HIV Research and Treatment
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Findings indicate that trimeric germline-targeting immunogens can elicit neutralizing antibodies toward conserved HIV Env epitopes, and underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.
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Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.
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@article{Carrasco2024Germline,
title = {Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site},
author = {María Ríos Carrasco and Tom G. Caniels and Max Medina-Ramírez and Shiyu Zhang and Sven Kratochvil and Yuejiao Xian and Ja‐Hyun Koo and Jonne L. Snitselaar and Jakob Samsel and Jelle van Schooten and Simone Pecetta and Edward Lamperti and Meng Yuan and Iván del Moral-Sánchez and Joel D. Allen and Anila Yasmeen and Thomas J. Ketas and Tom P. L. Bijl and Isabel Cuella Martin and Jonathan L. Torres and Albert Cupo and Lisa Shirreff and Kenneth A. Rogers and Rosemarie D. Mason and Mario Roederer and Kelli Greene and Hongmei Gao and Catarina Mendes Silva and Isabel J. L. Baken and Ming Tian and Frederick W. Alt and Bali Pulendran and Michael S. Seaman and Max Crispin and Marit J. van Gils and David C. Montefiori and Adrian B. McDermott and François Villinger and Richard A. Koup and John P. Moore and Per Johan Klasse and Gabriel Ozorowski and Facundo D. Batista and Ian A. Wilson and Andrew B. Ward and Rogier W. Sanders},
journal = {Science Immunology},
year = {2024},
doi = {10.1126/sciimmunol.adk9550},
url = {https://doi.org/10.1126/sciimmunol.adk9550}
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