1. Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted/founder sensitivity to broadly neutralizing antibodies.
- Author
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Parthasarathy D, Pothula KR, Ratnapriya S, Cervera Benet H, Parsons R, Huang X, Sammour S, Janowska K, Harris M, Sodroski J, Acharya P, and Herschhorn A
- Subjects
- Humans, HIV Infections immunology, HIV Infections virology, Epitopes immunology, Epitopes chemistry, Broadly Neutralizing Antibodies immunology, Broadly Neutralizing Antibodies chemistry, HEK293 Cells, CD4 Antigens metabolism, CD4 Antigens immunology, CD4 Antigens chemistry, Models, Molecular, HIV-1 immunology, env Gene Products, Human Immunodeficiency Virus immunology, env Gene Products, Human Immunodeficiency Virus chemistry, env Gene Products, Human Immunodeficiency Virus metabolism, Cryoelectron Microscopy, HIV Antibodies immunology, Protein Conformation, Antibodies, Neutralizing immunology
- Abstract
HIV-1 envelope glycoproteins (Envs) of most primary HIV-1 strains exist in closed conformation and infrequently sample open states, limiting access to internal epitopes. Thus, immunogen design aims to mimic the closed Env conformation as preferred target for eliciting broadly neutralizing antibodies (bnAbs). Here we identify incompletely closed Env conformations of 6 out of 13 transmitted/founder (T/F) strains that are sensitive to antibodies that recognize internal epitopes typically exposed on open Envs. A 3.6 Å cryo-electron microscopy structure of unliganded, incompletely closed T/F Envs (1059-SOSIP) reveals protomer motion that increased sampling of states with incompletely closed trimer apex. We reconstruct de novo the post-transmission evolutionary pathway of a second T/F. Evolved viruses exhibit increased Env resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial., (© 2024. The Author(s).)
- Published
- 2024
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