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Dendritic Cells Infected with vpr-Positive Human Immunodeficiency Virus Type 1 Induce CD8⁺ T-Cell Apoptosis via Upregulation of Tumor Necrosis Factor Alpha

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

Received 2 May 2006/ Accepted 23 April 2007

Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) plays a crucial role in viral replication and pathogenesis by inducing cell cycle arrest, apoptosis, translocation of preintegration complex, potentiation of glucocorticoid action, impairment of dendritic cell (DC) maturation, and T-cell activation. Recent studies involving the direct effects of Vpr on DCs and T cells indicated that HIV-1 containing Vpr selectively impairs phenotypic maturation, cytokine network, and antigen presentation in DCs and dysregulates costimulatory molecules and cytokine production in T cells. Here, we have further investigated the indirect effect of HIV-1 Vpr⁺ virus-infected DCs on the bystander CD8⁺ T-cell population. Our results indicate that HIV-1 Vpr⁺ virus-infected DCs dysregulate CD8⁺ T-cell proliferation and induce apoptosis. Vpr-containing virus-infected DC-mediated CD8⁺ T-cell killing occurred in part through enhanced tumor necrosis factor alpha production by infected DCs and subsequent induction of death receptor signaling and activation of the caspase 8-dependent pathway in CD8⁺ T cells. Collectively, these results provide evidence that Vpr could be one of the important contributors to the host immune escape by HIV-1 through its ability to dysregulate both directly and indirectly the DC biology and T-cell functions.

Published ahead of print on 2 May 2007.

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