Journal Article

Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies

Taylor, Megan L, Westfall, Dylan H, Cohn, Lillian B, Clyde, Abigail E, Azam, Walker, Romero, Elena V, Feder, Alison F, Giorgi, Elena E, Caskey, Marina

2025

Overview

Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope ( ) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify routes and parallelism underlying HIV escape from each bNAb, providing new insights into this evolutionary process: 10-1074 escape is restricted to a small number of previously documented pathways, but these escape mutations 1) pre-exist in intra-host viral populations before therapy, 2) are not all equally preferred, and 3) emerge with a high degree of genetic parallelism within and across viral populations. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one population rarely emerge or spread in other populations, but often still exhibit parallel evolutionary responses within their host. That bNAbs elicit starkly different escape profiles depending on their Env target exposes the limitations of generalizing escape patterns across therapies and highlights the substantial challenges in predicting a viral population's bNAb susceptibility from genetic diversity alone.

• Publisher: Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Preprints
• Subject: Molecular Biology