Abstract
Human anti-HIV-1 broadly neutralizing antibodies (bNAbs) protect against infection in animal models. However, bNAbs have not been elicited by vaccination in diverse wild-type animals or humans, in part because B cells expressing the precursors of these antibodies do not recognize most HIV-1 envelopes (Envs). Immunogens have been designed that activate these B cell precursors in vivo, but they also activate competing off-target responses. Here we report on a complementary approach to expand specific B cells using an anti-idiotypic antibody, iv8, that selects for naive human B cells expressing immunoglobulin light chains with 5-amino acid complementarity determining region 3s, a key feature of anti-CD4 binding site (CD4bs)-specific VRC01-class antibodies. In mice, iv8 induced target cells to expand and mature in the context of a polyclonal immune system and produced serologic responses targeting the CD4bs on Env. In summary, the results demonstrate that an anti-idiotypic antibody can specifically recognize and expand rare B cells that express VRC01-class antibodies against HIV-1.
Highlights
Despite nearly four decades of investigation, there is still no vaccine against HIV-1
It does not bind to mature VRC01-class or all tested non–VRC01-class anti-HIV-1 bNAbs (Fig. 1 A). iv8 bound a synthetic intermediate (SI) antibody comprising the mature 3BNC60 Ig heavy chain (IgH) and its germline Ig light chains (IgLs) (3BNC60SI), but not to a 3BNC60 chimera composed of the germline IgH and mature IgL
Iv8 bound to a chimeric antibody comprising the germline 8ANC131 IgH paired with germline VRC01 IgL, but not to germline NIH45-46 IgH paired with germline 8ANC131 IgL that contains a 9-aa CDRL3 (Fig. 1 A), indicating that binding mostly depends on VRC01-class germline light chains
Summary
Despite nearly four decades of investigation, there is still no vaccine against HIV-1. Mice receiving 3BNC60SI B cell transfers developed eODGT8–binding serum antibodies in response to both 426cN276D-2W1S and iv8 Fab-2W1S nanoparticles, but control mice did not (Fig. 4 A).
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