Differences in Neurovirulence among Isolates of Herpes Simplex Virus Types 1 and 2 in Mice using Four Routes of Infection

During studies to determine a role for tumor necrosis factor (TNF) in herpes simplex virus type 1 (HSV-1) infection using TNF receptor null mutant mice, we discovered a genetic locus, closely linked to the TNF p55 receptor (Tnfrsf1a) gene on mouse chromosome 6 (c6), that determines resistance or susceptibility to HSV-1. We named this locus the herpes resistance locus, Hrl, and showed that it also mediates resistance to HSV-2. Hrl has at least two alleles, Hrl r , expressed by resistant strains like C57BL/6 (B6), and Hrl s , expressed by susceptible strains like 129S6 (129) and BALB/c. Although Hrl is inherited as an autosomal dominant gene, resistance to HSV-1 is strongly sex biased such that female mice are significantly more resistant than male mice. Analysis of backcrosses between resistant B6 and susceptible 129 mice revealed that a second locus, tentatively named the sex modifier locus, Sml, functions to augment resistance of female mice. Besides determining resistance, Hrl is one of several genes involved in the control of HSV-1 replication in the eye and ganglion. Remarkably, Hrl also affects reactivation of HSV-1, possibly by interaction with some unknown gene(s). We showed that Hrl is distinct from Cmv1, the gene that determines resistance to murine cytomegalovirus, which is encoded in the major NK cell complex just distal of p55 on c6. Hrl has been mapped to a roughly 5-centimorgan interval on c6, and current efforts are focused on obtaining a high-resolution map for Hrl.

Section: Vol 77 2003mentioning

confidence: 82%

A Locus on Mouse Chromosome 6 That Determines Resistance to Herpes Simplex Virus Also Influences Reactivation, While an Unlinked Locus Augments Resistance of Female Mice

Lundberg

Welander

Openshaw

et al. 2003

“…Previously published studies on the sequence variability of the glycoprotein B and D genes did not reveal mutations specific for HSV-1 DNA sequences amplified from cerebrospinal fluid samples from encephalitis patients (40,44). However, different reports have shown that clinical HSV-1 isolates differ in virulence when tested in animal models (3,11,37). Recently, Mao and Rosenthal (23) reported that neuroinvasiveness properties of different HSV-1 strains derived from different organs of a neonate were associated with genetic alterations, including tandem repeats within the ICP34.5 gene.…”

Section: Discussionmentioning

confidence: 99%

Phylogenetic Analysis of Clinical Herpes Simplex Virus Type 1 Isolates Identified Three Genetic Groups and Recombinant Viruses

Norberg

Bergström

Rekabdar

et al. 2004

148

192

Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen which establishes lifelong infections. In the present study, we determined the sequence diversity of the complete genes coding for glycoproteins G (gG), I (gI), and E (gE), comprising 2.3% of the HSV-1 genome and located within the unique short (US) region, for 28 clinical HSV-1 isolates inducing oral lesions, genital lesions, or encephalitis. Laboratory strains F and KOS321 were sequenced in parallel. Phylogenetic analysis, including analysis of laboratory strain 17 (GenBank), revealed that the sequences were separated into three genetic groups. The identification of different genogroups facilitated the detection of recombinant viruses by using specific nucleotide substitutions as recombination markers. Seven of the isolates and strain 17 displayed sequences consistent with intergenic recombination, and at least four isolates were intragenic recombinants. The observed frequency of recombination based on an analysis of a short stretch of the US region suggests that most full-length HSV-1 genomes consist of a mosaic of segments from different genetic groups. Polymorphic tandem repeat regions, consisting of two to eight blocks of 21 nucleotides in the gI gene and seven to eight repeats of 3 nucleotides in the gG gene, were also detected. Laboratory strain KOS321 displayed a frameshift mutation in the gI gene with a subsequent alteration of the deduced intracellular portion of the protein. The presence of polymorphic tandem repeat regions and the different genogroup identities can be used for molecular epidemiology studies and for further detection of recombination in the HSV-1 genome.The family Herpesviridae is a large family comprising at least 100 herpesviruses which are highly disseminated among animals. Eight human herpesviruses have been described, and molecular phylogenetic analysis has established three subfamilies (24). These three groups correspond to the current taxonomic classification based on biological properties and include the Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. Herpes simplex virus (HSV) belongs to the Alphaherpesvirinae and is classified in this subfamily on the basis of a wide host cell range, an efficient and rapid reproductive cell cycle, and the capacity to establish latency in the sensory ganglia (38).A major mechanism which upholds the accuracy of replication involves the 3Ј35Ј-exonuclease activity associated with DNA polymerases. Proofreading activity has been demonstrated for the HSV type 1 (HSV-1) DNA polymerase (1). In addition, it is likely that cellular repair mechanisms contribute to the stability of the virus genome. The overall mutation rate for HSV-1 has been estimated to be 3.5 ϫ 10 Ϫ8 mutations/site/ year (41), and the genome is therefore more stable than that described for RNA viruses (13, 18). Although genetic variations and classification into different genogroups have been described for other herpesviruses, such as varicella-zoster virus (31), Epstein-Barr virus (42), cytomegaloviru...

“…Studies have shown that the severity of HSV-1 ocular infections in animal models is influenced by three main factors; innate immunity, host immune response, and viral strain (12,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Several host gene mapping studies in mice have identified factors influencing the severity of general clinical disease (35), resistance and reactivation (25), mortality (12), encephalitis (36,37), and viral spread to the brain (38).…”

mentioning

confidence: 99%

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

Lee

Kolb

Larsen

et al. 2016

Herpes simplex virus 1 (HSV-1) most commonly causes recrudescent labial ulcers; however, it is also the leading cause of infectious blindness in developed countries. Previous research in animal models has demonstrated that the severity of HSV-1 ocular disease is influenced by three main factors: host innate immunity, host immune response, and viral strain. We have previously shown that mixed infection with two avirulent HSV-1 strains (OD4 and CJ994) results in recombinants with a wide range of ocular disease phenotype severity. Recently, we developed a quantitative trait locus (QTL)-based computational approach (vQTLmap) to identify viral single nucleotide polymorphisms (SNPs) predicted to influence the severity of the ocular disease phenotypes. We have now applied vQTLmap to identify HSV-1 SNPs associated with corneal neovascularization and mean peak percentage weight loss (MPWL) using 65 HSV-1 OD4-CJ994 recombinants. The vQTLmap analysis using Random Forest for neovascularization identified phenotypically meaningful nonsynonymous SNPs in the ICP4, UL41 (VHS), UL42, UL46 (VP11/ 12), UL47 (VP13/14), UL48 (VP22), US3, US4 (gG), US6 (gD), and US7 (gI) coding regions. The ICP4 gene was previously identified as a corneal neovascularization determinant, validating the vQTLmap method. Further analysis detected an epistatic interaction for neovascularization between a segment of the unique long (UL) region and a segment of the inverted repeat short (IRS)/unique short (US) region. Ridge regression was used to identify MPWL-associated nonsynonymous SNPs in the UL1 (gL), UL2, UL4, UL49 (VP22), UL50, and ICP4 coding regions. The data provide additional insights into virulence gene and epistatic interaction discovery in HSV-1. IMPORTANCEHerpes simplex virus 1 (HSV-1) typically causes recurrent cold sores; however, it is also the leading source of infectious blindness in developed countries. Corneal neovascularization is critical for the progression of blinding ocular disease, and weight loss is a measure of infection severity. Previous HSV-1 animal virulence studies have shown that the severity of ocular disease is partially due to the viral strain. In the current study, we used a recently described computational quantitative trait locus (QTL) approach in conjunction with 65 HSV-1 recombinants to identify viral single nucleotide polymorphisms (SNPs) involved in neovascularization and weight loss. Neovascularization SNPs were identified in the ICP4, VHS, UL42, VP11/12, VP13/14, VP22, gG, US3, gD, and gI genes. Further analysis revealed an epistatic interaction between the UL and US regions. MPWL-associated SNPs were detected in the UL1 (gL), UL2, UL4, VP22, UL50, and ICP4 genes. This approach will facilitate future HSV virulence studies. Herpes simplex virus 1 (HSV-1) is most commonly responsible for recurrent vesicular lesions of the oral mucosa; however, HSV-1 is increasingly found in genital infections, and it is the leading cause of infectious blindness and sporadic encephalitis in developed countries (1-4). The ...