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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{triangledown}

Kyra Oswald-Richter,1,{dagger} Victor J. Torres,2,{dagger} Mark S. Sundrud,1,{ddagger} Scott E. VanCompernolle,1 Timothy L. Cover,1,2,3* and Derya Unutmaz1*

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.

* Corresponding author. Mailing address for Timothy L. Cover: Division of Infectious Diseases, A2200 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 322-2035. E-mail: Timothy.L.Cover{at}vanderbilt.edu. Mailing address for Derya Unutmaz: Department of Microbiology and Immunology, Vanderbilt University Medical School, 21st Avenue South, Medical Center North, Room AA-5206, Nashville, TN 37232-2363. Phone: (615) 322-1436. Fax: (615) 343-7392. E-mail: derya.unutmaz{at}vanderbilt.edu.

{triangledown} Published ahead of print on 27 September 2006.

{dagger} These authors contributed equally.

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

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.



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]  


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