Germline-Targeting Strategies to Induce bNAbs against HIV-1

Developing an effective HIV-1 vaccine remains a critical global health challenge, hin-dered by the virus's high genetic diversity, immune evasion strategies, and structural complexity of its Envelope (Env) glycoprotein. Broadly neutralizing antibodies (bNAbs), capable of targeting conserved Env epitopes, offer a promising path for vaccine design. Germline-targeting (GT) strat-egies have emerged as a promising approach to engage naive B cell precursors that have the po-tential to mature into bNAb-producing cells. Advances in GT have enabled the design of immu-nogens capable of recruiting specific bNAb precursors in animal models and early clinical trials. Despite these successes, achieving neutralization breadth requires sequential immunizations with tailored boosting strategies to guide B cell maturation. Studies underscore the importance of using immunogens that mimic native Env structures while modulating glycosylation patterns to focus immune responses. Emerging approaches, such as membrane-bound presentation and mRNA de-livery, hold the potential for enhancing immunogen effectiveness and rapid pre-clinical and in human screening to identify combinations of immunogens that foster bNAb lineages. This review seeks to synthesize key developments in GT strategies for HIV-1 vaccines, highlighting the de-sign and implementation of immunogens that drive bNAb precursor maturation. It aims to under-score the importance of integrating structural insights, immunogen sequence design, and delivery methods to enhance the induction of bNAbs, offering direction for future research to address ex-isting gaps and optimize vaccine efficacy.