Evidence of a Direct Evolutionary Selection for Strong Folding and Mutational Robustness Within HIV Coding Regions

A large number of studies demonstrated the importance of different HIV RNA structural elements at all stages of the viral life cycle. Nevertheless, the significance of many of these structures is unknown, and plausibly new regions containing RNA structure-mediated regulatory signals remain to be identified. An important characteristic of genomic regions carrying functionally significant secondary structures is their mutational robustness, that is, the extent to which a sequence remains constant in spite of despite mutations in terms of its underlying secondary structure. Structural robustness to mutations is expected to be important in the case of functional RNA structures in viruses with high mutation rate; it may prevent fitness loss due to disruption of possibly functional conformations, pointing to the specific significance of the corresponding genomic region. In the current work, we perform a genome-wide computational analysis to detect signals of a direct evolutionary selection for strong folding and RNA structure-based mutational robustness within HIV coding sequences. We provide evidence that specific regions of HIV structural genes undergo an evolutionary selection for strong folding; in addition, we demonstrate that HIV Rev responsive element seems to undergo a direct evolutionary selection for increased secondary structure robustness to point mutations. We believe that our analysis may enable a better understanding of viral evolutionary dynamics at the RNA structural level and may benefit to practical efforts of engineering antiviral vaccines and novel therapeutic approaches.