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Journal of Virology, September 2006, p. 8351-8361, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00896-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Identification of Protective Lassa Virus Epitopes That Are Restricted by HLA-A2

Jason Botten,1* Jeff Alexander,2 Valerie Pasquetto,3 John Sidney,3 Polly Barrowman,1 Joey Ting,1 Bjoern Peters,3 Scott Southwood,2 Barbara Stewart,2 Maria P. Rodriguez-Carreno,1 Bianca Mothe,3,4 J. Lindsay Whitton,1 Alessandro Sette,3 and Michael J. Buchmeier1*

Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, 92037,1 Pharmexa-Epimmune, San Diego, California, 92121,2 La Jolla Institute of Allergy and Immunology, San Diego, California, 92121,3 Department of Biological Sciences, California State University, San Marcos, California 920964

Received 2 May 2006/ Accepted 15 June 2006

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 (GPC42-50, GLVGLVTFL; GPC60-68, SLYKGVYEL; and GPC441-449, YLISIFLHL) that displayed high-affinity binding (≤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 GPC42-50 or GPC60-68 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.

* Corresponding author. Mailing address: Molecular and Integrative Neurosciences Department, The Scripps Research Institute, SP30-2020, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone for Jason Botten: (858) 784-7162. Fax: (858) 784-7369. E-mail: jbotten{at}scripps.edu. Phone for Michael J. Buchmeier: (858) 784-7056. Fax: (858) 784-7369. E-mail: buchm{at}scripps.edu.

Journal of Virology, September 2006, p. 8351-8361, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00896-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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