Evaluating the role of non-HIV antigens in the initiation of QA013.2 HIV bnAb lineage

Broadly neutralizing antibodies (bnAbs) are a major goal of HIV vaccine design because they neutralize diverse viral strains. Breadth is typically achieved via affinity maturation and accumulated somatic mutations. However, the inferred naïve precursors of some bnAbs fail to bind the HIV epitopes targeted by their mature counterparts. Consequently, the initiating antigens remain elusive, complicating vaccine design. Building on our previous identification of the HIV bnAb QA013.2 and evidence that its lineage acquired somatic mutations prior to HIV seroconversion, we explored the hypothesis that QA013.2 maturation may be initiated by non-HIV antigens. We screened the inferred naïve precursor and a pre-HIV mutated intermediate of this lineage against > 114.000 antigens, including microbial and parasite glycans, the human proteome and peptides from the human virome. Although human proteome profiling yielded reproducible signals for seven candidates, these interactions lacked a defining structural motif or clear context for B cell priming. Across all platforms, no definitive initiating antigen was identified under the conditions tested, suggesting that if early maturation is indeed driven by non-HIV exposure, the required antigen may involve low-affinity interactions or complex conformational features or glycosylation patterns that remain challenging to detect in standard high-throughput screens.