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

Reviewers: C Derdeyn (University of Washington) | 📗📗📗📗◻️ • Anonymous | 📒📒📒 ◻️◻️ • S Mallick & R Krause (University of Pennsylvania) | 📒📒📒◻️◻️

Published onOct 25, 2023
Reviews of "Germline-targeting Chimpanzee SIV Envelopes Induce V2-apex Broadly Neutralizing-like B Cell Precursors in a Rhesus Macaque Infection Model"
key-enterThis Pub is a Review of
Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model
Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model
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.

To read the original manuscript, click the link above.

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

To read the reviews, click the links below. 

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