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

• Published in: Cell reports (Cambridge) Vol. 27; no. 9; pp. 2593 - 2607.e5
• Main Authors: Wang, Qian, Liu, Lihong, Ren, Wuze, Gettie, Agegnehu, Wang, Hua, Liang, Qingtai, Shi, Xuanling, Montefiori, David C., Zhou, Tongqing, Zhang, Linqi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.05.2019; Elsevier
• Subjects: bnAbs; closed conformation; envelope trimer; gp41; HIV-1; HR2; neutralizing antibody; open conformation; SHIV; structure; HIV-1; SHIV; closed conformation; gp41; open conformation; neutralizing antibody; HR2; envelope trimer; bnAbs; structure
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.108

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. [Display omitted] •SHIV with “open” envelope adapts into “closed” conformation during passages in monkeys•E658K substitution in the gp41 HR2 region is a major cause of the conformational change•E658K disrupts an intermolecular salt bridge with E601 and renders antibody resistance•gp41 plays a critical role in shaping Env conformation and neutralization profile 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.