Herpes Simplex Virus Type 2 Virion Host Shutoff Protein Regulates Alpha/Beta Interferon but Not Adaptive Immune Responses during Primary Infection In Vivo

Abstract

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are ubiquitous human pathogens that cause a variety of serious diseases. Primary HSV infections typically initiate at mucosal surfaces, where lytic replication in epithelial cells generates mucosal lesions. Peripheral replication amplifies the virus load and increases uptake of virus into sensory nerve termini. Establishment of latent infections in sensory neurons secures shelter for the virus throughout the life of the host. Periodic reactivations result in disease recurrence and provide an opportunity for transmission to new hosts.The virion host shutoff (vhs) protein of HSV plays a significant role in promoting pathogenesis at the cell and organismal levels. In the infected cell, vhs possesses both endo-and exonuclease activity (8, 9, 57) and mediates the rapid shutoff of protein synthesis via degradation of both cellular and viral mRNAs (22,23,39,43). As a component of the virion tegument, vhs is released directly into the cytosol and can immediately exert its effects on the newly infected cell. Cellular mRNAs are almost completely degraded within 6 h of infection with HSV-1, and within just 2 h by HSV-2 (19). The activity of HSV-2 vhs is also approximately 40-fold stronger than that of HSV-1 (10, 11). In vivo, vhs null mutants of HSV-1 and HSV-2 are profoundly attenuated, implicating vhs as a virulence factor that helps HSV establish robust infection. HSV-1 lacking vhs activity replicates to 1,000-fold-lower titers in the cornea, trigeminal ganglia, and brain of mice than wildtype virus and has impaired capacity to enter the central nervous system, establish latency, and undergo reactivation (48-50). vhs-deficient HSV-2 strains (333-vhsB or 333d41) also replicate much less efficiently than wild-type virus in the genital mucosa and nervous tissue of mice and cause less disease (47). vhs has been implicated in down-regulating major histocompatibility complex (MHC) class I (18, 54) and class II (55) molecules. This activity has functional implications because it is associated with reduced cytotoxic T-lymphocyte recognition

Herpes Simplex Virus Virion Host Shutoff Protein: Immune Evasion Mediated by a Viral RNase?

“…However, the effect is not as striking as would have been expected if the interferon response were the main target of vhs. In contrast, recent studies by Murphy et al (38) demonstrate that the virulence of HSV-2 vhs mutants is almost fully restored in these mutant mice. The effect is specific to vhs, as the host mutation did not restore virulence to an HSV-2 mutant lacking thymidine kinase.…”

HSV ICP0 recruits USP7 to modulate TLR-mediated innate response

“…12,13 The multiplicity of pattern recognition receptors (PRRs) detecting HSV necessitates a robust ability of the virus to effectively block multiple innate signaling pathways to survive. Previous studies identified several HSVencoded mechanisms that interfere with antiviral host immunity including nonspecific degradation of host mRNA by the RNAse VHS, 14 inhibition of PKR by US11 15 and ␥34.5, 16 inhibition of MHC-I peptide loading by ICP47, 17,18 and suppression of interferon response by ICP0. 19,20 However, to date, no HSV-encoded protein has been shown to interfere with TLR responses.…”

Depletion of T Cells by Type I Interferon: Differences between Young and Aged Mice

“…IFN-␣␤ is induced quickly and efficiently in many types of cells upon infection by various viruses (12,13), and limits virus replication by establishing an antiviral state in uninfected cells (14). Mice deficient in IFN-␣␤ receptor (IFN-␣␤R) are much more susceptible to viral infection (15,16); replication and virulence of profoundly attenuated viruses are largely restored to levels of wild-type virus in mice lacking the IFN-␣␤R (17).…”