Reviews of "Germline-targeting Chimpanzee SIV Envelopes Induce V2-apex Broadly Neutralizing-like B Cell Precursors in a Rhesus Macaque Infection Model"

Cynthia Derdeyn; Anonymous; Suvadip Mallick; Ryan Krause

doi:doi:10.1162/2e3983f5.6391c8d5

Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model

by Rami Musharrafieh, Yana Safonova, Ge Song, Ryan S. Roark, Fang-Hua Lee, Shiyu Zhang, Jonathan Hurtado, Peter Yong, Shuyi Wang, Ronnie M. Russell, Wenge Ding, Yingying Li, Juliette Rando, Alexander I. Murphy, Emily Lindemuth, Chengyan Zhao, Andrew Jesse Connell, Wen-Hsin Lee, Nitesh Mishra, Gabriel Avillion, Wanting He, Sean Callaghan, Katharina Dueker, Anh L. Vo, Xuduo Li, Tazio Capozzola, Collin Joyce, Fangzhu Zhao, Fabio Anzanello, Weimin Liu, Frederic Bibollet-Ruche, Alejandra Ramos, Hui Li, Mark G. Lewis, Gabriel Ozorowski, Elise Landais, Brian T. Foley, Kshitij Wagh, Devin Sok, Bryan Briney, Andrew B. Ward, Beatrice H. Hahn, Dennis R. Burton, George M. Shaw, and Raiees Andrabi

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Published on Sep 23, 2023
www.biorxiv.org

Description

Eliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that a soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in V2-apex bnAb precursor-expressing knock-in mice. Here, we tested the immunogenicity of three MT145 variants (MT145, MT145K, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) in rhesus macaques-(RMs). All three viruses established productive infections with high setpoint vRNA titers. RMs infected with the germline-targeting SCIV_MT145K and SCIV_MT145K.dV5 exhibited larger and more clonally expanded B cell lineages featuring long anionic heavy chain complementary-determining-regions-(HCDR3s) compared with wildtype SCIV_MT145. Moreover, antigen-specific B cell analysis revealed enrichment for long-CDHR3-bearing antibodies in SCIV_MT145K.dV5 infected animals with paratope features resembling prototypic V2-apex bnAbs and their precursors. Although none of the animals developed bnAbs, these results show that germline-targeting SCIVs can activate and preferentially expand B cells expressing V2-apex bnAb-like precursors, the first step in bnAb elicitation.

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Summary of Reviews: This preprint analyzes B cell and antibody responses in macaques infected with SCIVs expressing wildtype or germline-targeting Env. Reviewers provided positive feedback on the rationale, methods, and findings. They recognized the novelty of using SCIVs to evaluate immunogen design strategies for eliciting V2-apex bnAbs against HIV-1. Germline-targeting SCIVs elicited more B cell lineages with features resembling known V2-apex bnAb precursors than wildtype SCIV, but neutralization breadth did not develop, highlighting challenges in recapitulating bnAb maturation. Reviewers suggested experiments to strengthen conclusions about V2-apex specificity and relating antibody features to function. They deemed the preprint potentially informative pending revisions addressing limitations around conclusively demonstrating V2-apex specificity and relating antibody features to properties.

Reviewer 1 (Cynthia D…) | 📗📗📗📗◻️

Reviewer 2 (Anonymous) | 📒📒📒 ◻️◻️

Reviewer 3 (Suvadip M… & Ryan K…) | 📒📒📒 ◻️◻️

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

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