Anti-idiotypic antibodies elicit anti-HIV-1–specific B cell responses

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.

Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

“…Proteins were purified from culture supernatants using Ni-NTA Agarose beads (Macherey-Nagel) according to the manufacturer's instructions and stored at À80 C until further use after buffer exchange to PBS. eOD-GT8 was produced as previously described (Dosenovic et al, 2019). 93THO527 (Anderson et al, 2000) was produced in 293-6E cells in the presence of kifunensine at a concentration of 1 mg/l.…”

Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials

“…First, concentration of VRC01 at sites of HIV exposure may be lower than concentrations measured in serum. Additionally, in vivo neutralization in mucosa might theoretically be reduced due to anti-idiotype antibodies or competitive exclusion [46]. Both mechanisms represent a global reduction in VRC01 neutralizing impact based on deviations from serum PK and/or in vitro IC50 [27].…”

Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus

“…This suggests the existence of gene-endowed targeting solutions that could support pathway-based amplification through genetic reproducibility (Lerner, 2011;Peterhoff and Wagner, 2017;Zhou et al, 2015). To exploit this, germline B cell-stimulating immunogens have been engineered that prime and expand the corresponding variable heavy-chain gene (V H )constrained HIV bnAb cell lineages within human V H geneknockin mice (Briney et al, 2016;Duan et al, 2018;McGuire et al, 2016;Tian et al, 2016;Verkoczy et al, 2017) and in mice containing adoptively transferred bnAb precursors (Abbott et al, 2018;Dosenovic et al, 2018Dosenovic et al, , 2019. However, these maturation pathways typically require exceptional levels of somatic hypermutation (SHM) to achieve broad neutralization of HIV, and the number and configuration of ''shepherding'' immunogens needed to boost and mature the vaccine response to generate this activity remain unclear (Bonsignori et al, 2018;Peterhoff and Wagner, 2017;Umotoy et al, 2019).…”