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Recombinant HIV Envelope Proteins Fail to Engage Germline Versions of Anti-CD4bs bNAbs

Hoot, Sam and McGuire, Andrew T. and Cohen, Kristen W. and Strong, Roland K. and Hangartner, Lars and Klein, Florian and Diskin, Ron and Scheid, Johannes F. and Sather, D. Noah and Burton, Dennis R. and Stamatatos, Leonidas (2013) Recombinant HIV Envelope Proteins Fail to Engage Germline Versions of Anti-CD4bs bNAbs. PLoS Pathogens, 9 (1). Art. No. e1003106. ISSN 1553-7366. PMCID PMC3536657.

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Vaccine candidates for HIV-1 so far have not been able to elicit broadly neutralizing antibodies (bNAbs) although they express the epitopes recognized by bNAbs to the HIV envelope glycoprotein (Env). To understand whether and how Env immunogens interact with the predicted germline versions of known bNAbs, we screened a large panel (N:56) of recombinant Envs (from clades A, B and C) for binding to the germline predecessors of the broadly neutralizing anti-CD4 binding site antibodies b12, NIH45-46 and 3BNC60. Although the mature antibodies reacted with diverse Envs, the corresponding germline antibodies did not display Env-reactivity. Experiments conducted with engineered chimeric antibodies combining the mature and germline heavy and light chains, respectively and vice-versa, revealed that both antibody chains are important for the known cross-reactivity of these antibodies. Our results also indicate that in order for b12 to display its broad cross-reactivity, multiple somatic mutations within its VH region are required. A consequence of the failure of the germline b12 to bind recombinant soluble Env is that Env-induced B-cell activation through the germline b12 BCR does not take place. Our study provides a new explanation for the difficulties in eliciting bNAbs with recombinant soluble Env immunogens. Our study also highlights the need for intense efforts to identify rare naturally occurring or engineered Envs that may engage the germline BCR versions of bNAbs.

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Diskin, Ron0000-0002-2837-5897
Additional Information:© 2013 Hoot et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: August 29, 2012; Accepted: November 10, 2012; Published: January 3, 2013. Editor: Jeffrey Lifson, SAIC-Frederick, United States of America. We would like to acknowledge all those who contributed reagents utilized in this study. Funding: This work was supported by NIAID/HIVRAD grant P01AI081625 (LS). We also acknowledge support by the UW/CFAR and the J.B Pendleton Charitable Trust. Partial support was also received by the University of Washington Center for AIDS Research (CFAR), an NIH funded program (P30 AI027757). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author Contributions: Conceived and designed the experiments: LS SH ATM KWC RKS. Performed the experiments: SH ATM KWC. Analyzed the data: LS SH ATM RKS DRB. Contributed reagents/materials/analysis tools: LH DRB FK RD JFS. Wrote the paper: LS SH ATM DNS DRB JF
Funding AgencyGrant Number
J.B. Pendleton Charitable TrustUNSPECIFIED
University of WashingtonUNSPECIFIED
NIHP30 AI027757
Issue or Number:1
PubMed Central ID:PMC3536657
Record Number:CaltechAUTHORS:20130305-090810064
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Official Citation:Citation: Hoot S, McGuire AT, Cohen KW, Strong RK, Hangartner L, et al. (2013) Recombinant HIV Envelope Proteins Fail to Engage Germline Versions of Anti-CD4bs bNAbs. PLoS Pathog 9(1): e1003106. doi:10.1371/journal.ppat.1003106
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37295
Deposited By: Ruth Sustaita
Deposited On:05 Mar 2013 17:56
Last Modified:12 Feb 2020 00:19

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