Mentored Scientist Award

HIV treatment has been transformed by highly active antiretroviral therapy. However, this progress is fragile as HIV is constantly evolving to escape these drugs. Moreover, investigational cures have been stymied by evolution of immune escape. Predicting when genetic changes in the virus will translate into clinically meaningful phenotypes—like drug resistance or immune escape —remains an unsolved problem. This challenge reflects a fundamental gap in our understanding of how genotype maps to phenotype: the effect of a mutation often depends on other mutations, a phenomenon known as epistasis. Because the number of possible mutational combinations is astronomical, predicting HIV evolution under therapy or immune pressure has remained out of reach.

This project seeks to uncover general principles governing how HIV genotype gives rise to phenotype by systematically mapping epistasis in two viral proteins that are major drug and immune targets: capsid and integrase. Using high-throughput experimental systems, this work will measure the effects of ~10⁵ mutations on viral growth and drug resistance. These data will be integrated with large clinical and population-level HIV datasets to identify how mutational interactions shape viral evolution in patients. The central hypothesis is that the nature and number of a mutation’s interactions predict its impact on viral phenotypes and evolution. The expected outcome is a set of experimentally grounded models to forecast how resistance and immune escape are likely to emerge within patients.

By uncovering how genotype gives rise to phenotype in HIV, this work will improve prediction of treatment failure and help ensure our best drugs remain effective. Furthermore, the viral regions identified as evolutionarily constrained could represent targets for immune-based cure therapies. More broadly, this work will advance our understanding of how genotype maps to phenotype map – a question fundamental to diverse biological systems, including cancer, antibiotic-resistant bacteria, and human genetic disorders.