Phylogenetic Reconstruction of HIV B Cell Lineages with Dowser: Applications to Vaccine Design скачать в хорошем качестве

Phylogenetic Reconstruction of HIV B Cell Lineages with Dowser: Applications to Vaccine Design

2025 Immcantation Users Group Meeting https://immcantation.github.io/users-... Title: Phylogenetic Reconstruction of HIV B Cell Lineages with Dowser: Applications to Mutation-Guided Vaccine Design Speaker: Dr. Emmanuel San, Duke Human Vaccine Institute A protective HIV vaccine must elicit broadly neutralizing antibodies (bnAbs). HIV bnAbs are challenging to elict because they are the result of long maturation pathways which include mutations that are not routinely made by the somatic hypermutation machinery. To address this challenge, we recently developed the mutation-guided vaccine design strategy in which developmentally rate-limiting bnAb mutations are targeted for selection by specifically designed immunogens. This vaccine strategy relies on accurate reconstruction of the maturation history of target bnAb clones including inferring the unmutated common ancestor and the ancestral sequences in the B cell clonal genealogy. Although recent advancements in sequencing have enabled paired heavy and light chain sequencing, there remains a shortage of tools capable of analyzing paired chain data and accurately reconstructing B cell maturation histories. Dowser is a newly developed lineage reconstruction tool in the Immcantation framework. Using data from highly curated HIV B cell lineages, we compared ancestral states and clonal genealogy trees reconstructed by Dowser to previous methods. Our results demonstrated that Dowser reconstructed highly similar trees to the previously inferred HIV bnAb clonal genealogies. Furthermore, analysis of the inferred ancestral sequences showed that Dowser placed most of the critical, improbable mutations responsible for the breadth and binding affinity of the lineages along similar branches as previous methods. We also used Dowser to reconstruct a large clone elicited in a rhesus macaque demonstrating that Dowser can be applied to paired sequence data from a non-human primate animal model widely used in vaccine research. These findings establish Dowser as a robust and reliable tool for B cell lineage reconstruction, providing a valuable asset for advancing mutation-guided vaccine design strategies.