Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies

LaBranche, Celia C.; Henderson, Rory; Hsu, Allen; Behrens, Shay; Chen, Xuejun; Zhou, Tongqing; Wiehe, Kevin; Saunders, Kevin O.; Alam, S. Munir; Bonsignori, Mattia; Borgnia, Mario J.; Sattentau, Quentin J.; Eaton, Amanda; Greene, Kelli; Gao, Hongmei; Liao, Hua-Xin; Williams, Wilton B.; Peacock, James; Tang, Haili; Perez, Lautaro G.; Edwards, Robert J.; Kepler, Thomas B.; Korber, Bette T.; Kwong, Peter D.; Mascola, John R.; Acharya, Priyamvada; Haynes, Barton F.; Montefiori, David C.

doi:10.1371/journal.ppat.1008026

Title: Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies

Journal Article · Tue Sep 17 00:00:00 EDT 2019 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1008026· OSTI ID:1627919

^[1]; Henderson, Rory ^[2];

^[3];

^[1];

^[4];

^[4]; Wiehe, Kevin ^[5];

^[6]; Alam, S. Munir ^[5];

^[5];

^[3];

^[7]; Eaton, Amanda ^[1]; Greene, Kelli ^[1];

^[1]; Liao, Hua-Xin ^[5]; Williams, Wilton B. ^[5]; Peacock, James ^[5]; Tang, Haili ^[1]; Perez, Lautaro G. ^[1] more »

Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery
Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
Dept. of Health and Human Services, Research Triangle Park, NC (United States). National Institutes of Health. National Institute of Environmental Health Sciences. Genome Integrity and Structural Biology Lab.
National Inst. of Health (NIH), Bethesda, MD (United States). National Institute of Allergy and Infectious Diseases. Vaccine Research Center
Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.; Duke Univ., Durham, NC (United States). Medical Center. Dept. of Medicine
Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery; Rory Henderson Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
Univ. of Oxford (United Kingdom). The Sir William Dunn School of Pathology
Boston Univ., MA (United States). School of Medicine. Dept. of Microbiology
Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery; Rory Henderson Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.

The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505. N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1627919

Journal Information:: PLoS Pathogens, Vol. 15, Issue 9; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements Henderson, Rory; Lu, Maolin; Zhou, Ye Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-019-14196-w	journal	January 2020

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