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Functional differences in hepatitis C virus nonstructural (NS) 3/4A- and 5A-specific T cell responses

2016; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/srep24991

2045-2322

Fredrik Holmström, Margaret Chen, Anangi Balasiddaiah, Matti Sällberg, Gustaf Ahlén, Lars Frelin,

Viral Infections and Immunology Research

Abstract The hepatitis C virus nonstructural (NS) 3/4A and NS5A proteins are major targets for the new direct-acting antiviral compounds. Both viral proteins have been suggested as modulators of the response to the host cell. We have shown that NS3/4A- and NS5A-specific T cell receptors confer different effector functions and that killing of NS3/4A-expressing hepatocytes is highly dependent on IFN-γ. We here characterize the functional differences in the T cell responses to NS3/4A and NS5A. NS3/4A- and NS5A-specific T cells could be induced at various frequencies in wild-type-, NS3/4A- and NS5A-transgenic mice. Priming of NS5A-specific T cells required a high DNA dose and was unlike NS3/4A dependent on both CD4 + and CD8 + T cells, but less influenced by CD25 + /GITR + regulatory T cells. The presence of IL-12 greatly improved specific CD8 + T cell priming by NS3/4A but not by NS5A, suggesting a less dependence of IFN-γ for NS5A. This notion was supported by the observation that NS5A-specific T cells could eliminate NS5A-expressing hepatocytes also in the absence of IFN-γ-receptor-2. This supports that NS3/4A- and NS5A-specific T cells become activated and eliminate antigen expressing, or infected hepatocytes, by distinct mechanisms and that NS5A-specific T cells show an overall less dependence of IFN-γ.