Speaker
Description
The development of durable antibody-based HIV treatments requires understanding not only which mutations confer resistance, but also how frequently those mutations emerge. Prior work has characterized the effects of individual mutations on viral fitness and antigenic escape; however, these evolutionary outcomes are also constrained by the mutational supply of new variants. How these mutational biases shape the evolution of HIV escape pathways in vivo remains largely unquantified. Here, we present a site-specific mutational supply framework and use it to explain viral escape from broadly neutralizing antibodies (bNAbs).
We measured the in vivo mutation rate across the HIV NL4-3 genome using our Error Rate of Replication Sequencing (ERR-Seq) platform, revealing extensive site-specific heterogeneity, with pronounced mutational hot and cold spots. Modeling analyses revealed that this variation was explained by a combination of local nucleotide context, RNA secondary structure, and mutation-type biases. Notably, our data support a model in which APOBEC3 proteins frequently perform sub-lethal mutagenesis, increasing the effective mutation rate of HIV.
By integrating these measurements into a generative mutation supply model, we can predict the rate of every nucleotide change across the genome. We applied this framework to a prior study of AAV-delivered bNAbs, focusing on two competing bNAb escape pathways. In that study, the higher fitness cost escape was twice as likely to emerge as the lower fitness cost escape. We found that this outcome is explained by mutational supply, as the higher fitness cost pathway is favored by its higher mutation and recombination rates.
This data shows strong heterogeneity in mutational supply across the HIV genome and demonstrates that mutational biases can shape escape trajectories. Incorporating the mutational supply framework into models of viral evolution should improve quantitative predictions of escape pathways and assist in the design of more durable antibody-based interventions.
| Expedited Notification | No thanks, I do not require Expedited Notification |
|---|
