Not all cytokine-producing CD8+ T cells suppress simian immunodeficiency virus replication.
Journal: 2007/July - Journal of Virology
ISSN: 0022-538X
Abstract:
Current assays of CD8+ T-lymphocyte function measure cytokine production rather than the ability of these lymphocytes to suppress viral replication. Here we show that CD8+ T-cell clones recognizing the same epitope vary enormously in the ability to suppress simian immunodeficiency virus SIVmac239 replication in an in vitro suppression assay. However, all Nef(165-173)IW9- and Vif(66-73)HW8-specific clones from elite controllers effectively suppressed SIV replication. Interestingly, in vitro suppression efficacy was not always associated with the ability to produce gamma interferon, tumor necrosis factor alpha, or interleukin-2.
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J Virol 81(3): 1517-1523

Not All Cytokine-Producing CD8<sup>+</sup> T Cells Suppress Simian Immunodeficiency Virus Replication<sup><a href="#fn1" rid="fn1" class=" fn">▿</a></sup>

+2 authors
Wisconsin National Primate Research Center, Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, Madison, Wisconsin 53715-1299, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 352943
Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, 555 Science Dr., Madison, WI 53711. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail: ude.csiw.etamirp@sniktaw.
Received 2006 Aug 16; Accepted 2006 Nov 9.

Abstract

Current assays of CD8 T-lymphocyte function measure cytokine production rather than the ability of these lymphocytes to suppress viral replication. Here we show that CD8 T-cell clones recognizing the same epitope vary enormously in the ability to suppress simian immunodeficiency virus SIVmac239 replication in an in vitro suppression assay. However, all Nef165-173IW9- and Vif66-73HW8-specific clones from elite controllers effectively suppressed SIV replication. Interestingly, in vitro suppression efficacy was not always associated with the ability to produce gamma interferon, tumor necrosis factor alpha, or interleukin-2.

Abstract

Several lines of evidence suggest that CD8 T lymphocytes are critical in controlling human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. Depletion of CD8 cells from SIV-infected macaques results in increased viremia (27, 37, 49). The appearance of HIV-specific CD8 T lymphocytes is correlated temporally with a precipitous reduction in viremia (10, 32). Furthermore, particular major histocompatibility complex (MHC) class I alleles are associated with control of viral replication (40, 41, 43, 56). In addition, CD8 T lymphocytes exert selective pressure on viral sequences in vivo, selecting for escape variants (5-7, 11, 15, 21, 24, 42, 45).

Unfortunately, T-cell correlates of control of viral replication after HIV or SIV infection are not clearly defined. Neither the magnitude nor the breadth of CD8 T-lymphocyte responses is consistently correlated with clinical outcome (1). Since these quantifiable traits of CD8 T-lymphocyte responses do not appear to affect disease outcome, control of viral replication might instead be affected by the “quality” of CD8 T lymphocytes. Factors that may influence HIV- or SIV-specific CD8 T-lymphocyte antiviral efficacy include epitope expression kinetics, evolutionary constraints on epitope sequences, T-cell receptor (TCR) repertoire, and functional avidity (2, 14, 19, 25, 30, 31, 35, 42, 47, 55).

The SIV-infected rhesus macaque is the best animal model of HIV infection. The Mamu-B17 allele in macaques and the HLA-B57 allele in HIV-infected individuals appear to have similar protective benefits (40, 48, 56). However, fewer than one-third of Mamu-B17-positive macaques become elite controllers after SIVmac239 infection (56). Since the presence of the Mamu-B17 allele is not sufficient to confer elite control, it is likely that additional factors influence the quality of protective CD8 T-lymphocyte responses.

CD8 T-cell clones specific for a particular epitope may differ greatly in antiviral efficacy. Epitope-specific CD8 T cells in SIV or HIV infection are clonally diverse (16, 29). CD8 T cells with unique TCRs may be crucial to control viral replication in long-term survivors after HIV infection (19). However, the relationship of clonal variation to antiviral efficacy has not been carefully examined. In the present study, we explored the possibility that epitope-specific CD8 T cells exhibit clonal variation in antiviral efficacy and cytokine expression.

Acknowledgments

We thank Jason Reed, Shari Piaskowski, and Jason Stephany for technical assistance. We also appreciate David O'Connor and Jonah Sacha for helpful discussions.

The NIH AIDS Research and Reference Reagent Program provided recombinant human IL-2. This research was supported by National Institutes of Health grants R01 AI049120, R24 RR015371, R01 AI052056, and P51 RR000167. This work was conducted in part at a facility constructed with support from Research Facility Improvement grants RR15459-01 and RR020141-01 to the Wisconsin National Primate Research Center.

Acknowledgments

Footnotes

Published ahead of print on 29 November 2006.

Footnotes

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