HLA-A2-restricted protection against lethal lymphocytic choriomeningitis.
The consequences of human lymphocytic choriomeningitis virus (LCMV) infection can be severe, including aseptic meningitis in immunocompetent individuals, hydrocephalus or chorioretinitis in fetal infection, or a highly lethal outcome in immunosuppressed individuals. In murine models of LCMV infection, CD8(+) T cells play a primary role in providing protective immunity, and there is evidence that cellular immunity may also be important in related arenavirus infections in humans. For this reason, we sought to identify HLA-A2 supertype-restricted epitopes from the LCMV proteome and evaluate them as vaccine determinants in HLA transgenic mice. We identified four HLA-A*0201-restricted peptides-nucleoprotein NP(69-77), glycoprotein precursor GPC(10-18), GPC(447-455), and zinc-binding protein Z(49-58)-that displayed high-affinity binding (< or =275 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 LCMV antigens in HLA-restricted human antigen presenting cells. One of the epitopes (GPC(447-455)), after peptide immunization of HLA-A*0201 mice, induced CD8(+) T cells capable of killing peptide-pulsed HLA-A*0201-restricted target cells in vivo and protected mice against lethal intracranial challenge with LCMV.
Botten
Jason
J
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, SP30-2020, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. jbotten@scripps.edu
Whitton
J Lindsay
JL
Barrowman
Polly
P
Sidney
John
J
Whitmire
Jason K
JK
Alexander
Jeff
J
Ting
Joey P C
JP
Bui
Huynh-Hoa
HH
Sette
Alessandro
A
Buchmeier
Michael J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D000939:Epitopes / Q000235:genetics; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006801:Humans; D007114:Immunization; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020543:Proteome; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D022223:Vaccines, Subunit / Q000235:genetics; D014765:Viral Vaccines / Q000235:genetics
D000956:Antigens, Viral; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D020543:Proteome; D011994:Recombinant Proteins; D022223:Vaccines, Subunit; D014765:Viral Vaccines