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Review 3: "Germline-targeting Chimpanzee SIV Envelopes Induce V2-apex Broadly Neutralizing-like B Cell Precursors in a Rhesus Macaque Infection Model"

Reviewers deemed the preprint potentially informative pending revisions addressing limitations around conclusively demonstrating V2-apex specificity and relating antibody features to properties.

Published onOct 28, 2023
Review 3: "Germline-targeting Chimpanzee SIV Envelopes Induce V2-apex Broadly Neutralizing-like B Cell Precursors in a Rhesus Macaque Infection Model"
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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

SUMMARY 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.Graphical Abstract

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



This study shows that rare bnAb- like B cell precursors can be selectively stimulated by germline targeting immunogens. This study also elucidates that rational antigen design may enable to reduce the interference of the off-target epitopes while having potential bnAb responses that can be implemented for HIV-1 vaccine development. 

As HIV-1 vaccine research expands on broadly neutralizing antibody (bnAb) elicitation, the non-human primate model can emulate the pathogenesis of natural infection in humans and serve as a platform for novel elicitation strategies. Infecting rhesus macaques using chimeric viruses with selectively modified regions can prime B cells to exhibit and expand rare lineages targeting specific envelope (env) epitopes sensitive to neutralization. Musharrafieh and colleagues explore infection of three Simian-Chimpanzee Immunodeficiency Viruses (SCIVs) containing wildtype SIV chimpanzee (SIVcpz) MT145 envelope, MT145 with additional lysine enrichment in the C strand of V2 (MT145K), and MT145K with a truncated V5 variable loop (MT145K.dV5) to characterize the associated V2-apex directed responses. Their findings suggest minimally modified, germline-targeting infection trends more towards expanded B cell lineages with V2-apex directed neutralizing responses when compared to wildtype infection. Additionally, these responses are compared with other, previously characterized bnAb precursors and show similar clonal expansion for antibody components synonymous with V2-apex bnAb development: components such as ≥24 amino acid heavy-chain complementarity determining region 3 (HCDR3) loops, usage of the IGHD3-09 gene, and motifs with anionic residues and sulfated tyrosines. However, while these findings show observable trends towards V2-apex directed responses, the statistical significance supporting differences in responses to wildtype and modified viruses remains ambiguous (Figure 4). Additionally, though autologous neutralization was characterized to have “high titer” (Line 165-166) responses, dV5 infected animals beginning at week 24 displayed moderate to low titer autologous neutralization with a decline over time (Figure S1). Lastly, whether any of these precursors have the potential to increase in autologous potency develop heterologous breadth is undetermined. Future directions investigating immunogens promoting bnAb maturation in these inferred precursors would expand on these limitations. 

This experimental study with the Non-human primate suggests that a minimal modification in the virus binding surface to the host cell can elicit required response through specific antibody generation that may be used as a strategy to develop vaccines against HIV infection. 

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