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Title: Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) identifies immune-selected HIV variants

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. Here, with well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Finally, 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 inmore » polyvalent “cocktail” vaccines.« less
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [4] ;  [4] ;  [4] ;  [5] ;  [5] ;  [5] ;  [5] ;  [5] ;  [5] ;  [5]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Santa Fe Inst. (SFI), Santa Fe, NM (United States)
  3. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
  4. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
  5. Duke Univ. Medical Center, Durham, NC (United States). Duke Human Vaccine Inst.
Publication Date:
OSTI Identifier:
1263552
Grant/Contract Number:
UM1 AI100645
Type:
Accepted Manuscript
Journal Name:
Viruses
Additional Journal Information:
Journal Volume: 7; Journal Issue: 10; Journal ID: ISSN 1999-4915
Publisher:
MDPI
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE; National Institute of Allergy and Infectious Disease (NIAID)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES human immunodeficiency virus type 1; vaccine; neutralizing antibodies; immunogen design; envelope glycoprotein; coevolution; immune escape; quasispecies; antigenic swarm; selection