Immunogenicity and Structural Features of a Stabilized Clade-C HIV-1 Env Derived from a Pediatric Elite-neutralizer

Singh, S.; Kumar, S.; Chatterjee, A.; Malhotra, L.; Rahman, A.; Andrabi, I.; Mondal, B.; Katpara, S.; Sharma, S.; Bhakri, H.; Gaur, A.; Bansal, T.; Pervez, M.; Iyer, V.; Hussain, A. W.; Ahmed, S.; Kumar, R.; Ethayathulla, A. S.; Lodha, R.; Dutta, S.; Luthra, K.

doi:10.1101/2025.04.26.649701

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bioRxiv · 10.1101/2025.04.26.649701

Immunogenicity and Structural Features of a Stabilized Clade-C HIV-1 Env Derived from a Pediatric Elite-neutralizer

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Abstract

The envelope (Env) glycoprotein derived from circulating viruses in elite-neutralizers (who naturally develop broadly neutralizing antibodies (bNAbs)), serves as potential template for HIV-1 vaccine design. Herein, we report the structure and immunogenicity of soluble clade-C HIV-1 Env trimer (330) derived from a pediatric elite-neutralizer (AIIMS_330). Using SOSIP, NFL and ferritin-nanoparticle (NP) platforms, we engineered immunogens that preserved native-like Env conformation, exhibited high thermostability and nanomolar affinity for diverse bNAbs, with minimal reactivity to non-neutralizing antibodies. Cryo-EM structure solved at 5 [A] resolution of 330-SOSIP trimer-autologous bNAb 44m complex revealed interactions at GDIR motif, N332 supersite along with additional contacts at E293, K337, K446 and glycans N326, N442, N448, as compared to our previously reported BG505-44m structure. Rabbit immunizations with soluble and NP-displayed formats elicited autologous, and heterologous neutralization of tier-1 clade-C viruses. Herein we define a structurally resolved HIV-1 clade C Env that supports multivalent vaccine strategies and provides mechanistic insights toward rational HIV-1 immunogen design.

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Singh, S., Kumar, S., Chatterjee, A., Malhotra, L., Rahman, A., Andrabi, I., Mondal, B., Katpara, S., Sharma, S., Bhakri, H., Gaur, A., Bansal, T., Pervez, M., Iyer, V., Hussain, A. W., Ahmed, S., Kumar, R., Ethayathulla, A. S., Lodha, R., Dutta, S., Luthra, K.. 2025-04-28. Immunogenicity and Structural Features of a Stabilized Clade-C HIV-1 Env Derived from a Pediatric Elite-neutralizer. https://doi.org/10.1101/2025.04.26.649701

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