HIV broadly neutralizing antibody escapability drives the therapeutic efficacy of vectored immunotherapy.
Nicolas M S GalvezYi CaoAdam D NitidoCailin E DealChristine L BoutrosScott W MacDonaldYentli E Soto AlbrechtEvan C LamMaegan L SheehanDylan ParsonsAllen Z LinMartin J DeymierJacqueline M BradyBenjamin MoonChristopher B BullockSerah TannoAmarendra PeguXuejun ChenCuiping LiuRichard A KoupJohn R MascolaVladimir D VrbanacDaniel LingwoodAlejandro B BalazsPublished in: bioRxiv : the preprint server for biology (2024)
Broadly neutralizing antibodies (bNAbs) have shown great promise for prevention and treatment of HIV infection. Breadth of bNAb neutralization, measured in vitro across panels of diverse viral isolates, is often used as a predictor of clinical potential. However, recent prevention studies demonstrate that the clinical efficacy of a broad and potent bNAb (VRC01) is undermined by neutralization resistance of circulating strains. Using HIV-infected humanized mice, we find that therapeutic efficacy of bNAbs delivered as Vectored ImmunoTherapy (VIT) is a function of both the fitness cost and resistance benefit of mutations that emerge during viral escape, which we term 'escapability'. Applying this mechanistic framework, we find that the sequence of the envelope V5-loop alters the resistance benefits of mutants that arise during escape, thereby impacting the therapeutic efficacy of VIT-mediated viral suppression. We also find that an emtricitabine-based antiretroviral drug regimen dramatically enhances the efficacy of VIT, by reducing the fitness of mutants along the escape path. Our findings demonstrate that bNAb escapability is a key determinant to consider in the rational design of antibody regimens with maximal efficacy and illustrates a tractable means of minimizing viral escape from existing bNAbs.
Keyphrases
- hiv infected
- antiretroviral therapy
- sars cov
- human immunodeficiency virus
- hiv positive
- hiv aids
- physical activity
- hiv infected patients
- body composition
- escherichia coli
- hepatitis c virus
- dengue virus
- heart rate
- transcription factor
- big data
- wild type
- machine learning
- blood pressure
- resistance training
- metabolic syndrome
- climate change
- adipose tissue
- case control
- deep learning
- gestational age
- genetic diversity
- aedes aegypti
- amino acid