The C3/465 glycan hole cluster in BG505 HIV-1 envelope is the major neutralizing target involved in preventing mucosal SHIV infection

• Type of Material: Article
• Authors: Tysheena P Charles, Emory University; Samantha L Burton, Emory University; Prabhu S Arunachalam, Stanford University; Christopher A Cottrell, Scripps Research Institute; Leigh M Sewall, Scripps Research Institute; Ventaka S Bollimpelli, Emory University; Sailaja Gangadhara, Emory University; Antu K Dey, International AIDS Vaccine Initiative; Andrew B Ward, Scripps Research Institute; George M Shaw, University of Pennsylvania; Eric Hunter, Emory University; Rama Amara, Emory University; Bali Pulendran, Emory University; Marit J van Gils, University of Amsterdam; Cynthia Derdeyn, Emory University
• Language: English
• Date: 2021-02-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Charles et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1009257
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 17
• Issue: 2
• Start Page: e1009257
• End Page: e1009257
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH.gov) grants UM1 AI124436 (Emory Consortium for Innovative AIDS Research in Nonhuman Primates, E.H. and R.R.A.), Emory CFAR (P30AI050409), the Bill and Melinda Gates Foundation through the VxPDC core (OPP1153692) and manufacturing (OPP1147661), UM1 AI144462 and OPP1115782 (A.B.W.), R01 AI128837 (C.A.D.), and R21 AI150292 (C.A.D). This project was funded in part by the Yerkes National Primate Research Center Grant No. ORIP/OD P51OD011132, supported by the NIH, Office of Research Infrastructure Programs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: RESISTANCE; SHIELD; DOMAINS; Parasitology; Virology; ENV; PROTECTION; NONHUMAN-PRIMATES; Life Sciences & Biomedicine; Microbiology; SINGLE-CELL; RNA-SEQ; ANTIBODY-RESPONSES; RHESUS MACAQUES; Science & Technology
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology; Biology, Biostatistics; Biology, Microbiology

Abstract

Stabilized HIV-1 envelope (Env) trimers elicit tier 2 autologous neutralizing antibody (nAb) responses in immunized animals. We previously demonstrated that BG505 SOSIP.664. T332N gp140 (BG505 SOSIP) immunization of rhesus macaques (RM) provided robust protection against autologous intra-vaginal simian-human immunodeficiency virus (SHIV) challenge that was predicted by high serum nAb titers. Here, we show that nAb in these protected RM targeted a glycan hole proximal to residue 465 in gp120 in all cases. nAb also targeted another glycan hole at residues 241/289 and an epitope in V1 at varying frequencies. Non-neutralizing antibodies directed at N611-shielded epitopes in gp41 were also present but were more prevalent in RM with low nAb titers. Longitudinal analysis demonstrated that nAb broadened in some RM during sequential immunization but remained focused in others, the latter being associated with increases in nAb titer. Thirty-eight monoclonal antibodies (mAbs) isolated from a protected RM with an exceptionally high serum neutralization titer bound to the trimer in ELISA, and four of the mAbs potently neutralized the BG505 Env pseudovirus (PV) and SHIV. The four neutralizing mAbs were clonally related and targeted the 465 glycan hole to varying degrees, mimicking the serum. The data demonstrate that the C3/465 glycan hole cluster was the dominant neutralization target in high titer protected RM, despite other co-circulating neutralizing and non-neutralizing specificities. The isolation of a neutralizing mAb family argues that clonotype expansion occurred during BG505 SOSIP immunization, leading to high titer, protective nAb and setting a desirable benchmark for HIV vaccines.