Herpes Simplex Virus 1 Tegument Protein UL41 Counteracts IFIT3 Antiviral Innate Immunity

In response to viral infection,secretion of type I interferon(IFN-I)is a key step in the host innate immune responses.The antiviral actions of IFN-I are embodied by the products of the IFN-stimulated genes(ISGs).Among these ISGs,the IFN-induced protein with tetratricopeptide repeats 3(IFIT3)has gained a great deal of attention due to its broad antiviral activity.IFIT3 was demonstrated to inhibit the replication of many DNA and RNA viruses,such as hepatitis B virus(HBV),Dengue virus(DV),vesicular stomatitis virus(VSV)and others.However,little is known about the function of IFIT3 upon herpes simplex virus 1(HSV-1)infection.This study focuses on the role of IFIT3 in HSV-1 infection and the underlying molecular mechanism applied by HSV-1 to dampen host antiviral responses via molecular biology and immunology techniques.In this study,we show for the first time that HSV-1 tegument protein UL41 plays an important role on inhibiting the antiviral activity of IFIT3.Here,our experiments demonstrated that ectopically expressed IFIT3 could restrict the replication of VSV,but had little effect on the replication of wild-type(WT)-HSV-1.Further study showed that WT HSV-1 infection down-regulated the expression of IFIT3,and ectopic expression of UL41,but not the immediate early protein ICP0,notably reduced the expression of IFIT3.The underlying molecular mechanism was that UL41 diminished the accumulation of IFIT3 mRNA to abrogate its antiviral activity.In addition,our results illustrated that ectopic expression or stably knockdown of IFIT3 inhibited or facilitated the replication of UL41-null mutant virus(R2621),respectively.Our data also suggested that stably knockdown of IFIT3 failed to affect the replication of WT HSV-1.Taken these findings together,HSV-1 was shown for the first time to counteract the antiviral function of IFIT3 via UL41,revealing a strategy by which HSV-1 evades host innate immunity.