Graduate Student Stanford Univ. Sch. of Med. San Francisco, California, United States
Disclosure(s):
Ipsita Krishnamurthy: No financial relationships to disclose
Introduction/Rationale: Eliciting broadly neutralizing antibodies (bnAbs) that target the HIV-1 envelope glycoprotein (Env) remains a central goal of HIV vaccine design. Among these, antibodies directed against the V1/V2 apex epitope represent an important class of bnAbs with potent and broad neutralizing activity. As HIV-1 bnAbs often require extensive somatic hypermutation, a complete understanding of bnAb maturation pathways is essential to guide bnAb development during immunization.
Methods: Here, we combine negative-stain electron microscopy polyclonal epitope mapping (nsEMPEM) and cryo-electron microscopy (cryo-EM) to characterize potent and broad V1/V2 apex antibodies elicited in rhesus macaques immunized with the germline targeting immunogen CAP256.GT1.
Results: nsEMPEM analyses identified apex-targeting antibodies present in sera twelve weeks after the priming immunization, indicating successful engagement of desired precursor lineages. Polyclonal epitope mapping and biophysical characterization of antibody responses to candidate immunogens guided subsequent boosting strategies and successfully facilitated bnAb development. High-resolution cryo-EM structures of bnAbs isolated over a year after the priming immunization revealed that these antibodies recapitulate the binding modes and structural features observed in human-derived V1/V2 apex bnAbs isolated from chronically infected donors, further supporting the utility of nonhuman primate models for evaluating germline-targeting immunogens.
Conclusion: Together, these findings demonstrate the applicability of structural and polyclonal epitope mapping approaches in guiding rational vaccine design.
