Modeling the evolution of multi-drug resistance in HIV
By Alison Feder
HIV-1 is treated with combination therapies of multiple simultaneous drugs targeting different stages of the viral lifecycle, such that no single mutation confers resistance to all drugs used in a treatment. Complete drug resistance should require the co-occurrence of multiple resistance mutations in a single reverse transcription step - an extremely rare event probabilistically. Nevertheless, HIV does evolve resistance even on combination therapy, suggesting an incomplete understanding of the dynamics at play. In this presen-tation, I'll describe several key features identi˝ed in clinical trial and genetic data that a model of drug resistance evolution must match - namely resistance mutations emer-ging one at a time in a partially predictable order, even years after therapy onset. I will then describe our efforts to model this process of multi-drug resistance emergence, using temporally- or spatially-varying drug levels within individuals. We find that a model of spatial heterogeneity more straightforwardly matches the patterns found in clinical data, and I close by discussing how we can use these findings to design more evolution-proof combination therapies.