Speaker
Description
Broadly neutralizing antibodies (bNAbs) are an emerging HIV therapeutic approach undermined by frequent intra-host viral escape. Predicting escape pathways for different bNAbs is a crucial step in combining them into effective multi-component therapies, but identifying escape mutations from in vitro screens may not yield results that are portable across the diverse genetic backgrounds found in different hosts. We investigated the predictability of realized escape pathways in vivo during two monotherapy trials of bNAbs 10-1074 and 3BNC117, which respectively target the V3 glycan and CD4 binding site. We performed longitudinal, long-read deep sequencing (6729 sequences from 20 participants; median 42 sequences per sampling timepoint) using a SMRT-UMI method designed to preserve genetic linkage, providing a dataset well-suited for discovering escape mutations in the context of their intra-host genetic backgrounds. We found that escape pathways from 10-1074 exhibited almost no background specific effects: different viruses both across and within participants escaped by repeatedly producing identical mutations to eliminate the N332 V3 glycan to which 10-1074 binds. Notably, the pervasiveness of these escape mutations further allowed intra-host HIV populations to select those escape mutations that best mitigated fitness costs. In contrast, 3BNC117 escape was highly background-dependent, with heterogeneity in putative escape loci across participants. Despite this background specificity, we observe some shared escape pathways at shorter genetic distances, such as recurrent mutations at the intra-host level and shared escape loci across two study participants who constitute a transmission pair. Together, these results indicate that the predictability of bNAb escape pathways is shaped by their target region and inform when we can – and cannot – predict escape phenotypes from genetic data alone.
| Expedited Notification | No thanks, I do not require Expedited Notification |
|---|
