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Journal of Virology, July 2008, p. 7189-7200, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.01979-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Infection with Vpr-Positive Human Immunodeficiency Virus Type 1 Impairs NK Cell Function Indirectly through Cytokine Dysregulation of Infected Target Cells{triangledown}

Biswanath Majumder, Narasimhan J. Venkatachari, Shaylee O'Leary, and Velpandi Ayyavoo*

Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, 130 Desoto Street, Pittsburgh, Pennsylvania 15261

Received 9 September 2007/ Accepted 8 April 2008

Human immunodeficiency virus type 1 (HIV-1) infection has been implicated in impairing various aspects of NK cell function in viremic condition, and several viral factors contribute to these defects. Here, we evaluated the effect of HIV-1 Vpr on NK cell cytolytic function and cytokine (gamma interferon [IFN-{gamma}]) production in the context of infection and exposure. Our data indicate that NK cells derived from a peripheral blood mononuclear cell culture infected in vitro with HIV-1 vpr(+) virus or exposed to recombinant Vpr protein exhibited reduced target cell killing in conjunction with diminished expression of CD107a and reduced IFN-{gamma} production compared to their Vpr-negative counterparts. This Vpr-induced NK cell defect is in part through differential regulation of interleukin-12 and transforming growth factor β production by the infected target cells and concomitant activation of Smad3 signaling pathway. Collectively, these results illustrate the ability of Vpr to impair NK cell-mediated innate immune functions indirectly by dysregulating multiple cytokines in the infected target cells, thus increasing disease severity and affecting the final outcome in HIV-1 infection.

* Corresponding author. Mailing address: Department of Infectious Diseases and Microbiology, University of Pittsburgh, GSPH, 130 Desoto Street, Pittsburgh, PA 15261. Phone: (412) 624-3070. Fax: (412) 624-5612. E-mail: address: velpandi{at}pitt.edu

{triangledown} Published ahead of print on 16 April 2008.

Journal of Virology, July 2008, p. 7189-7200, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.01979-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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