Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features

• 成果类型: Article
• 署名作者: Juraska, Michal; Bai, Hongjun; deCamp, Allan C.; Magaret, Craig A.; Li, Li; Gillespie, Kevin; Carpp, Lindsay N.; Giorgi, Elena E.; Ludwig, James; Molitor, Cindy; Hudson, Aaron; Williamson, Brian D.; Espy, Nicole; Simpkins, Brian; Rudnicki, Erika; Shao, Danica; Rossenkhan, Raabya; Edlefsen, Paul T.; Westfall, Dylan H.; Deng, Wenjie; Chen, Lennie; Zhao, Hong; Bhattacharya, Tanmoy; Pankow, Alec; Murrell, Ben; Yssel, Anna; Matten, David; York, Talita; Beaume, Nicolas; Gwashu-Nyangiwe, Asanda; Ndabambi, Nonkululeko; Thebus, Ruwayhida; Karuna, Shelly T.; Morris, Lynn; Montefiori, David C.; Hural, John A.; Cohen, Myron S.; Corey, Lawrence; Rolland, Morgane; Gilbert, Peter B.; Williamson, Carolyn; Mullins, James I.
• 署名单位: Fred Hutchinson Cancer Center; United States Department of Defense; United States Army; Walter Reed Army Institute of Research (WRAIR); Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc; Kaiser Permanente; Claremont Colleges; Pitzer College; University of Washington; University of Washington Seattle; United States Department of Energy (DOE); Los Alamos National Laboratory; Karolinska Institutet; University of Cape Town; University of Cape Town; National Health Laboratory Service; National Institute for Communicable Diseases (NICD); University of Witwatersrand; University of Kwazulu Natal; Duke University; University of North Carolina; University of North Carolina Chapel Hill; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12851
• DOI: 10.1073/pnas.2308942121
• 发表日期: 2024-01-23
• 关键词: randomized-trials; vaccine; tool

摘要

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing anti-body (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 mu g/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.