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Journal of Virology, May 2007, p. 4973-4980, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.02362-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Epitope-Dependent Avidity Thresholds for Cytotoxic T-Lymphocyte Clearance of Virus-Infected Cells{triangledown}

Michael S. Bennett,1 Hwee L. Ng,2 Mirabelle Dagarag,2 Ayub Ali,2 and Otto O. Yang1,2*

Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095,1 Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 900952

Received 27 October 2006/ Accepted 21 February 2007

Cytotoxic T lymphocytes (CTLs) are crucial for immune control of viral infections. "Functional avidity," defined by the sensitizing dose of exogenously added epitope yielding half-maximal CTL triggering against uninfected target cells (SD50), has been utilized extensively as a measure of antiviral efficiency. However, CTLs recognize infected cells via endogenously produced epitopes, and the relationship of SD50 to antiviral activity has never been directly revealed. We elucidate this relationship by comparing CTL killing of cells infected with panels of epitope-variant viruses to the corresponding SD50 for the variant epitopes. This reveals a steeply sigmoid relationship between avidity and infected cell killing, with avidity thresholds (defined as the SD50 required for CTL to achieve 50% efficiency of infected cell killing [KE50]), below which infected cell killing rapidly drops to none and above which killing efficiency rapidly plateaus. Three CTL clones recognizing the same viral epitope show the same KE50 despite differential recognition of individual epitope variants, while CTLs recognizing another epitope show a 10-fold-higher KE50, demonstrating epitope dependence of KE50. Finally, the ability of CTLs to suppress viral replication depends on the same threshold KE50. Thus, defining KE50 values is required to interpret the significance of functional avidity measurements and predict CTL efficacy against virus-infected cells in pathogenesis and vaccine studies.

* Corresponding author. Mailing address: Division of Infectious Diseases, 37-121 CHS, UCLA Medical Center, 10833 LeConte Ave., Los Angeles, CA 90095. Phone: (310) 794-9491. Fax: (310) 825-3632. E-mail: oyang{at}mednet.ucla.edu

{triangledown} Published ahead of print on 28 February 2007.

Journal of Virology, May 2007, p. 4973-4980, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.02362-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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