Abstract
<jats:p>Many urgent medical and agricultural challenges are driven by resistance evolution via soft selective sweeps of multiple simultaneous mutations. Standard approaches to detect these mutations involve genome scans for regions with reduced diversity and increased haplotype lengths. However, it is unknown the extent to which those signatures persist as the number of mutations driving resistance grows. Here, we analyzed longitudinal linkage-resolved data from 10 intra-host HIV populations treated with broadly neutralizing antibody 10-1074. We found that HIV escapes 10-1074 with minimal perturbations to diversity and haplotype homozygosity in the region surrounding the sweep in the majority (8/10) of treated individuals. We matched these in vivo escape trajectories to forward simulations and found that adaptive mutations conferring escape must have been present on 20 or more genetic backgrounds to generate these signatures. These "ultra-soft" sweep signatures more closely resemble genetic patterns in a treatment non-responder without an adaptive response to 10-1074 than those of two other trial participants where adaptation occurred via harder selective sweeps. Our results demonstrate that HIV can adapt to a broadly neutralizing antibody treatment while retaining nearly all of its standing genetic diversity and that selection scans dependent on regional diversity and haplotype homozygosity signatures fail in this "ultra-soft" regime.</jats:p>