Speaker
Description
Intra-host molecular evolution of HIV-1 genome sequences is thought to be critical for ensuring HIV-1 persistence during chronic, untreated infection. We have previously employed a high-throughput, single-genome amplification and sequencing (HT-SGS) approach for studies of intra-host virus diversity and evolution using unique molecular identifiers (UMIs) and the Pacific Biosciences long-read platform. Here, we applied HT-SGS to measure HIV-1 env allele frequency changes over time in longitudinal samples from people with chronic, untreated HIV-1 infection who received one dose of VRC01, a broadly neutralizing antibody (bNAb) that targets the CD4 receptor binding site region of HIV-1 env. We utilized two approaches to identify changes adaptive to VRC01 escape. The first is a codon based dN/dS approach executed by HYPHY with the FUBAR algorithm to identify positions under positive selection uniquely post infusion (where positive selection is not identified pre-infusion). The second approach is a population genetics approach where Tajima’s D is used to identify positive selective sweeps along the env gene, and then a score for the Selected Allele Favored in Evolution (SAFE) is calculated for each variation with >0.1 frequency change between pre and post infusion. In two individuals both approaches identify the same positions as adaptive. In another four individuals the evolutionary scenarios are more complicated and suggest the existence of several adaptive mutations in each host. In two of them, subpopulation structure affected by cell tropism is associated with different escape mutations. These results suggest that like HIV-1, the virological responses and the adaptive pathways to bNAb escape are diverse among different individuals, and while some changes are easily identified as adaptive, a variety of escape mutations in a single host, as well as compartmentalized sub populations may result in more obscured signals that are more challenging to interpret.
