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. 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.
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. phraber@lanl.gov.
Peter
P
Hraber
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. btk@lanl.gov.
Bette
B
Korber
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. kshitij@lanl.gov.
Kshitij
K
Wagh
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. egiorgi@lanl.gov.
Elena E
EE
Giorgi
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. tanmoy@lanl.gov.|Santa Fe Institute, Santa Fe, NM 87501, USA. tanmoy@lanl.gov.
Tanmoy
T
Bhattacharya
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. gnana@lanl.gov.
S
S
Gnanakaran
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. asl@lanl.gov.
Alan S
AS
Lapedes
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. glearn@mail.med.upenn.edu.
Gerald H
GH
Learn
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. fkreider@mail.med.upenn.edu.
Edward F
EF
Kreider
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. yingyl@mail.med.upenn.edu.
Yingying
Y
Li
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. shawg@upenn.edu.
George M
GM
Shaw
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. bhahn@upenn.edu.
Beatrice H
BH
Hahn
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. monte@duke.edu.
David C
DC
Montefiori
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. alam0004@mc.duke.edu.
S Munir
SM
Alam
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. mattia.bonsignori@duke.edu.
Mattia
M
Bonsignori
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. tony.moody@duke.edu.
M Anthony
MA
Moody
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. hliao@duke.edu.
Hua-Xin
HX
Liao
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. feng.gao@duke.edu.
Feng
F
Gao
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. hayne002@mc.duke.edu.
Barton F
BF
Haynes
D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D014644:Genetic Variation; D006678:HIV / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D006801:Humans; D057131:Immune Evasion; D008137:Longitudinal Studies; D012641:Selection, Genetic; D014773:Virology / Q000379:methods*
D000956:Antigens, Viral
antigenic swarm; coevolution; envelope glycoprotein; human immunodeficiency virus type 1; immune escape; immunogen design; neutralizing antibodies; quasispecies; selection; vaccine