A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning
Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is transiently exposed in the HIV-1 PHI, exhibit enhanced broad neutralization in cells expressing the Fc receptor, FcγRI. To enhance neutralization in cells lacking FcγRI, we here develop a bispecific antibody (bsAb) by fusing an NHR-targeting antibody to an antibody against CD4, the HIV-1 receptor on T cells. The bsAb provides a 5000-fold neutralization enhancement and shows unprecedented neutralization breadth compared to existing broadly neutralizing antibodies. Importantly, the bsAb reduces viral load in HIV-1-infected humanized male mice, and viral envelope sequencing under bsAb pressure revealed an NHR mutation that potentially impairs viral fitness. These findings validate the NHR as a potential HIV-1 therapeutic target, setting the stage for a new class of broadly neutralizing antibodies.
Authors
- Duy Pham (ORCID: https://orcid.org/0000-0002-7753-8744)
- Jonathan Do
- Maria V. Filsinger Interrante (ORCID: https://orcid.org/0000-0002-7728-799X)
- Caelan E. Radford
- Scott G. Kitchen (ORCID: https://orcid.org/0000-0001-6182-6082)
- Duo Xu (ORCID: https://orcid.org/0000-0003-0483-8719)
- Valerie Rezek (ORCID: https://orcid.org/0000-0002-2336-7599)
- Michael S. Seaman (ORCID: https://orcid.org/0000-0001-6444-3562)
- Theodora U. J. Bruun (ORCID: https://orcid.org/0000-0002-7462-2537)
- Jesse D. Bloom (ORCID: https://orcid.org/0000-0003-1267-3408)
- Soohyun Kim (ORCID: https://orcid.org/0000-0002-5584-5073)
- Peter S. Kim (ORCID: https://orcid.org/0000-0001-6503-4541)
- B. J. Wilder
- Junwei Zhong
- M. Sánchez Palomares
- Katie A. Travisano
Institutions
- Beth Israel Deaconess Medical Center (US)
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- University of California, Los Angeles (US)
- Fred Hutch Cancer Center (US)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford Medicine (US)
- Broad Center (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-18
- DOI
- https://doi.org/10.1038/s41467-025-60035-6
- Citations
- 5
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.18
Funders
- Virginia and D.K. Ludwig Fund for Cancer Research
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases