Identification of protective Lassa virus epitopes that are restricted by HLA-A2.
Recovery from Lassa virus (LASV) infection usually precedes the appearance of neutralizing antibodies, indicating that cellular immunity plays a primary role in viral clearance. To date, the role of LASV-specific CD8(+) T cells has not been evaluated in humans. To facilitate such studies, we utilized a predictive algorithm to identify candidate HLA-A2 supertype epitopes from the LASV nucleoprotein and glycoprotein precursor (GPC) genes. We identified three peptides (GPC(42-50), GLVGLVTFL; GPC(60-68), SLYKGVYEL; and GPC(441-449), YLISIFLHL) that displayed high-affinity binding (< or =98 nM) to HLA-A*0201, induced CD8(+) T-cell responses of high functional avidity in HLA-A*0201 transgenic mice, and were naturally processed from native LASV GPC in human HLA-A*0201-positive target cells. HLA-A*0201 mice immunized with either GPC(42-50) or GPC(60-68) were protected against challenge with a recombinant vaccinia virus that expressed LASV GPC. The epitopes identified in this study represent potential diagnostic reagents and candidates for inclusion in epitope-based vaccine constructs. Our approach is applicable to any pathogen with existing sequence data, does not require manipulation of the actual pathogen or access to immune human donors, and should therefore be generally applicable to category A through C agents and other emerging pathogens.
Botten
Jason
J
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA. jbotten@scripps.edu
Alexander
Jeff
J
Pasquetto
Valerie
V
Sidney
John
J
Barrowman
Polly
P
Ting
Joey
J
Peters
Bjoern
B
Southwood
Scott
S
Stewart
Barbara
B
Rodriguez-Carreno
Maria P
MP
Mothe
Bianca
B
Whitton
J Lindsay
JL
Sette
Alessandro
A
Buchmeier
Michael J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D007835:Lassa Fever / Q000276:immunology / Q000517:prevention & control; D007836:Lassa virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019590:Nucleocapsid Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D019590:Nucleocapsid Proteins; D010455:Peptides; D014759:Viral Envelope Proteins; D014765:Viral Vaccines