Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates

Chuang, G.-Y.; Zhou, J.; Rawi, R.; Shen, C.-H.; Sheng, Z.; West, A. P.; Zhang, B.; Zhou, T.; Bailer, R. T.; Doria-Rose, N. A.; Louder, M. K.; McKee, K.; Mascola, J. R.; Bjorkman, P. J.; Shapiro, L.; Kwong, P. D.

doi:10.1101/312579

bioRxiv · 10.1101/312579

Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates

Chuang, G.-Y.·Zhou, J.·Rawi, R.·Shen, C.-H.·Sheng, Z.·West, A. P.·Zhang, B.·Zhou, T.·Bailer, R. T.·Doria-Rose, N. A.·Louder, M. K.·McKee, K.·Mascola, J. R.·Bjorkman, P. J.·Shapiro, L.·Kwong, P. D.

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Abstract

HIV-1 broadly neutralizing antibodies are desired for their therapeutic potential and as templates for vaccine design. Such antibodies target the HIV-1-envelope (Env) trimer, which is shielded from immune recognition by extraordinary glycosylation and sequence variability. Recognition by broadly neutralizing antibodies thus provides insight into how antibody can bypass these immune-evasion mechanisms. Remarkably, antibodies neutralizing >25% of HIV-1 strains have now been identified that recognize all major exposed surfaces of the prefusion-closed Env trimer. Here we analyzed all 206 broadly neutralizing antibody-HIV-1 Env complexes in the PDB with resolution suitable to define their interaction chemistries. These segregated into 20 antibody classes based on ontogeny and recognition, and into 6 epitope categories (V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide, and subunit interface) based on recognized Env residues. We measured antibody neutralization on a 208-isolate panel and analyzed features of paratope and B cell ontogeny. The number of protruding loops, CDR H3 length, and level of somatic hypermutation for broadly HIV-1 neutralizing antibodies were significantly higher than for a comparison set of non-HIV-1 antibodies. For epitope, the number of independent sequence segments was higher (P < 0.0001), as well as the glycan component surface area (P = 0.0005). Based on B cell ontogeny, paratope, and breadth, the CD4-binding site antibody IOMA appeared to be a promising candidate for lineage-based vaccine design. In terms of epitope-based vaccine design, antibody VRC34.01 had few epitope segments, low epitope-glycan content, and high epitope-conformational variability, which may explain why VRC34.01-based design is yielding promising vaccine results.

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Chuang, G.-Y., Zhou, J., Rawi, R., Shen, C.-H., Sheng, Z., West, A. P., Zhang, B., Zhou, T., Bailer, R. T., Doria-Rose, N. A., Louder, M. K., McKee, K., Mascola, J. R., Bjorkman, P. J., Shapiro, L., Kwong, P. D.. 2018-05-02. Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates. https://doi.org/10.1101/312579

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