Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution\n (LASSIE) Identifies Immune-Selected HIV Variants

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Within-host genetic sequencing from samples collected over time provides a\ndynamic view of how viruses evade host immunity. Immune-driven mutations might\nstimulate neutralization breadth by selecting antibodies adapted to cycles of\nimmune escape that generate within-subject epitope diversity. Comprehensive\nidentification of immune-escape mutations is experimentally and computationally\nchallenging. With current technology, many more viral sequences can readily be\nobtained than can be tested for binding and neutralization, making\ndown-selection necessary. Typically, this is done manually, by picking variants\nthat represent different time-points and branches on a phylogenetic tree. Such\nstrategies are likely to miss many relevant mutations and combinations of\nmutations, and to be redundant for other mutations. Longitudinal Antigenic\nSequences and Sites from Intrahost Evolution (LASSIE) uses transmitted-founder\nloss to identify virus "hot-spots" under putative immune selection and chooses\nsequences that represent recurrent mutations in selected sites. LASSIE favors\nearliest sequences in which mutations arise. With well-characterized\nlongitudinal Env sequences, we confirmed selected sites were concentrated in\nantibody contacts and selected sequences represented diverse antigenic\nphenotypes. Practical applications include rapidly identifying immune targets\nunder selective pressure within a subject, selecting minimal sets of reagents\nfor immunological assays that characterize evolving antibody responses, and for\nimmunogens in polyvalent "cocktail" vaccines.\n

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