Short CDRL1 in intermediate VRC01-like mAbs is not sufficient to overcome key glycan barriers on HIV-1 Env
HIV-1 broadly neutralizing antibodies will be a key component of an effective HIV-1 vaccine, as they prevent viral acquisition. Over the past decade, numerous broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV. Despite an in-depth knowledge of their structures, epitopes, ontogenies, and, in a few rare cases, their maturation pathways during infection, bnAbs have, so far, not been elicited by vaccination. This necessitates the identification of key obstacles that prevent their elicitation by immunization and overcoming them. Here we examined whether CDRL1 shortening is a prerequisite for the broadly neutralizing potential of VRC01-class bnAbs, which bind within the CD4 receptor binding site of Env. Our findings indicate that CDRL1 shortening by itself is important but not sufficient for the acquisition of neutralization breadth, and suggest that particular combinations of amino acid mutations, not elicited so far by vaccination, are most likely required for the development of such a feature.
Authors
- Leonidas Stamatatos (ORCID: https://orcid.org/0000-0002-1106-7097)
- David C. Montefiori (ORCID: https://orcid.org/0000-0003-0856-6319)
- Latha Kallur Siddaramaiah
- Gargi Kher (ORCID: https://orcid.org/0000-0002-8198-2418)
- Nicholas K. Hurlburt (ORCID: https://orcid.org/0000-0001-9891-916X)
- Kelsey R. Salladay
- Marie Pancera (ORCID: https://orcid.org/0000-0001-9217-6270)
- Harry B. Gristick (ORCID: https://orcid.org/0000-0002-1957-2821)
- Maria L. Knudsen (ORCID: https://orcid.org/0009-0007-7057-4308)
- Xiaoying Shen (ORCID: https://orcid.org/0000-0002-8387-3952)
- Andrew B. Stuart
- Pamela J. Björkman (ORCID: https://orcid.org/0000-0002-2277-3990)
- Ilja Bontjer (ORCID: https://orcid.org/0000-0002-8406-7733)
- Anna J. MacCamy (ORCID: https://orcid.org/0000-0001-5552-9209)
- Arineh Khechaduri
- Parul Agrawal
- Rogier W. Sanders
Institutions
- California Institute of Technology (US)
- Duke University (US)
- University of Washington (US)
- Cornell University (US)
- Fred Hutch Cancer Center (US)
- National Institute of Allergy and Infectious Diseases (US)
- Amsterdam University Medical Centers (NL)
- University of Amsterdam (NL)
Publication Details
- Journal
- Journal of Virology
- Published
- 2024-09-06
- DOI
- https://doi.org/10.1128/jvi.00744-24
- Citations
- 8
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.92
Funders
- U.S. Department of Energy
- California Institute of Technology
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences