The evolutionary landscape of HIV broadly neutralizing antibody development

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PROJECT SUMMARY The human immunodeficiency virus (HIV) pandemic remains a global health threat, responsible for an estimated 35 million active infections and one million deaths per year. Small molecule drugs have transformed HIV prognosis and prophylaxis, but a preventative vaccine that elicits protective neutralizing antibodies is a critical priority. Because of HIV’s vast global diversity, it remains an open challenge to elicit antibodies via vaccination with sufficient antiviral breadth and potency to protect against diverse viral isolates. Rare broadly neutralizing antibodies (bnAbs) that can inhibit the majority of circulating HIV strains have been isolated from HIV-infected patients, establishing a targeted endpoint for an effective HIV vaccine. These bnAbs are also promising molecules for direct therapeutic or prophylactic use. However, our understanding of HIV bnAb function and development has not yet proven sufficient to effectively harness their protective potential. In this proposal, I outline innovative high-throughput biochemical approaches to study the molecular evolutionary basis for bnAb function. With a focus on bnAbs targeting the HIV Envelope CD4 receptor-binding site, we will use high-throughput mutational scanning methods to reveal how all amino acid mutations in select bnAbs and their naive precursors impact specificity versus breadth of binding to diverse HIV Env antigens and to rationally designed candidate vaccine immunogens. In parallel, we will measure mutational effects on orthogonal antibody properties that can constrain antibody development including thermodynamic stability, polyspecificity, and autoreactivity. By synthesizing this wealth of mutational data together with existing natural antibody sequencing data from infection and vaccination, we will identify the molecular evolutionary forces that guide and constrain bnAb affinity maturation. These observations will enable the design of improved antibody therapeutics and vaccine immunogens for this promising class of HIV bnAb. More broadly, the proposed studies will provide important perspectives on the molecular and evolutionary basis for antibody development and pioneer interdisciplinary methodological approaches with utility for various pathogens where the need for broad immune recognition presents a challenge to therapeutic control.