Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates

• 成果类型: Article
• 署名作者: Steichen, Jon M.; Phung, Ivy; Salcedo, Eugenia; Ozorowski, Gabriel; Willis, Jordan R.; Baboo, Sabyasachi; Liguori, Alessia; Cottrell, Christopher A.; Torres, Jonathan L.; Madden, Patrick J.; Ma, Krystal M.; Sutton, Henry J.; Lee, Jeong Hyun; Kalyuzhniy, Oleksandr; Allen, Joel D.; Rodriguez, Oscar L.; Adachi, Yumiko; Mullen, Tina-Marie; Georgeson, Erik; Kubitz, Michael; Burns, Alison; Barman, Shawn; Mopuri, Rohini; Metz, Amanda; Altheide, Tasha K.; Diedrich, Jolene K.; Saha, Swati; Shields, Kaitlyn; Schultze, Steven E.; Smith, Melissa L.; Schiffner, Torben; Burton, Dennis R.; Watson, Corey T.; Bosinger, Steven E.; Crispin, Max; Yates III, John R.; Paulson, James C.; Ward, Andrew B.; Sok, Devin; Crotty, Shane; Schief, William R.
• 署名单位: Scripps Research Institute; International AIDS Vaccine Initiative; Scripps Research Institute; Scripps Research Institute; University of California System; University of California San Diego; Scripps Research Institute; Scripps Research Institute; University of Southampton; University of Louisville; Emory University; Emory University; Harvard University; Massachusetts Institute of Technology (MIT); Ragon Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13655
• DOI: 10.1126/science.adj8321
• 发表日期: 2024-05-17
• 关键词: affinity maturation; cryo-em; protein; hypermutation; repertoire; refinement; supersite; toolkit; DESIGN; cells

摘要

Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.