Profiling a large HIV-1 elite neutralizer cohort reveals remarkable CD4bs bNAb for HIV-1 prevention and therapy

作者：Lutz Gieselmann, Andrew T. DeLaitsch, Malena Rohde, Henning Gruell, Christoph Kreer, Meryem S. Ercanoglu, Harry B. Gristick, Philipp Schommers, Elvin Ahmadov, Caelan E. Radford, Andrea Mazzolini, Lily Zhang, Anthony P. West, Johanna Worczinski, Anna Momot, Maren L. Reichwein, Jacqueline Knüfer, Ricarda Stumpf, Nonhlanhla N. Mkhize, Haajira Kaldine, Sinethemba Bhebhe, Sharvari Deshpande, Frederico Giovannoni, Erin Stefanutti, Fabio Benigni, Colin Havenar‐Daughton, Davide Corti, Arne Kroidl, Anurag Adhikari, Aubin Nanfack, Georgia Ambada, Ralf Duerr, Lucas Maganga, Wiston William, Nyanda Elias Ntinginya, Timo Wolf, Christof Geldmacher, Michael Hoelscher, Clara Lehmann, Penny L. Moore, Thierry Mora, Aleksandra M. Walczak, Peter B. Gilbert, Nicole A. Doria‐Rose, Yunda Huang, Jesse D. Bloom, Michael S. Seaman, Pamela J. Björkman, Florian Klein · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.08.27.672638 · 被引用次数：1 · 研究领域：HIV Research and Treatment、Monoclonal and Polyclonal Antibodies Research、Immune Cell Function and Interaction

Abstract Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo . However, clinical use is challenged by broad envelope sequence diversity and rapid emergence of viral escape 1–9 . Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies (bNAbs) with highest potency and breadth for clinical application. From 831 expressed monoclonal antibodies, we identified 04_A06, a new V H 1-2-encoded CD4 binding site bNAb with remarkable breadth and potency against extended multiclade pseudovirus panels (GeoMean IC 50 = 0.059 µg/ml, breadth = 98.5%, 332 virus strains). Moreover, 04_A06 was not susceptible to classic viral CD4bs escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed that antiviral activity is mediated by an unusually long 11-amino acid heavy chain insertion. This insertion facilitates inter-protomer contacts and interactions with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody Mediated Prevention (AMP) trials (GeoMean IC 50 = 0.082 µg/ml, breadth = 98.4%, 191 virus strains) and in silico modeling for 04_A06LS predicted HIV-1 prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention strategies of HIV-1 infection.