(342k) Mechanistic Insights into HIV Common Escape Pathways from Broadly Neutralizing Antibodies Via Molecular Dynamics Simulations

The delivery of broadly neutralizing antibodies (bnAbs) via adeno-associated virus gene transfer has shown potential as a therapeutic for treating HIV patients [1]. However, despite the ability of bnAbs to neutralize diverse strains of a pathogen by binding to conserved regions on the surface of pathogenic proteins, studies have shown that HIV can still evolve mutations permitting escape from these bnAbs, thereby reducing the immune system’s ability to control viral load [2]. Motivated by recent in vivo experiments characterizing common HIV mutational escape pathways from the VRC07 bnAb, we performed molecular dynamics (MD) simulations of these same components/mutations to determine the molecular basis of escape in each case. The homology modelling program Modeller and Visual Molecular Dynamics (VMD) were employed to generate glycosylated structures of strains REJOc and JRCSF of the HIV-1 envelope (Env) trimer, incorporated with the observed escape mutations and in complex with VRC07. Simulations were carried out using GROMACS 2018.3 for 40 ns, after which the average change in binding free energy was calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method and a bootstrapping analysis. We found trends in the binding free energies calculated from MD to be in strong qualitative agreement with trends in the experimentally determined EC₅₀ values. We also found that weakened electrostatic binding was the major driving force for escape in multiple instances. Furthermore, visual analysis of the simulation trajectories in VMD revealed many commonalities in the escape mechanisms across the observed mutations, including consistently disrupted interactions between VRC07 and the D-loop and V5-loop of each HIV strain. Lastly, we observed a unique role of glycans in assisting in escape from the antibody. Our results may assist in the future development of bnAb therapies that are more resistant to mutational escape, enabling complete suppression of various HIV strains.

1. Casazza, J. P. Durable HIV-1 antibody production in humans after AAV8-mediated gene transfer. In Conference on Retroviruses and Opportunistic Infections (CROI) 2020, Oral abstract(Vol. 41).
2. Scheid, J., Horwitz, J., Bar-On, Y. et al.HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535, 556–560 (2016). https://doi.org/10.1038/nature18929