Vaccine induction of CD4-mimicking broadly neutralizing antibody precursors in macaques

Saunders, K.; Counts, J.; Stalls, V.; Edwards, R.; Manne, K.; Lu, X.; Thakur, B.; Mansouri, K.; Chen, Y.; Parks, R.; Barr, M.; Sutherland, L.; Bal, J.; Havill, N.; Chen, H.; Machiele, E.; Jamieson, N.; Hora, B.; Kopp, M.; Janowska, K.; Anasti, K.; Jiang, C.; Venkatayogi, S.; Eaton, A.; Henderson, R.; Barbosa, C.; Alam, S. M.; Santra, S.; Weissman, D.; Moody, M. A.; Cain, D. W.; Tam, Y.; Lewis, M.; Williams, W. B.; Wiehe, K.; Montefiori, D.; Acharya, P.; Haynes, B. F.

doi:10.1101/2023.03.05.531154

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bioRxiv · 10.1101/2023.03.05.531154

Vaccine induction of CD4-mimicking broadly neutralizing antibody precursors in macaques

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Abstract

The CD4 binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the CD4bs is occluded by glycans, immunogen expansion of appropriate naive B cells, and selection of functional antibody mutations. Here, we demonstrate immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAbs bound to HIV-1 Env demonstrated binding angles similar to human bnAbs and heavy chain second complementarity determining region-dependent binding characteristic of all known human CD4-mimicking bnAbs. Macaque nAbs were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAbs. This vaccine study initiated the B cells from which derive CD4bs bnAbs in primates, accomplishing the key first step in development of an effective HIV-1 vaccine.

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Saunders, K., Counts, J., Stalls, V., Edwards, R., Manne, K., Lu, X., Thakur, B., Mansouri, K., Chen, Y., Parks, R., Barr, M., Sutherland, L., Bal, J., Havill, N., Chen, H., Machiele, E., Jamieson, N., Hora, B., Kopp, M., Janowska, K., Anasti, K., Jiang, C., Venkatayogi, S., Eaton, A., Henderson, R., Barbosa, C., Alam, S. M., Santra, S., Weissman, D., Moody, M. A., Cain, D. W., Tam, Y., Lewis, M., Williams, W. B., Wiehe, K., Montefiori, D., Acharya, P., Haynes, B. F.. 2023-03-05. Vaccine induction of CD4-mimicking broadly neutralizing antibody precursors in macaques. https://doi.org/10.1101/2023.03.05.531154

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