Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted/founder sensitivity to broadly neutralizing antibodies
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.
Authors
- Priyamvada Acharya (ORCID: https://orcid.org/0000-0002-0089-277X)
- Héctor Cervera (ORCID: https://orcid.org/0000-0002-0369-8104)
- Karunakar R. Pothula (ORCID: https://orcid.org/0000-0003-0073-2511)
- Salam Sammour
- Ruth Parsons (ORCID: https://orcid.org/0000-0002-2630-2344)
- Xiao Huang (ORCID: https://orcid.org/0000-0002-5225-3224)
- Sneha Ratnapriya (ORCID: https://orcid.org/0000-0003-0466-4771)
- Durgadevi Parthasarathy (ORCID: https://orcid.org/0000-0001-6105-1192)
- Alon Herschhorn (ORCID: https://orcid.org/0000-0002-9323-4820)
- Joseph Sodroski (ORCID: https://orcid.org/0000-0002-9750-1615)
- Katarzyna Janowska (ORCID: https://orcid.org/0000-0002-7936-2244)
- Miranda Harris (ORCID: https://orcid.org/0000-0003-0403-4278)
Institutions
- University of Minnesota (US)
- Harvard University (US)
- Duke University (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-26
- DOI
- https://doi.org/10.1038/s41467-024-51656-4
- Citations
- 19
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.29
Funders
- National Science Foundation
- amfAR, The Foundation for AIDS Research
- University of Pennsylvania
- University of Minnesota
- Tulane University
- Universiteit van Amsterdam
- National Institutes of Health
- National Institute on Drug Abuse
- National Institute of Allergy and Infectious Diseases
- Division of Electrical, Communications and Cyber Systems
- Los Alamos National Laboratory