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Altered Env conformational dynamics as a mechanism of resistance to peptide-triazole HIV-1 inactivators
Journal article   Open access   Peer reviewed

Altered Env conformational dynamics as a mechanism of resistance to peptide-triazole HIV-1 inactivators

Shiyu Zhang, Andrew P Holmes, Alexej Dick, Adel A Rashad, Lucía Enríquez Rodríguez, Gabriela A Canziani, Michael J Root and Irwin M Chaiken
Retrovirology, v 18(1), pp 31-31
09 Oct 2021
DOI: https://doi.org/10.1186/s12977-021-00575-z
PMID: 34627310
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1186/s12977-021-00575-zView
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Binding Sites Drug Resistance, Viral HIV Envelope Protein gp120 - chemistry HIV Envelope Protein gp120 - genetics HIV Envelope Protein gp120 - metabolism HIV Infections - virology HIV-1 - chemistry HIV-1 - drug effects HIV-1 - genetics HIV-1 - metabolism Humans Molecular Docking Simulation Mutation Peptides - chemistry Peptides - pharmacology Protein Conformation Triazoles - chemistry Triazoles - pharmacology Virus Internalization - drug effects
We previously developed drug-like peptide triazoles (PTs) that target HIV-1 Envelope (Env) gp120, potently inhibit viral entry, and irreversibly inactivate virions. Here, we investigated potential mechanisms of viral escape from this promising class of HIV-1 entry inhibitors. HIV-1 resistance to cyclic (AAR029b) and linear (KR13) PTs was obtained by dose escalation in viral passaging experiments. High-level resistance for both inhibitors developed slowly (relative to escape from gp41-targeted C-peptide inhibitor C37) by acquiring mutations in gp120 both within (Val255) and distant to (Ser143) the putative PT binding site. The similarity in the resistance profiles for AAR029b and KR13 suggests that the shared IXW pharmacophore provided the primary pressure for HIV-1 escape. In single-round infectivity studies employing recombinant virus, V255I/S143N double escape mutants reduced PT antiviral potency by 150- to 3900-fold. Curiously, the combined mutations had a much smaller impact on PT binding affinity for monomeric gp120 (four to ninefold). This binding disruption was entirely due to the V255I mutation, which generated few steric clashes with PT in molecular docking. However, this minor effect on PT affinity belied large, offsetting changes to association enthalpy and entropy. The escape mutations had negligible effect on CD4 binding and utilization during entry, but significantly altered both binding thermodynamics and inhibitory potency of the conformationally-specific, anti-CD4i antibody 17b. Moreover, the escape mutations substantially decreased gp120 shedding induced by either soluble CD4 or AAR029b. Together, the data suggest that the escape mutations significantly modified the energetic landscape of Env's prefusogenic state, altering conformational dynamics to hinder PT-induced irreversible inactivation of Env. This work therein reveals a unique mode of virus escape for HIV-1, namely, resistance by altering the intrinsic conformational dynamics of the Env trimer.

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Web of Science research areas
Virology
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