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Journal of Virology
Year: 2008  |  Volume: 82  |  Issue: 19  |  Page No.: 9668 - 9677

Ligand-Independent Exhaustion of Killer Immunoglobulin-Like Receptor-Positive CD8+ T Cells in Human Immunodeficiency Virus Type 1 Infection

Galit Alter, Suzannah Rihn, Hendrik Streeck, Nickolas Teigen, Alicja Piechocka-Trocha, Kristin Moss, Kristen Cohen, Angela Meier, Florencia Pereyra, Bruce Walker and Marcus Altfeld    

Abstract: Virus-specific CD8+ T cells play a central role in the control< of viral infections, including human immunodeficiency virus< type 1 (HIV-1) infection. However, despite the presence of strong< and broad HIV-specific CD8+ T-cell responses in chronic HIV-1< infection, these cells progressively lose critical effector< functions and fail to clear the infection. Mounting evidence< suggests that the upregulation of several inhibitory regulatory< receptors on the surface of CD8+ T cells during HIV-1 infection< may contribute directly to the impairment of T-cell function.< Here, we investigated the role of killer immunoglobulin receptors< (KIR), which are expressed on NK cells and on CD8+ T cells,< in regulating CD8+ T-cell function in HIV-1 infection. KIR expression< was progressively upregulated on CD8+ T cells during HIV-1 infection< and correlated with the level of viral replication. Expression< of KIR was associated with a profound inhibition of cytokine< secretion, degranulation, proliferation, and activation by CD8+< T cells following stimulation with T-cell receptor (TCR)-dependent< stimuli. In contrast, KIR+ CD8+ T cells responded potently to< TCR-independent stimulation, demonstrating that these cells< are functionally competent. KIR-associated suppression of CD8+< T-cell function was independent of ligand engagement, suggesting< that these regulatory receptors may constitutively repress TCR< activation. This ligand-independent repression of TCR activation< of KIR+ CD8+ T cells may represent a significant barrier to< therapeutic interventions aimed at improving the quality of< the HIV-specific CD8+ T-cell response in infected individuals.

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