Objective: The development of a vaccine candidate for specific active immunoprophylaxis against HIV-1 infection, based on the structure-guided design of HIV-1 Env proteins, is considered one of the most promising approaches to creating an immunogen capable of inducing broadly neutralizing antibodies (bnAbs). However, the high diversity of HIV-1 implies that immunogens based on a single specific strain may be ineffective against other circulating variants. Consequently, there is a need to develop an antigen capable of neutralizing a broad spectrum of HIV-1 genetic variants while accounting for regional strain characteristics. Methods: In this study, based on the sequences of Russian strains, a HIV-1 Env surface antigen and its variant with additional mutations—optimized for engagement with germline precursors of VRC01-class bnAbs—were developed and characterized. Results and Discussion: The CON-RUS SOSIP-v. 9. 3 antigen was designed based on a consensus amino acid sequence derived from the most prevalent HIV-1 variants in the Russian Federation (A6, B, CRF02AG, and CRF63₀2A6), with stabilizing SOSIP. v9. 3 and TD8 mutations. The CON-RUS SOSIP-v. 9. 3GT01 variant was further engineered with additional mutations to enhance binding affinity for the germline precursor of the VRC01 antibody. Biochemical characterization by BN-PAGE and SEC-MALS confirmed that both constructs predominantly form trimers with a molecular weight consistent with the expected size (~220 kDa excluding glycans). Negative-stain electron microscopy revealed that the majority of CON-RUS SOSIP-v. 9. 3 molecules adopt a closed conformation, as demonstrated by 2D class averaging and 3D reconstruction fitting to the closed-state BG505 SOSIP. 664 structure (PDB ID: 3J5M). ELISA showed that mature VRC01 (mVRC01) binds both CON-RUS SOSIP-v. 9. 3 and CON-RUS SOSIP-v. 9. 3GT01 with affinity comparable to reference BG505 SOSIP proteins. However, while no binding of CON-RUS SOSIP-v. 9. 3 to germline VRC01 (gVRC01) was detected, the GT01 modification enabled weak binding to gVRC01, although this was significantly lower than that of the BG505 SOSIP variant carrying analogous mutations. Conclusions: Based on the consensus sequence of HIV-1 strains prevalent in the Russian Federation, two recombinant Env constructs (CON-RUS SOSIP-v. 9. 3 and CON-RUS SOSIP-v. 9. 3GT01) were developed, which predominantly adopt a trimeric organization and effectively engage the mature VRC01 antibody.
Favorskaya et al. (Wed,) studied this question.
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