Tat(28-35)SL8-specific CD8+ T lymphocytes are more effective than Gag(181-189)CM9-specific CD8+ T lymphocytes at suppressing simian immunodeficiency virus replication in a functional in vitro assay.
Journal: 2006/January - Journal of Virology
ISSN: 0022-538X
Abstract:
Epitope-specific CD8+ T lymphocytes may play an important role in controlling human immunodeficiency virus (HIV)/simian immunodeficiency virus replication. Unfortunately, standard cellular assays do not measure the antiviral efficacy (the ability to suppress virus replication) of CD8+ T lymphocytes. Certain epitope-specific CD8+ T lymphocytes may be better than others at suppressing viral replication. We compared the antiviral efficacy of two immunodominant CD8+ T lymphocyte responses--Tat(28-35)SL8 and Gag(181-189)CM9--by using a functional in vitro assay. Viral suppression by Tat-specific CD8+ T lymphocytes was consistently greater than that of Gag-specific CD8+ T lymphocytes. Such differences in antigen-specific CD8+-T-lymphocyte efficacy may be important for selecting CD8+ T lymphocyte epitopes for inclusion in future HIV vaccines.
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J Virol 79(23): 14986-14991

Tat<sub>28-35</sub>SL8-Specific CD8<sup>+</sup> T Lymphocytes Are More Effective than Gag<sub>181-189</sub>CM9-Specific CD8<sup>+</sup> T Lymphocytes at Suppressing Simian Immunodeficiency Virus Replication in a Functional In Vitro Assay

Wisconsin National Primate Research Center, Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 537152
Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 585 Science Dr., Madison, WI 53711. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail:ude.csiw.etamirp@sniktaw.
Received 2005 Jul 14; Accepted 2005 Sep 3.

Abstract

Epitope-specific CD8 T lymphocytes may play an important role in controlling human immunodeficiency virus (HIV)/simian immunodeficiency virus replication. Unfortunately, standard cellular assays do not measure the antiviral efficacy (the ability to suppress virus replication) of CD8 T lymphocytes. Certain epitope-specific CD8 T lymphocytes may be better than others at suppressing viral replication. We compared the antiviral efficacy of two immunodominant CD8 T lymphocyte responses—Tat28-35SL8 and Gag181-189CM9—by using a functional in vitro assay. Viral suppression by Tat-specific CD8 T lymphocytes was consistently greater than that of Gag-specific CD8 T lymphocytes. Such differences in antigen-specific CD8-T-lymphocyte efficacy may be important for selecting CD8 T lymphocyte epitopes for inclusion in future HIV vaccines.

Abstract

Several lines of evidence suggest that CD8 T lymphocytes are important in suppressing human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. The appearance of HIV-specific CD8 T lymphocytes is correlated temporally with a precipitous reduction in viral load (8, 20) implying that these virus-specific effector cells control viral replication. However, the massive loss of memory CD4 T cells during acute HIV/SIV infection also likely contributes to the initial reduction in viral replication (21, 26). Additional evidence implicating CD8 T cells in the control of viral replication comes from the depletion of circulating CD8 lymphocytes in SIV-infected macaques, which results in an increase in plasma viral concentrations (16, 24, 35). In addition, CD8-T-lymphocytes exert selective pressure on viral sequences in vivo, selecting for immune escape variants in both the acute (3, 9, 30) and the chronic (6, 7, 10, 11, 14, 32) phase of HIV/SIV infection.

Over the past decade, new methodologies have improved our ability to detect CD8-T-lymphocyte responses against HIV/SIV. However, we still do not know which of these HIV-specific CD8 T lymphocytes actually contributes to control of viral replication. While neutralization assays distinguish effective antibodies from ineffective ones, most current cellular assays rely on indirect readouts to measure CD8-T-lymphocyte efficacy (44). Early studies demonstrated that CD8 cells (38) and later virus-specific cytotoxic T lymphocytes (45) inhibited immunodeficiency virus replication in vitro. Recently, investigators using functional in vitro assays suggested that CD8-T-lymphocyte clones directed against early-expressed viral proteins, Nef (1, 46) and Rev (39, 40), may be particularly effective in suppressing viral replication. Another study demonstrated effective viral suppression using Pol-specific CD8 T lymphocytes (37). Furthermore, dendritic cells pulsed with inactivated autologous virus can expand virus-specific CD8 T cells, which are then capable of controlling HIV replication (23). While most data suggest that there are differences among the various CD8-T-lymphocyte populations in their antiviral efficacy (the ability to suppress virus replication), current studies are limited by relying on a small number of well-defined clones. Moreover, the attributes of an effective CD8-T-lymphocyte response are still undefined.

Acknowledgments

We thank William Rehrauer, Jess Maxwell, and Tim Jacoby for MHC class I PCR-SSP typing and gratefully acknowledge Laura Valentine, Alex Ko, and Andrea Weiler for immunological assay assistance. David O'Connor and Thomas Friedrich provided helpful discussions. We also thank the Immunology and Virology Core Laboratories at the National Primate Research Center, University of Wisconsin-Madison for technical assistance.

This research was supported by National Institutes of Health grants R01 AI049120-04 to D.I.W. and P51 RR 000167 to the Wisconsin National Primate Research Center (WNPRC). This study was conducted in part at a facility constructed with support from Research Facilities Improvement grant numbers RR15459-01 and RR020141-01 (WNPRC).

Acknowledgments

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