Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies

Area of Science:

• Immunology
• Virology
• Evolutionary Biology

Background:

• Broadly neutralizing antibodies (bNAbs) offer potential for HIV therapy and prevention.
• Viral resistance evolution poses a significant challenge to the efficacy of bNAb treatments.
• Understanding in vivo viral escape mechanisms is crucial for developing durable bNAb combination therapies.

Purpose of the Study:

• To comprehensively characterize in vivo viral escape from two distinct bNAbs, 10-1074 and 3BNC117.
• To identify specific evolutionary pathways and patterns of HIV escape under bNAb monotherapy.
• To gain insights into the genetic basis and predictability of bNAb resistance.

Main Methods:

• Deep, longitudinal sequencing of full-length HIV envelope (env) genes from participants receiving bNAb monotherapy.
• Application of advanced computational evolutionary analyses to track viral escape dynamics.
• Comparative analysis of escape profiles for bNAbs 10-1074 and 3BNC117.

Main Results:

• HIV-1 escape from bNAb 10-1074 involved pre-existing mutations, preferred pathways, and high genetic parallelism.
• HIV-1 escape from bNAb 3BNC117 exhibited background-specific patterns with intra-host parallelism.
• Distinct in vivo escape profiles were observed for the two bNAbs, challenging generalized predictions.

Conclusions:

• Viral escape pathways from bNAbs are antibody-specific and influenced by the viral genetic background.
• Predicting bNAb susceptibility solely from viral genetic diversity is challenging due to complex evolutionary dynamics.
• These findings underscore the need for tailored bNAb strategies to overcome HIV resistance.