Speaker
Description
Intra-host HIV populations overwhelmingly evolved resistance to broadly neutralizing antibodies (bNAbs) given as monotherapies in clinical trials, often doing so via multiple distinct amino acid substitutions that spread in concert. Quantifying the number of origins of bNAbs resistance within individuals is crucial for predicting how many simultaneous bNAbs must be applied to effectively suppress HIV. Using a novel sequencing strategy optimized to control for PCR artifacts and yield long-range (≈ 3kb) viral haplotypes at high depth, we longitudinally sequenced HIV env sequences before, during and 4 weeks after treatment with the bNAb 10-1074. Using these long reads to examine the linkage structure surrounding resistance mutations, we found repeated emergence of the exact same drug resistance mutation on multiple distinct viral haplotypes across participants. This indicates that resistance mutations occur significantly more frequently than can be revealed using only the amino acid identity at known resistance loci. We considered if recombination could move drug resistance mutations on to multiple distinct haplotypes and create the observed linkage signals, but found that extensive recurrent mutation was necessary to parsimoniously explain linkage structure in many study participants. These results suggest that HIV’s ability to evolve resistance to bNAbs is driven by a vast reservoir of minority variants that readily emerge under selection, leading to little reduction in population diversity post-treatment. Moving forward, this type of quantitative information will be critical for designing combination interventions that limit HIV’s evolutionary capacity. More broadly, we demonstrate that incorporating the linkage structure surrounding resistance mutations is a powerful strategy for disentangling the multiple evolutionary forces that shape population diversity during unsuccessful therapeutic regimens.
