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

Kavli Affiliate: Robert Edwards

| Authors: Kevin Saunders, James Counts, Victoria Stalls, Robert Edwards, Kartik Manne, Xiaozhi Lu, Bhishem Thakur, Katayoun Mansouri, Yue Chen, Rob Parks, Maggie Barr, Laura Sutherland, Joena Bal, Nicholas Havill, Haiyan Chen, Emily Machiele, Nolan Jamieson, Bhavna Hora, Megan Kopp, Katarzyna Janowska, Kara Anasti, Chuancang Jiang, Sravani Venkatayogi, Amanda Eaton, Rory Henderson, Christopher Barbosa, S. Munir Alam, Sampa Santra, Drew Weissman, M. Anthony Moody, Derek W. Cain, Ying Tam, Mark Lewis, Wilton B. Williams, Kevin Wiehe, David Montefiori, Priyamvada Acharya and Barton F. Haynes

| Summary:

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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