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Absence of CTL Responses to Early Viral Antigens Facilitates Viral Persistence¹

Institute of Experimental Immunology, University Hospital Zurich, Zurich, Switzerland

CD8⁺ T cells are crucial for the control of intracellular pathogens such as viruses and some bacteria. Using lymphocytic choriomeningitis virus (LCMV) infection of mice—the prototypic arenavirus evolutionarily closely related to human Lassa fever and South American hemorrhagic fever viruses, we have shown previously that the kinetics of Ag presentation determine immunodominance of the LCMV-specific CTL response due to progressive exhaustion of LCMV nucleoprotein (NP)-specific CTL upon increasing viral load. In this study, we provide evidence that CTL against early LCMV NP-derived epitopes are more important in virus control than those against late glycoprotein-derived epitopes. We show that mice that are tolerant to all NP-derived T cell epitopes are severely compromised in their ability to control larger inocula of LCMV, supporting our hypothesis that CD8⁺ T cells specific for early viral Ags play a major role in acute virus control. Thus, the kinetics with which virus-derived T cell epitopes are presented has a strong impact on the efficacy of the antiviral immunity. This aspect should be taken into consideration for the development of vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Swiss National Science Foundation and the European Community (MUGEN LSHG-CT-2005-005203).

² Address correspondence and reprint requests to Dr. Anita Schildknecht at the current address, Clinical Immunology, University Hospital Zurich, Häldeliweg 4, CH-8044 Zurich, Switzerland. E-mail address: anita_schildknecht{at}bluewin.ch or Dr. Maries van den Broek, Experimental Immunology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland. E-mail address: maries{at}van-den-broek.ch

³ Current address: Intestinal Disease Research Program, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

⁴ Current address: Department of Immunology, IMM2, The Scripps Research Institute, La Jolla, CA 92037.

⁵ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; NP, nucleoprotein; moi, multiplicity of infection; VV, vaccinia virus; DC, dendritic cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ICS, intracellular cytokine staining.