Herpes simplex virus type 1 (HSV-1) UL56 gene is involved in viral intraperitoneal pathogenicity to immunocompetent mice

Abstract

A comparison of the pathogenicity in mice of the recombinant herpes simplex virus type 1 (HSV-1) strain HSV-1-M-LacZ, in which the UL56 gene has been deleted, was made with its parental strain F, following infection in different mouse strains. The polymerase chain reaction (PCR) technique was used to study the migration of virus DNA in the mouse model. Tissues from adult mice infected intraperitoneally (IP) with one of three HSV-1 strains (F, HFEM or HSV-1-LacZ) were examined for the presence of viral DNA. DNA of the pathogenic strain F was detected in the adrenal glands, spinal cord, brain, liver and pancreas. DNA of HSV-1-M-LacZ was detected in the same tissues. However, DNA of the apathogenic strain HFEM was detected transiently (on days 2 and 3 p.i., but not days 1, 5 or 7), only in the adrenal glands and no viral DNA was detected in any of the other tissues. HSV-1 pathogenic strains injected intraperitoneally into newborn mice (7 days old) killed most of the mice. In the surviving mice viral DNA of the three virus strains was found in peritoneal exudate cells (PEC), adrenal glands, spinal cord, liver and spleen. It was found that HSV-1-M-LacZ, which lacks the UL56 gene, resembled in pathogenicity to the newborn mice the pathogenic HSV-1 strains F and KOS. The PCR technique was used to trace viral DNA in tissues of the mice which survived HSV-1 infection at 7 weeks of age. Only HSV-1 (KOS) DNA was detected in the pancreas. The brains of these mice did not contain viral DNA. It is suggested that HSV-1 DNA may reside in surviving HSV-1- infected newborn mice in a "latent" state in nonneural tissues.

Evolution and Diversity in Human Herpes Simplex Virus Genomes

“…Culturing a virus necessarily removes a variety of selection pressures and bottlenecks present in vivo and introduces new selection pressures unique to cell growth in vitro. The HFMs and deletions described above are very likely to be deleterious for virus spread in humans (95)(96)(97)(98)(99)(121)(122)(123)(124)(125)(126)(127). This is likewise true for frameshifts and deletions recognized in previously sequenced strains (e.g., US9 in KOS or glycoprotein N [UL49.5] and UL56 in HF10) (47,135).…”

“…3C). These genes are not required for growth in vitro, but UL56 appears to be important for virulence and the establishment of latency in vivo (95)(96)(97)(98)(99). Deletions in one or both of these genes have been noted in two attenuated strains, namely, HF10, which harbors a deletion in UL56 and a homopolymer-based frameshift in UL55 (47), and HFEM, where restoration of the UL56 gene restored virulence in vivo (97,99).…”

Herpes Simplex Virus Type 2 UL56 Interacts with the Ubiquitin Ligase Nedd4 and Increases Its Ubiquitination

“…GenBank database [http://www.ncbi.nlm.nih.gov/Genbank/index .html] accession number NC_001847) and has been shown to play an important role in HSV type 1 (HSV-1) pathogenicity in vivo. UL56-deficient HSV-1 mutants are substantially less neuroinvasive (4,58), although little is known molecularly about how this attenuation occurs. HSV-2 UL56 is a 235-amino-acid, C-terminally anchored, type II membrane protein (39) that is predicted to be inserted into the viral envelope so that the N-terminal domain is located in the virion tegument.…”

Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte–macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus

“…UL56 associates with the kinesin motor protein KIF1A, and the absence of UL56 causes decreased pathogenicity without affecting viral replication in tissue culture. [44][45][46] Thus, the lack of UL56 may be responsible for the attenuated nature of HF10.…”