Herpes Simplex Virus I UL41 Disarms Viperin’s Antiviral Function Via Its Endonuclease Activity

The innate immune system is the first line of defense for invading pathogens,among which interferon(interferon, IFN)-mediated antiviral innate immunity is the main form. Type I IFN(IFN- I) can be induced by viral infection in most types of cells,which then binds with specific receptors on the cell surface, and triggers expression of more than 300 kinds of interferon stimulated genes(IFN-stimulating gene, ISG).Viperin(virus inhibitory protein, endoplasmic reticulum associated, interferon inducible)is one of the ISGs which have been shown to have direct antiviral activity.Viperin is encoded by Cig5 gene and was initially identified in fibroblasts during cytomegalovirus(HCMV) infection. Subsequently, its m RNA sequence was officially named viperin. The constructive expression of viperin is low. However, IFN-I, poly(I:C)and lipopolysaccharide can strongly induce its expression. Besides HCMV, many DNA and RNA viruses can induce the expression of viperin and inhibit the replication of these viruses, including pseudo rabies virus(PRV), hepatitis C virus(HCV), influenza virus and dengue virus(DENV) and so on. Therefore, viperin has also been considered as an antiviral protein. However, the role of viperin in HSV-1(Herpes simplex virus type 1) replication has not been reported. We focus on the role of viperin in HSV-1infection and strategies utilized by HSV-1 to evade host antiviral innate immunity.Though viperin has been reported to antagonize a variety of DNA or RNA virus,viral replication and Western blotting(WB) experiments found that viperin had no effect on the wild-type(WT) HSV-1. HSV-1 UL41 protein was screened to reduce expression of viperin. Biochemical experiments showed that both WT HSV-1 infection and ectopically expressed UL41 degraded viperin m RNA, whereas ΔUL41 HSV-1 did not. Meanwhile, over-expressed viperin significantly inhibited ΔUL41 HSV-1replication, but exerted no effect on WT HSV-1 replication. RNA interference(RNAi)experiments showed that decreased expression of viperin in HEK293 T cells enhenced the replication of ΔUL41 HSV-1, but not WT HSV-1. Further experiments showed that over expression of viperin inhibited replication of ΔUL41 HSV-1, but not ΔUs11HSV-1. Collectively, these data have shown that HSV-1 evades the antiviral activity of viperin by degrading its m RNA through UL41 protein. The study identidy a novel mechanism that HSV-1 evades the host innate immunity and this will lay the theoretical foundations to develop new drugs and vaccines for prevention and treatment of HSV-1infection.