Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein
Year: 2017
Type: article
Abstract: Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state. We generated a stabilized, soluble clade C Env (16055 NFL) and determined its crystal structure at 3.9 Å. Its overall conformation is similar to SOSIP.664 and native Env trimers but includes a covalent linker between gp120 and gp41, an engineered 201-433 disulfide bond, and density corresponding to 22 N-glycans. Env-structure-guided design strategies resulted in multiple homogeneous cross-clade immunogens with the potential to advance HIV vaccine development.
Source: Immunity
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,596
Funders: United States Agency for International Development, Bill and Melinda Gates Foundation, International AIDS Vaccine Initiative, Irish Aid, Department for International Development, UK Government, Udenrigsministeriet, Ministry of Finance Japan, Ministerie van Buitenlandse Zaken, National Institutes of Health, Office of Science, Direktoratet for Utviklingssamarbeid, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W2615102730