Antiviral drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase occur in specific RNA structural regions

A statistically significant correlation exists between the locations of drug resistance mutations (DRMs) observed for various reverse transcriptase inhibitors and features of the secondary structure predicted for the RNA coding for human immunodeficiency virus type 1 reverse transcriptase. The known DRMs map onto "unstable" bases, which are predominantly nonhelical regions (i.e., loops, bulges, and bends) of the predicted RNA secondary structure, whereas codons for the key conserved residues of polymerase sequence motifs map onto "stable" paired bases involved in helical regions. On the basis of these results, we hypothesize that the secondary structure of the RNA template (in this case, the reverse transcriptase gene itself) may be a previously unrecognized factor contributing to base misincorporation errors during reverse transcription and that, rather than being randomly distributed, mutations are more likely to occur in specific regions of the genome. The results suggest that these "mutation-prone" regions can be predicted by using a standard algorithm for RNA secondary structure.