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

Abstract

Summary: 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. : Wang et al. find that simian-human immunodeficiency virus (SHIV) with an “open” envelope adapts into a “closed” conformation in monkeys. This is largely due to a single E658K substitution in gp41, which disrupts an intermolecular salt bridge and improves viral entry efficiency. In vivo adaptation at gp41 impacts envelope conformation and the neutralization profile. Keywords: HIV-1, SHIV, envelope trimer, open conformation, closed conformation, neutralizing antibody, bnAbs, structure, gp41, HR2