A Single Substitution in gp41 Modulates the Neutralization Profile of SHIV during In Vivo Adaptation.

Published

Journal Article

The HIV-1 envelope glycoprotein (Env) maintains a delicate balance between mediating viral entry and escaping antibody neutralization. Adaptation during transmission of neutralization-sensitive Envs with an "open" conformation remains poorly understood. By passaging a replication-competent simian-human immunodeficiency virus carrying a highly neutralization-sensitive Env (SHIVCNE40) in rhesus macaques, we show that SHIVCNE40 develops enhanced replication kinetics associated with neutralization resistance against antibodies and autologous serum. A gp41 substitution, E658K, functions as the major determinant for these properties. Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, thereby promoting fusion and facilitating immune evasion. This effect is applicable across diverse HIV-1 subtypes. Our results highlight the critical role of gp41 in shaping the neutralization profile and the overall conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 envelope trimers.

Full Text

Duke Authors

Cited Authors

  • Wang, Q; Liu, L; Ren, W; Gettie, A; Wang, H; Liang, Q; Shi, X; Montefiori, DC; Zhou, T; Zhang, L

Published Date

  • May 28, 2019

Published In

Volume / Issue

  • 27 / 9

Start / End Page

  • 2593 - 2607.e5

PubMed ID

  • 31141685

Pubmed Central ID

  • 31141685

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2019.04.108

Language

  • eng

Conference Location

  • United States