Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted/founder sensitivity to broadly neutralizing antibodies.

Autor: Parthasarathy D; Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Pothula KR; Duke Human Vaccine Institute, Duke University, Durham, NC, USA., Ratnapriya S; Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Cervera Benet H; Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Parsons R; Duke Human Vaccine Institute, Duke University, Durham, NC, USA.; Department of Biochemistry, Duke University, Durham, NC, USA., Huang X; Duke Human Vaccine Institute, Duke University, Durham, NC, USA., Sammour S; Duke Human Vaccine Institute, Duke University, Durham, NC, USA., Janowska K; Duke Human Vaccine Institute, Duke University, Durham, NC, USA., Harris M; Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Sodroski J; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Acharya P; Duke Human Vaccine Institute, Duke University, Durham, NC, USA.; Department of Biochemistry, Duke University, Durham, NC, USA.; Department of Surgery, Duke University, Durham, NC, USA., Herschhorn A; Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA. aherschh@umn.edu.; Institute for Molecular Virology, University of Minnesota, University of Minnesota, Minneapolis, MN, USA. aherschh@umn.edu.; Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, USA. aherschh@umn.edu.; The College of Veterinary Medicine Graduate Program, University of Minnesota, Minneapolis, MN, USA. aherschh@umn.edu.; Molecular Pharmacology and Therapeutics Graduate Program, University of Minnesota, Minneapolis, MN, USA. aherschh@umn.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 26; Vol. 15 (1), pp. 7334. Date of Electronic Publication: 2024 Aug 26.
DOI: 10.1038/s41467-024-51656-4
Abstrakt: 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).)
Databáze: MEDLINE
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