HIV-1 frameshift efficiency is primarily determined by the stability of base pairs positioned at the mRNA entrance channel of the ribosome

Mouzakis, Kathryn D.; Lang, Andrew L.; Vander Meulen, Kirk A.; Easterday, Preston D.; Butcher, Samuel E.

HIV-1 group M subtype B is the dominant form of HIV-1 in North and South America, Europe, Japan, Thailand and Australia. The less common non-B subtypes (A, C, D, E, F, G, H, J and K) have decreased local stabilities; for example, a frequent C to U mutation in the first base pair of the stem-loop in these subtypes results in formation of a U-G wobble pair in place of a C-G (28, 84) . Interestingly, the exponential relationship we observe predicts that such a change would have little effect on frameshift efficiency. For instance, mutants MS10-12 all incorporate U-G wobble pairs at these positions, which significantly destabilize the local stability by +5.5 kcal/mol relative to WT ( Figure 1 ). Nevertheless, these mutations result in near WT frameshift efficiencies ( Figure 3A ), owing to the exponential relationship between local stability and frameshift efficiency (Figures 3C, 4F and G). These results are consistent with the observed frameshift efficiencies of the less common subtypes (28) . Finally, a randomized trial of HIV patients receiving protease inhibitor therapy examined mutations in the Gag-Pol frameshift site and found no relationship between overall stability of the stem-loop and virological response (85) . This observation is consistent with our results that show no correlation between overall stability and frameshifting (Figures 3B and 4E) .