Herpes Simplex Virus Virion Host Shutoff ( vhs ) Activity Alters Periocular Disease in Mice

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The virion host shutoff (vhs) protein encoded by herpes simplex virus type 1 (HSV-1) destabilizes both viral and host mRNAs. An HSV-1 strain with a mutation in vhs is attenuated in virulence and induces immune responses in mice that are protective against corneal infection with virulent HSV-1, but it has the capacity to establish latency. Similarly, a replication-incompetent HSV-1 strain with a mutation in ICP8 elicits an immune response protective against corneal challenge, but it may be limited in viral antigen production. We hypothesized therefore that inactivation of vhs in an ICP8؊ virus would yield a replication-incompetent mutant with enhanced immunogenicity and protective capacity. ؊ mutant virus. The data indicate that inactivation of vhs in a replicationincompetent virus significantly enhances its protective efficacy while retaining its safety for potential human vaccination. Possible mechanisms of enhanced immunogenicity are discussed.Herpes simplex virus type 1 (HSV-1) is a common human pathogen, infecting approximately 80% of individuals by adulthood (49). The virus typically enters the body at epithelial and mucosal surfaces, where lytic infection of epithelial cells and fibroblasts leads to infection of sensory neurons innervating the mucosa and to the rapid establishment of latent infection in the neuronal cell bodies. In this latent reservoir, HSV infection is maintained for the life of the host. Either initial infection or reactivation can result in serious human disease, including rare but devastating encephalitis and keratitis, which is the second most common cause of nontraumatic corneal blindness (49). A vaccine to obviate or therapeutically alleviate these HSV-1-mediated diseases is a desirable goal.Development of an antiviral vaccine requires consideration of both safety and immunogenicity. An effective balance between these can be difficult to achieve, especially when faced with HSV that has a complex and persistent lifestyle. Immunization with live attenuated virus has the potential advantages of generating immune responses to a broad spectrum of viral proteins and induction of type 1 T-cell as well as humoral responses. In the development of prototypic live virus vaccines, several viral proteins that regulate host cell and viral synthetic processes have been manipulated to advantage. During infection, one of the earliest viral activities is that mediated by the virion host shutoff (vhs) protein, a product of the UL41 gene. This viral tegument component exerts its effects immediately upon entry into the cell, prior to viral gene expression (13,39). The vhs protein is associated with degradation of both cellular and viral mRNAs (24-26, 36, 39, 43) and endoribonucleolytic activity (9, 52), and the destabilization of viral messages mediated by vhs has been theorized to promote the switch from transcription of one kinetic class of viral genes to the next (43). We have previously shown that mice immunized with an HSV-1 strain that is deficient in vhs activity, UL41NHB, are significantly pro...

Section: ϫ 10contrasting

confidence: 42%

Disruption of Virion Host Shutoff Activity Improves the Immunogenicity and Protective Capacity of a Replication-Incompetent Herpes Simplex Virus Type 1 Vaccine Strain

Geiss

Smith

Leib

et al. 2000

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“…However, a caveat to this observation was that there was a 10-fold reduction in the HSV-2 challenge employed to infect mice compared to the HSV-1 challenge applied to the eye. In another study, an intertypic recombinant HSV-1 strain expressing the HSV-2 (strain 333) virion host shutoff (vhs) protein was found to elicit less blepharitis associated with increased clearance of the recombinant virus in comparison to the parental or marker-rescued virus following ocular infection (31). Since the HSV-2-encoded vhs protein displayed significantly greater activity than its HSV-1 counterpart in vitro, those authors concluded that vhs expression alters the host immune response to the pathogen, including the activation of T cells and the IFN pathway (31).…”

mentioning

confidence: 99%

Comparison of the Host Immune Response to Herpes Simplex Virus 1 (HSV-1) and HSV-2 at Two Different Mucosal Sites

Zheng

Conrady

Ward

et al. 2012

A study was undertaken to compare the host immune responses to herpes simplex virus 1 (HSV-1) and HSV-2 infection by the ocular or genital route in mice. Titers of HSV-2 from tissue samples were elevated regardless of the route of infection. The elevation in titers of HSV-2, including cell infiltration and cytokine/chemokine levels in the central nervous system relative to those found following HSV-1 infection, was correlative with inflammation. These results underscore a dichotomy between the host immune responses to closely related alphaherpesviruses.

“…Alternatively, the attenuation of HSV-1 and HSV-2 vhs null mutants within 24 to 48 h postinfection (47)(48)(49)(50) suggests a pivotal role for mediators of innate immunity in controlling acute infection. A key mediator of innate antiviral immunity to virus infection is the alpha/beta interferon (IFN-␣/␤) response.…”

mentioning

confidence: 99%

“…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)(49)(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).…”

mentioning

confidence: 99%

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

Murphy¹,

Duerst²,

Smith

et al. 2003

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109

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