Immunogenicity and structure of a stabilized HIV-1 clade C Env from a pediatric elite neutralizer in complex with an autologous bnAb
6 affiliations
- 1Department of Biochemistry, All India Institute of Medical Sciences
- 2Molecular Biophysics Unit, Indian Institute of Science
- 3Department of Biophysics, All India Institute of Medical Sciences
- 4Centralized Core Research Facility, All India Institute of Medical Sciences
- 5Department of Biosciences and Bioengineering, Indian Institute of Technology
- 6Department of Pediatrics, All India Institute of Medical Sciences
Abstract
Introduction: The envelope (Env) glycoproteins derived from circulating viruses in elite-neutralizers (ENs), who naturally develop potent broadly neutralizing antibody (bnAb) responses, serve as a potential template for HIV-1 vaccine design. Here, we investigated the immunogenicity and structure of a clade C HIV-1 Env trimer (330) derived from the pediatric elite-neutralizer AIIMS_330.
Methods: The 330 Env was engineered as SOSIP.664, NFL.664, and multivalent ferritin-nanoparticle (NP) immunogens. Biophysical and antigenic properties were assessed using HIV-1 trimer-specific bnAbs and non-neutralizing antibodies. Immunogenicity was evaluated in rabbits immunized with Addavax-formulated SOSIP.664, NFL.664, or ferritin NP immunogens (n = 4), with an adjuvant only placebo group (n = 2). Structural characterization was performed by cryo-electron-microscopy (cryo-EM) using the autologous Env 330 SOSIP.664 trimer in complex with the bnAb 44m.
Results: The 330 Env trimers exhibited native-like antigenic properties, high thermostability, strong binding to trimer-specific bnAbs, and limited reactivity with non-neutralizing antibodies. Immunization of rabbits elicited strong autologous neutralizing antibody responses together with modest heterologous Tier-1 neutralization. Autologous neutralizing responses were significantly higher for ferritin-NP (P = 0.019) and SOSIP.664 (P = 0.048) than for NFL.664, with no significant difference between ferritin-NP and SOSIP.664 (P = 0.681). A 5.1 Å cryo-EM reconstruction of the autologous Env 330 SOSIP.664–44m complex revealed native-like presentation of the N332-V3 supersite. The structural analysis further suggested the interacting Env contacts E293, R327, K337, and K446, along with glycans N332, N326, N442, and N448 with the bnAb-44m. We identified R327 of the conserved GDIR-motif and the N332 glycan, within the V3-loop, as neutralizing determinants on the 330 Env, with a fold reduction of 116, on testing the mutant 330 viruses with autologous bnAb 44m.
Discussion: Pediatric elite-neutralizer AIIMS_330 derived Env trimers represent structurally and antigenically well-characterized clade C immunogens with ability to elicit strong autologous neutralizing antibodies, with modest heterologous Tier-1 neutralization. Together, these findings advance our understanding of clade C Env antigenic variability. Further, the structural and immunological insights support the potential utility of AIIMS_330 derived Env as an antigenic probe and may inform future rational design of Clade C HIV-1 vaccines and structure-guided strategies for eliciting neutralizing antibodies.
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BibTeX
@article{singh2026immunogenicity,
title = {{Immunogenicity and structure of a stabilized HIV-1 clade C Env from a pediatric elite neutralizer in complex with an autologous bnAb}},
author = {Swarandeep Singh and Sanjeev Kumar and Arnab Chatterjee and Lakshay Malhotra and Muneeb Pervez and Abdul Rahman and Ifrah Andrabi and Bapan Mondal and Sanket Katpara and Shaifali Sharma and Harsh Bhakhri and Anjli Gaur and Tanu Bansal and Vikram Iyer and Abdul Wahid Hussain and Shubbir Ahmed and Rajesh Kumar and Abdul Samath Ethayathulla and Rakesh Lodha and Somnath Dutta and Kalpana Luthra},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1919627},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1919627/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immunogenicity and structure of a stabilized HIV-1 clade C Env from a pediatric elite neutralizer in complex with an autologous bnAb
AU - Swarandeep Singh
AU - Sanjeev Kumar
AU - Arnab Chatterjee
AU - Lakshay Malhotra
AU - Muneeb Pervez
AU - Abdul Rahman
AU - Ifrah Andrabi
AU - Bapan Mondal
AU - Sanket Katpara
AU - Shaifali Sharma
AU - Harsh Bhakhri
AU - Anjli Gaur
AU - Tanu Bansal
AU - Vikram Iyer
AU - Abdul Wahid Hussain
AU - Shubbir Ahmed
AU - Rajesh Kumar
AU - Abdul Samath Ethayathulla
AU - Rakesh Lodha
AU - Somnath Dutta
AU - Kalpana Luthra
PY - 2026
DA - 2026/10/21
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1919627
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1919627/full
AB - Introduction: The envelope (Env) glycoproteins derived from circulating viruses in elite-neutralizers (ENs), who naturally develop potent broadly neutralizing antibody (bnAb) responses, serve as a potential template for HIV-1 vaccine design. Here, we investigated the immunogenicity and structure of a clade C HIV-1 Env trimer (330) derived from the pediatric elite-neutralizer AIIMS_330. Methods: The 330 Env was engineered as SOSIP.664, NFL.664, and multivalent ferritin-nanoparticle (NP) immunogens. Biophysical and antigenic properties were assessed using HIV-1 trimer-specific bnAbs and non-neutralizing antibodies. Immunogenicity was evaluated in rabbits immunized with Addavax-formulated SOSIP.664, NFL.664, or ferritin NP immunogens (n = 4), with an adjuvant only placebo group (n = 2). Structural characterization was performed by cryo-electron-microscopy (cryo-EM) using the autologous Env 330 SOSIP.664 trimer in complex with the bnAb 44m. Results: The 330 Env trimers exhibited native-like antigenic properties, high thermostability, strong binding to trimer-specific bnAbs, and limited reactivity with non-neutralizing antibodies. Immunization of rabbits elicited strong autologous neutralizing antibody responses together with modest heterologous Tier-1 neutralization. Autologous neutralizing responses were significantly higher for ferritin-NP (P = 0.019) and SOSIP.664 (P = 0.048) than for NFL.664, with no significant difference between ferritin-NP and SOSIP.664 (P = 0.681). A 5.1 Å cryo-EM reconstruction of the autologous Env 330 SOSIP.664–44m complex revealed native-like presentation of the N332-V3 supersite. The structural analysis further suggested the interacting Env contacts E293, R327, K337, and K446, along with glycans N332, N326, N442, and N448 with the bnAb-44m. We identified R327 of the conserved GDIR-motif and the N332 glycan, within the V3-loop, as neutralizing determinants on the 330 Env, with a fold reduction of 116, on testing the mutant 330 viruses with autologous bnAb 44m. Discussion: Pediatric elite-neutralizer AIIMS_330 derived Env trimers represent structurally and antigenically well-characterized clade C immunogens with ability to elicit strong autologous neutralizing antibodies, with modest heterologous Tier-1 neutralization. Together, these findings advance our understanding of clade C Env antigenic variability. Further, the structural and immunological insights support the potential utility of AIIMS_330 derived Env as an antigenic probe and may inform future rational design of Clade C HIV-1 vaccines and structure-guided strategies for eliciting neutralizing antibodies.
SN - 1664-3224
ER -