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Complex Impact of Reversion Mutations and CD8+ T Cell Escape Mutations on HIV-1 Fitness
Hongshuo Song, Tanmoy Bhattacharya, Nilu Goonetilleke, Kevin Wiehe, Andrew McMichael, George Shaw, Beatrice Hahn, Alan Perelson, Barton Haynes, Feng Gao *Duke Human Vaccine Institute Duke University Medical Center Durham NC United States, Los Alamos National Laboratory Los Alamos NM United States, Weatherall Institute of Molecular Medicine University of Oxford Oxford United Kingdom, Department of Microbiology University of Pennsylvania Philadelphia PA United States
Background: Mutations that revert back to the ancestral state frequently occur in the HIV-1 genome during infection and have been considered to render the viruses more fit. However, their impact on viral fitness and interactions with the immune escape mutations have not been evaluated in their cognate transmitted/founder (T/F) viral genomes. Methodology: Our previous study showed that viruses containing both cytotoxic T lymphocyte (CTL) escape mutations and reversion mutations are as fit as the T/F viruses. To precisely determine the role of reversion mutations, we generated the T/F mutants that contained either reversion mutation alone or together with CTL escape mutations and determined its impact on the viral fitness in primary CD4+ T cells using the PASS fitness assay. Results: The reversion mutation V247I in the TW10 CTL epitope in Gag could partially restore the fitness loss caused by the CTL escape mutation T242N in the same epitope. However, the reversion mutation V247I or I64T in Tat/Rev alone had no impact on fitness of the T/F virus. The CTL escape mutations G248A in Gag and R355K in Env did not have any fitness cost. Interestingly, the CTL escape mutation G248A, like the reversion mutation V247I, could also partially compensate the fitness loss caused by the T242N mutation. Both the V247I and G248A mutations together fully restored the fitness loss of the T242N mutant. Positions 242, 247 and 248 are not located at p24 pentamer or hexamer interfaces and therefore should not affect the capsid assembly. In addition, homology modeling of p24 monomers demonstrated that mutations at these positions are not expected to significantly affect stability of the helix 6 structure. Conclusions: Our results showed that reversion mutations might not render their cognate T/F virus more fit in vitro but could partially restore the fitness loss caused by the CTL escape mutation, and a CTL escape mutation could also partially compensate the fitness loss due to the other CTL escape mutation. These findings demonstrated that the overall viral fitness is influenced by the complex interplay of different mutations.