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Induction of cytokine expression by herpes simplex virus in human monocyte-derived macrophages and dendritic cells is dependent on virus replication and is counteracted by ICP27 targeting NF-B and IRF-3

Jesper Melchjorsen^1,2,

¹ Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland
² Institute of Medical Microbiology and Immunology, University of Aarhus, DK-8000 Aarhus C, Denmark

Correspondence
Jesper Melchjorsen
jesper{at}microbiology.au.dk

Macrophages and dendritic cells (DCs) play essential roles in host defence against microbial infections. In the present study, it is shown that human monocyte-derived macrophages and DCs express both type I and type III interferons (IFNs) [IFN-, IFN- and interleukin 28 (IL-28), IL-29, respectively], tumour necrosis factor alpha and the chemokines CCL5 and CXCL10 after herpes simplex virus 1 (HSV-1) infection. The cytokine-inducing activity of HSV-1 was dependent on viability of the virus, because UV-inactivated virus did not induce a cytokine response. Pretreatment of the cells with IFN- or IL-29 strongly enhanced the HSV-1-induced cytokine response. Both IFN- and IL-29 decreased viral immediate-early (IE) gene infected-cell protein 27 (ICP27) transcription, suggesting that IL-29 possesses antiviral activity against HSV-1 comparable to that of IFN-. Macrophage infection with HSV-1 lacking functional ICP27 (d27-1 virus) resulted in strongly enhanced cytokine mRNA expression and protein production. In contrast, viruses lacking functional IE genes ICP0 and ICP4 induced cytokine responses comparable to those of the wild-type viruses. The activation of transcription factors IRF-3 and NF-B was strongly augmented when macrophages were infected with the ICP27 mutant virus. Altogether, the results demonstrate that HSV-1 both induces and inhibits the antiviral response in human cells and that the type III IFN IL-29, together with IFN-, amplifies the antiviral response against the virus. It is further identified that viral IE-gene expression interferes with the antiviral response in human macrophages and ICP27 is identified as an important viral protein counteracting the early innate immune response.

Present address: Institute of Molecular Biology, University of Aarhus, DK-8000 Aarhus C, Denmark.

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