Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV V2 apex broadly neutralizing antibody development.
Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by 1 of 16 different simian-human immunodeficiency viruses (SHIVs). We identified the V2 apex region of the envelope (Env) as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is a primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as vaccine platforms.
Authors
- Jinery Lora (ORCID: https://orcid.org/0009-0008-3534-7967)
- Kasirajan Ayyanathan (ORCID: https://orcid.org/0000-0003-1643-4009)
- Bo Liang
- Weimin Liu (ORCID: https://orcid.org/0000-0003-2903-2834)
- Lorie Marchitto (ORCID: https://orcid.org/0000-0002-4367-0229)
- Rumi Habib (ORCID: https://orcid.org/0000-0002-2812-8263)
- Juliette M. Rando (ORCID: https://orcid.org/0000-0002-1742-9255)
- Ashwin N. Skelly (ORCID: https://orcid.org/0000-0002-1565-3376)
- Derek W. Cain (ORCID: https://orcid.org/0000-0002-5988-6729)
- Elizabeth Van Itallie (ORCID: https://orcid.org/0000-0002-0736-7345)
- Andrew Jesse Connell (ORCID: https://orcid.org/0000-0002-9393-3074)
- Ryan S. Roark (ORCID: https://orcid.org/0000-0003-0586-103X)
- Hui Li (ORCID: https://orcid.org/0000-0001-9198-3951)
- Colby J. Agostino (ORCID: https://orcid.org/0000-0002-1864-1848)
- Yong Li (ORCID: https://orcid.org/0000-0003-4038-0493)
- Samantha J. Plante
- Neha Chohan (ORCID: https://orcid.org/0000-0002-2665-4622)
- Rohan Roy Chowdhury (ORCID: https://orcid.org/0000-0003-3586-571X)
- Chengyan Zhao
- Wilton B. Williams (ORCID: https://orcid.org/0000-0002-2970-7259)
- Ajay Singh (ORCID: https://orcid.org/0000-0001-7751-2934)
- Shuyi Wang
- Christian L. Martella (ORCID: https://orcid.org/0009-0004-7175-9185)
- Wenge Ding (ORCID: https://orcid.org/0000-0002-7574-4202)
- Kirsten J. Sowers
- Emily E. Lewis (ORCID: https://orcid.org/0000-0001-5721-0787)
- Frédéric Bibollet‐Ruche (ORCID: https://orcid.org/0009-0003-7518-6487)
- Е.В. Голосов
- Kevin Wiehe
- Zizhang Sheng
- Raiees andrabi
- Xuduo Li
- Younghoon Park (ORCID: https://orcid.org/0009-0003-5069-504X)
- Bette Korber
- Kshitij Wagh
- Amrit R Ghosh
- Barton F Haynes
- Mary S Campion
- Dennis R Burton
- Michael P Hogarty
- Facundo D Batista
- Beatrice H Hahn
- Robert J Edwards
- George M Shaw
- Daniel W Kulp
- John W Carey
- Kevin O Saunders
- Katharine J Bar
- Lawrence Shapiro
- Peter D Kwong
Institutions
- The Wistar Institute (US)
- Scripps Research Institute (US)
- Harvard University (US)
- Aaron Diamond AIDS Research Center (US)
- Duke University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Bioqual (US)
- New Mexico Consortium (US)
- Massachusetts Institute of Technology (US)
- Columbia University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- PubMed
- Published
- 2026-02-13
- DOI
- https://doi.org/10.1126/sciimmunol.adz3933
- Citations
- 1
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 27.20