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Clinical and Diagnostic Laboratory Immunology, October 2005, p. 1223-1230, Vol. 12, No. 10
1071-412X/05/$08.00+0     doi:10.1128/CDLI.12.10.1223-1230.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Lassa Fever Virus Peptides Predicted by Computational Analysis Induce Epitope-Specific Cytotoxic-T-Lymphocyte Responses in HLA-A2.1 Transgenic Mice

Agnieszka Boesen,{dagger} Krishnan Sundar,{ddagger} and Richard Coico*

Department of Microbiology and Immunology, City University of New York Medical School, New York, New York 10031

Received 30 March 2005/ Returned for modification 17 May 2005/ Accepted 16 June 2005

Lassa fever is a hemorrhagic disease caused by Lassa fever virus (LV). Although the precise host defense mechanism(s) that affords protection against LV is not completely understood, cellular immunity mediated by cytotoxic T lymphocytes (CTLs) plays a pivotal role in controlling viral replication and LV infection. To date, there have been no reports mapping major histocompatibility complex (MHC) class I-binding CTL epitopes for LV. Using computer-assisted algorithms, we identified five HLA-A2.1-binding peptides of LV glycoprotein (GP) and two peptides from LV nucleoprotein (NP). Synthesized peptides were examined for their ability to bind to MHC class I molecules using a flow cytometric assay that measures peptide stabilization of class I. Three of the LV-GP peptides tested (LLGTFTWTL, SLYKGVYEL, and YLISIFLHL) stabilized HLA-A2. The LV-NP peptides tested failed to stabilize this HLA-A2. We then investigated the ability of the HLA-A2-binding LV-GP peptides to generate peptide-specific CTLs in HLA-A2.1 transgenic mice. Functional assays used to confirm CTL activation included gamma interferon enzyme-linked immunospot (ELISPOT) assays and intracellular cytokine staining of CD8+ T cells from peptide-primed mice. CTL assays were also performed to verify the cytolytic activity of peptide-pulsed target cells. Each of the LV-GP peptides induced CTL responses in HLA-A2-transgenic mice. MHC class I tetramers prepared using one LV-GP peptide that showed the highest cytolytic index (LLGTFTWTL) confirmed that peptide-binding CD8+ T cells were present in pooled lymphocytes harvested from peptide-primed mice. These findings provide direct evidence for the existence of LV-derived GP epitopes that may be useful in the development of protective immunogens for this hemorrhagic virus.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room A128, New York, NY 10021. Phone: (607) 254-6554. Fax: (607) 254-6376. E-mail: ric2008{at}med.cornell.edu.

{dagger} Present address: Allergic Inflammation Section, NIAID/NIH, Rockville, MD 20852.

{ddagger} Present address: Department of Medicine, UMDNJ—New Jersey Medical School, Newark, NJ 07103.

Clinical and Diagnostic Laboratory Immunology, October 2005, p. 1223-1230, Vol. 12, No. 10
1071-412X/05/$08.00+0     doi:10.1128/CDLI.12.10.1223-1230.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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