Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization

Summary: Broadly HIV-1 neutralizing VRC01 class antibodies target the CD4-binding site of Env. They are derived from VH1-2∗02 antibody heavy chains paired with rare light chains expressing 5-amino acid-long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naive B cells have been designed and evaluated in knockin mice. However, the elicited antibodies cannot bypass glycans present on the conserved position N276 of Env, which restricts access to the CD4-binding site. Efforts to guide the appropriate maturation of these antibodies by sequential immunization have not yet been successful. Here, we report on a two-step immunization scheme that leads to the maturation of VRC01-like antibodies capable of accommodating the N276 glycan and displaying autologous tier 2 neutralizing activities. Our results are relevant to clinical trials aiming to elicit VRC01 antibodies. : The conserved N276 glycan on the HIV-1 Env presents a major steric hindrance in the maturation of VRC01-class bnAbs. Here, Parks et al. discuss a two-step immunization scheme that leads to the development of VRC01-like antibodies that accommodate the N276 glycan on heterologous Env-derived proteins yet display limited neutralizing activities. Keywords: VRC01, broadly neutralizing antibodies, HIV-1, germline targeting, germline antibody, 426c Env, antibody maturation, CDRL1, CDRL3