HIV broadly neutralizing antibody precursors to the Apex epitope induced in nonhuman primates
An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination because of their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy-chain complementarity-determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA lipid nanoparticle (LNP) immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb-related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo-electron microscopy revealed that elicited Apex bnAb-related HCDR3s had structures combining elements of several prototype Apex bnAbs. These results achieve a critical HIV vaccine development milestone in outbred primates.
Authors
- Mariane B. Melo (ORCID: https://orcid.org/0000-0002-0409-2454)
- Xiaozhen Hu (ORCID: https://orcid.org/0000-0003-3890-0533)
- Ian A. Wilson (ORCID: https://orcid.org/0000-0002-6469-2419)
- Guido Silvestri (ORCID: https://orcid.org/0000-0001-6602-2470)
- Jon M. Steichen (ORCID: https://orcid.org/0000-0002-4586-3251)
- Parham Ramezani-Rad (ORCID: https://orcid.org/0000-0001-7276-6660)
- Jordan R. Willis (ORCID: https://orcid.org/0000-0002-0135-5263)
- Danny Lu (ORCID: https://orcid.org/0000-0002-2340-3377)
- Jeong Hyun Lee (ORCID: https://orcid.org/0000-0001-7371-845X)
- Michael Kubitz (ORCID: https://orcid.org/0000-0002-3917-453X)
- John R. Yates (ORCID: https://orcid.org/0000-0001-5267-1672)
- Shane Crotty (ORCID: https://orcid.org/0000-0002-6484-6262)
- Jolene K. Diedrich (ORCID: https://orcid.org/0000-0001-6489-4558)
- Sunny Himansu (ORCID: https://orcid.org/0000-0002-7954-9674)
- Sashank Agrawal (ORCID: https://orcid.org/0000-0001-8549-9602)
- James C. Paulson (ORCID: https://orcid.org/0000-0003-4589-5322)
- Henry J. Sutton (ORCID: https://orcid.org/0000-0002-6472-7116)
- Saman Eskandarzadeh (ORCID: https://orcid.org/0000-0002-0671-0770)
- Diane G. Carnathan (ORCID: https://orcid.org/0009-0001-7073-3723)
- Gabriel Ozorowski (ORCID: https://orcid.org/0000-0002-9695-8138)
- Devin Sok (ORCID: https://orcid.org/0000-0002-9354-1740)
- Christopher A. Cottrell (ORCID: https://orcid.org/0000-0002-3364-3083)
- Yumiko Adachi (ORCID: https://orcid.org/0000-0002-0795-9375)
- Patrick Madden (ORCID: https://orcid.org/0000-0003-4527-5692)
- Alessia Liguori (ORCID: https://orcid.org/0000-0002-8606-574X)
- Payal Pratap (ORCID: https://orcid.org/0000-0002-7170-6866)
- M. Krystal (ORCID: https://orcid.org/0000-0001-6519-2531)
- Dennis R. Burton (ORCID: https://orcid.org/0000-0001-6711-9864)
- Nicole Phelps (ORCID: https://orcid.org/0000-0001-9613-3921)
- Nushin Alavi (ORCID: https://orcid.org/0000-0003-3848-6280)
- Oleksandr Kalyuzhniy (ORCID: https://orcid.org/0000-0002-5273-1951)
- William R. Schief (ORCID: https://orcid.org/0000-0002-1120-0150)
- Erik Georgeson (ORCID: https://orcid.org/0000-0001-5137-4625)
- Murillo Silva (ORCID: https://orcid.org/0000-0003-4668-6290)
- Elise Landais (ORCID: https://orcid.org/0000-0002-8183-5565)
- Sabyasachi Baboo (ORCID: https://orcid.org/0000-0002-4547-5160)
- James C. Quinn
- Tina-Marie Mullen (ORCID: https://orcid.org/0000-0001-6150-8084)
- Darrell J. Irvine (ORCID: https://orcid.org/0000-0002-8637-1405)
- Tasha K. Altheide
- Xiaoya Zhou
- Vanessa Lewis (ORCID: https://orcid.org/0009-0006-6077-8975)
Institutions
- Scripps Research Institute (US)
- International AIDS Vaccine Initiative (US)
- La Jolla Institute for Immunology (US)
- Howard Hughes Medical Institute (US)
- Emory University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- University of California San Diego (US)
- Moderna Therapeutics (United States) (US)
- IIT@MIT (US)
- Allen Institute (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1126/sciimmunol.adt6660
- Citations
- 6
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 6.22