes and could play an important role in HIV pathogenesis.