Abstract
Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted founder loss to identify virus “hot-spots” under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. With well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent “cocktail” vaccines.
Highlights
It is not yet known how to elicit protective immunity against HIV-1, and neutralizing antibody induction remains a central focus of HIV vaccine research
Building upon recent insights into antibody/Env coevolution in individual CH505 [15,16,41], we first applied LASSIE to this subject as a test case, to determine how well the method performed in a situation where key epitopes had already been defined and characterized
When exploring the option of excluding TF insertions from the selection criteria, we found that different forms of hypervariable loops were still included in the antigenic swarm, but their representation was limited to evolutionary contexts in which they occurred together with sites that have high TF loss
Summary
It is not yet known how to elicit protective immunity against HIV-1, and neutralizing antibody induction remains a central focus of HIV vaccine research. Neutralizing antibodies are immune correlates of protection in all antiviral vaccines licensed to date [1,2]. HIV-1 is maintained as a continuously evolving quasispecies population throughout chronic infection [9], with diversification driven by adaptive immune responses, including antibody [10,11,12,13,14,15,16,17,18] and T cell responses [19,20,21]. Though neutral mutations may drift to higher frequency with rates that depend on the effective population size, positive selection exceeds drift at driving envelope evolution within hosts [22,23,24]
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