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Journal of Virology, December 2006, p. 11767-11775, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.00213-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Helicobacter pylori VacA Toxin Inhibits Human Immunodeficiency Virus Infection of Primary Human T Cells

Kyra Oswald-Richter,^1, Victor J. Torres,^2, Mark S. Sundrud,^1, Scott E. VanCompernolle,¹ Timothy L. Cover,^1,2,3* and Derya Unutmaz^1*

Department of Microbiology and Immunology,¹ Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2605,² Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212³

Received 30 January 2006/ Accepted 15 September 2006

Human CD4⁺ T cells are major targets for human immunodeficiency virus (HIV) infection. Resting T cells are resistant to HIV infection unless activated through the T-cell receptor (TCR) or by cytokine signals. How T-cell signaling promotes susceptibility of T cells to HIV infection remains poorly understood. Here we demonstrate that the VacA toxin produced by Helicobacter pylori can inhibit HIV infection of primary T cells, stimulated through the TCR or by cytokines alone. This activity of VacA was dependent on its ability to form membrane channels. VacA suppressed HIV infection of T cells at a stage after viral entry, post-reverse transcription and pre-two-long-terminal-repeat circle formation, similar to the cytokine signaling inhibitor rapamycin. Mechanistically, neither VacA nor rapamycin inhibited the activation of cytokine signal transduction components (STAT5, p42/44 mitogen-activated protein kinase, or p38), but both blocked activation of key regulatory proteins required for G₁ cell cycle transition. In contrast to rapamycin, VacA did not suppress phosphorylation of p70 S6 kinase but caused mitochondrial depolarization and ATP depletion within primary T cells. These results suggest that VacA inhibits T-cell activation and HIV infection via a novel mechanism. Identifying the host cell targets of VacA could be useful for elucidating the HIV life cycle within primary T cells.

Published ahead of print on 27 September 2006.

These authors contributed equally.

Present address: The CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115.

This article has been cited by other articles:

• Torres, V. J., VanCompernolle, S. E., Sundrud, M. S., Unutmaz, D., Cover, T. L. (2007). Helicobacter pylori Vacuolating Cytotoxin Inhibits Activation-Induced Proliferation of Human T and B Lymphocyte Subsets. J. Immunol. 179: 5433-5440 [Abstract] [Full Text]  
• Algood, H. M. S., Torres, V. J., Unutmaz, D., Cover, T. L. (2007). Resistance of Primary Murine CD4+ T Cells to Helicobacter pylori Vacuolating Cytotoxin. Infect. Immun. 75: 334-341 [Abstract] [Full Text]