Stabilized trimeric peptide immunogens of the complete HIV-1 gp41 N- heptad repeat and their use as HIV-1 vaccine candidates

• 成果类型: Article
• 署名作者: Wu, Chengwei; Raheem, Izzat T.; Nahas, Debbie D.; Citron, Michael; Kim, Peter S.; Montefiori, David C.; Ottinger, Elizabeth A.; Hepler, Robert W.; Hrin, Renee; Patel, Sangita B.; Soisson, Stephen M.; Joyce, Joseph G.
• 署名单位: Merck & Company; Merck & Company USA; Merck & Company; Merck & Company USA; Merck & Company; Merck & Company USA; Duke University; Merck & Company; Merck & Company USA; Stanford University; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS); Johnson & Johnson; Janssen Pharmaceuticals
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15385
• DOI: 10.1073/pnas.2317230121
• 发表日期: 2024-05-20
• 关键词: neutralizing antibodies; fusion intermediate; coiled-coil; potent; entry; inhibitors; mimetics; affinity; broad

摘要

Efforts to develop an HIV - 1 vaccine include those focusing on conserved structural elements as the target of broadly neutralizing monoclonal antibodies. MAb D5 binds to a highly conserved hydrophobic pocket on the gp41 N- heptad repeat (NHR) coiled coil and neutralizes through prevention of viral fusion and entry. Assessment of 17-mer and 36-mer NHR peptides presenting the D5 epitope in rodent immunogenicity studies showed that the longer peptide elicited higher titers of neutralizing antibodies, suggesting that neutralizing epitopes outside of the D5 pocket may exist. Although the magnitude and breadth of neutralization elicited by NHR- targeting antigens are lower than that observed for antibodies directed to other epitopes on the envelope glycoprotein complex, it has been shown that NHR- directed antibodies are potentiated in TZM-bl cells containing the Fc gamma RI receptor. Herein, we report the design and evaluation of covalently stabilized trimeric 51-mer peptides encompassing the complete gp41 NHR. We demonstrate that these peptide trimers function as effective antiviral entry inhibitors and retain the ability to present the D5 epitope. We further demonstrate in rodent and nonhuman primate immunization studies that our 51-mer constructs elicit a broader repertoire of neutralizing antibody and improved cross-clade neutralization of primary HIV - 1 isolates relative to 17-mer and 36-mer NHR peptides in A3R5 and Fc gamma R1-enhanced TZM-bl assays. These results demonstrate that sensitive neutralization assays can be used for structural enhancement of moderately potent neutralizing epitopes. Finally, we present expanded trimeric peptide designs which include unique low - molecular - weight scaffolds that provide versatility in our immunogen presentation strategy.