HIV broadly neutralizing antibody escape dynamics drive the outcome of AAV-vectored immunotherapy in humanized mice.

Broadly neutralizing antibodies (bNAbs) have shown promise for the prevention and treatment of HIV. Potency and breadth measured in vitro are often used as predictors of clinical potential; however, human studies demonstrate that the clinical efficacy of bNAbs can be undermined by both preexisting and de novo resistance. Here, we found that HIV-infected humanized mice receiving bNAbs delivered via adeno-associated virus (AAV) as vectored immunotherapy (VIT) could be used to identify antibody escape paths, which were largely conserved for each bNAb. Path selection and consequent therapeutic success were driven by the fitness cost and resistance benefit of emerging mutations. Applying this framework, we independently modulated bNAb resistance or the fitness cost of escape mutants, resulting in the enhanced efficacy of VIT. This escape-path analysis successfully explains the therapeutic efficacy of bNAbs and enables a tractable means of quantifying and comparing the potential for viral escape from therapeutics in vivo.