JVI Accepts, published online ahead of print on 4 November 2009

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J. Virol. doi:10.1128/JVI.01596-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Effective SIV-specific CD8+ T cells lack an easily detectable, shared characteristic

Lara Vojnov, Jason S. Reed, Kim L. Weisgrau, Eva G. Rakasz, John T. Loffredo, Shari M. Piaskowski, Jonah B. Sacha, Holly L. Kolar, Nancy A. Wilson, R. Paul Johnson, and David I. Watkins^*

Department of Pathology and Laboratory Medicine, University of Wisconsin- Madison, 555 Science Drive, Madison, Wisconsin 53711; Wisconsin National Primate Research Center, Madison, Wisconsin 53715; Division of Immunology, Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, Massachusetts 01772

^* To whom correspondence should be addressed. Email: watkins{at}primate.wisc.edu.

The immune correlates of human/simian immunodeficiency virus control remain elusive. While CD8+ T lymphocytes likely play a major role in reducing peak viremia and maintaining viral control in the chronic phase, the relative antiviral efficacy of individual virus-specific effector populations is unknown. Conventional assays measure cytokine secretion of virus-specific CD8+ T cells after cognate peptide recognition. Cytokine secretion, however, does not always directly translate into antiviral efficacy. Recently developed suppression assays assess the efficiency of virus-specific CD8+ T cells to control viral replication, but these assays often use cell lines or clones. We, therefore, designed a novel virus production assay to test the ability of freshly ex vivo sorted SIV-specific CD8+ T cells to suppress viral replication from SIVmac239-infected CD4+ T cells. Using this assay, we established an antiviral hierarchy when we compared CD8+ T cells specific for twelve different epitopes. Antiviral efficacy was unrelated to the disease status of each animal, the protein from which the tested epitopes were derived, or the MHC-class I restriction of the tested epitopes. Additionally, there was no correlation with the ability to suppress viral replication and epitope avidity, epitope affinity, CD8+ T cell cytokine multifunctionality, the percentage of central and effector memory cell populations, or the expression of PD-1. The ability of virus-specific CD8+ T cells to suppress viral replication, therefore, cannot be determined using conventional assays. Our results suggest that a single definitive correlate of immune control may not exist; rather a successful CD8+ T cell response may comprise of several factors.