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Cited by 1HIV Research and TreatmentAdvanced Electron Microscopy Techniques and ApplicationsSARS-CoV-2 and COVID-19 Research

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Conformational landscape of HIV-1 Env from closed to fully open

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Cui, Jiayan, Lin, Zi Jie, Ghosh, Sukanya, Du, Jianqiu, Sadeesh, Roopak, Weiner, David B., Pallesen, Jesper·2026·Nature Communications
DOI 10.1038/s41467-026-69921-z

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Abstract

The molecular mechanism of HIV-1 entry into host cells is governed by dynamic conformational changes to its envelope glycoprotein (Env), which are triggered by the engagement of the host receptor CD4 and coreceptors. Structural insights into these transitions have been advanced by cryo-electron tomography (cryo-ET), resolving Env structures in closed and multifarious open states within native membranes, and by cryo-electron microscopy (cryo-EM), which has provided atomic details of these states. In this study, we determine cryo-EM structures of soluble native-like Env in complex with antibody 3BC315, antibody b12, CD4, or a combination of 3BC315 and b12, capturing previously uncharacterized conformational states. Observing enhanced 3BC315 binding occupancy in the presence of b12, we investigate the cooperativity of these antibodies using mass photometry and neutralization assays. Integrating these states with the literature, we establish a classification framework for symmetric and asymmetric Env states, categorizing by their degree of openness and stepwise structural rearrangements. Our findings refine the mechanistic understanding of HIV-1 Env dynamics and provide a structural roadmap for targeting dynamic Env states to develop more potent vaccines and immunotherapies.

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Metadata

Authors
Cui, J., Lin, Z. J., Ghosh, S., Du, J., Sadeesh, R., Weiner, D. B., & Pallesen, J.
Affiliations
The Wistar Institute (US)
Corresponding author
Pallesen, Jesper
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-02-24
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-69921-z
OpenAlex
W7131270963
Cited by
1
References
3
Citations by year
2026: 1
FWCI
3.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (U19 AI166916)
  • W. W. Smith Charitable Trust (A2404)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
HIV-1 envelope glycoprotein, HIV-1 entry, CD4 binding, HIV vaccine targets
MeSH terms
Antibodies, Monoclonal, Humans, Models, Molecular, Protein Binding, Protein Conformation, HIV Antibodies, HIV-1, HIV Envelope Protein gp120, CD4 Antigens, Cryoelectron Microscopy, env Gene Products, Human Immunodeficiency Virus, Antibodies, Neutralizing

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