Characterization of a virulence determinant of herpes simplex virus type 1
Herpes Simplex Virus Type 1 (HSV-1) is a ubiquitous human pathogen that establishes lifelong latent infections in the nervous system. HSV-1 encephalitis is a rare, but severe, complication that can develop from either a primary infection or a reactivated latent infection. We investigated the pathogenesis of HSV-1 encephalitis in a mouse model. HSV-1 strain HFEM induces a fatal encephalitis in mice inoculated intracerebrally; however, mice infected peripherally do not develop encephalitis. We compared pathogenesis in mice infected intraperitoneally with strain HFEM or an encephalogenic HSV-1 strain (strain F). No significant differences were observed in the tropism of strains F and HFEM; however, strain HFEM did not spread as efficiently to visceral organs and was not detected in the brain. Additionally, infection with strain HFEM was cleared more rapidly than strain F infection, suggesting that strain HFEM may be more susceptible to host defenses. The avirulence of strain HFEM is a consequence of a deletion in its genome; repair of the deletion imparts peripheral virulence to the virus. The HFEM deletion precludes UL56 gene expression, and alters expression from the UL55 and ICP27 genes. We investigated whether UL55 or UL56 gene expression was required for peripheral virulence by constructing recombinant HSV-1 strains in which these genes had been inactivated by insertion mutagenesis. Both recombinant strains were virulent in mice inoculated intraperitoneally, therefore, UL55 and UL56 gene expression is not critical for virulence. We hypothesize that the avirulent phenotype of strain HFEM may be due to altered expression of the ICP27 gene. The HFEM deletion may alter ICP27 gene expression by removing an undefined enhancer element or by permitting readthrough transcription and antisense regulation by the ICP0 gene. Strains F and HFEM were investigated for their potential application as vectors for gene replacement in the nervous system. Recombinant viruses were constructed with human HPRT cDNA regulated by an HSV-1 promoter (LAT) that is active during latent infections. The recombinant viruses expressed chimeric LAT-HPRT RNA, however, functional HPRT was not detected. The signals required for processing and translation of HPRT RNA in HSV-1 infected cells have not been established.
Nash, Therese Carol, "Characterization of a virulence determinant of herpes simplex virus type 1" (1992). Dissertations available from ProQuest. AAI9308635.