Herpes simplex virus type 1 mutants containing the KOS strain ICP34.5 gene in place of the McKrae ICP34.5 gene have McKrae-like spontaneous reactivation but non-McKrae-like virulence

Perng, Guey Chuen; Mott, Kevin R.; Osório, Nelson; Yukht, Ada; Salina, Susan; Nguyen, Quynh-Hoa; Nesburn, Anthony B.; Wechsler, Steven L.

doi:10.1099/0022-1317-83-12-2933

Cited by 28 publications

(23 citation statements)

References 25 publications

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“…However, weight loss, mortality, lesion scores, and neurological scores remained consistent with no significant differences between the genotypes. WT mice with the highly virulent HSV-1 strain McKrae (HSV-1/ McKrae), originally isolated from a patient with ocular herpes (25,26), and monitored them for at least 21 d. Similar to other HSV-1 strains tested, titers of eye swabs from HVEM KO mice were significantly lower than those from WT mice (Fig. 4A).…”

Section: Hsv-2 Causes Severe Disease In Both Wt and Hvem Ko Mice Follmentioning

confidence: 93%

Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes

Karaba

Kopp

Longnecker

2012

Proc. Natl. Acad. Sci. U.S.A.

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Infection with herpes simplex virus type 1 (HSV-1) and HSV-2 is initiated by viral glycoprotein D (gD) binding to a receptor on the host cell. Two receptors, herpesvirus entry mediator (HVEM) and nectin-1, mediate entry in murine models of HSV-1 and HSV-2. HVEM is dispensable for HSV-2 infection of the vagina and brain, but is required for WT pathogenesis of HSV-1 infection of the cornea. By challenging WT and HVEM KO mice with multiple strains of HSV-1 and HSV-2, we demonstrate that without HVEM, all HSV-1 strains tested do not replicate well in the cornea and infection does not result in severe symptoms, as observed in WT mice. In contrast, all HSV-2 strains tested had no requirement for HVEM to replicate to WT levels in the cornea and still cause severe disease. These findings imply that HSV-2 does not require HVEM to cause disease regardless of route of entry, but HVEM must be present for HSV-1 to cause full pathogenesis in the eye. These findings uncover a unique role for HVEM in mediating HSV-1 infection in an area innervated by the trigeminal ganglion and may explain why the presence of HVEM can lead to severe inflammation in the cornea. Thus, the dependence on HVEM is a dividing point between HSV-1 and HSV-2 that evolved to infect areas innervated by different sensory ganglia.herpes stromal keratitis | viral pathogenesis | viral eye disease | eye infection H erpes simplex virus type 1 (HSV-1) and HSV-2 are common human pathogens with over 50% of United States adults seropositive for HSV-1 and over 15% seropositive for HSV-2 (1). Typically, HSV-1 is responsible for oral infections and HSV-2 is the cause of genital infections, but this division is becoming less distinct (2-4). Severe outcomes caused by both serotypes include encephalitis, stromal keratitis, and meningitis (4, 5). Importantly, HSV-1 remains a significant cause of ocular morbidity and blindness despite the availability of the antiviral drug, acyclovir (6, 7).Herpes infection begins when the viral envelope fuses with a host cell membrane. This process is dependent on envelope glycoprotein D (gD) binding to one of its receptors. The gDreceptor binding event triggers glycoproteins gB, gH, and gL to execute fusion by a yet unknown mechanism (8). The known gD receptors include: herpesvirus entry mediator (HVEM) (9), nectin-1 (10), nectin-2 (11), and 3-O-sulfated-heparan sulfate (3-O-S-HS) (12). Of these receptors, HVEM and nectin-1 have proven important in in vivo murine models of HSV infection (13-15). HVEM is a member of the TNF receptor superfamily and participates in a wide variety of cellular and physiological functions, including apoptosis (16) and immune cell signaling (17). Nectin-1 is a member of the Ig superfamily and functions in cell-cell adhesion (18).The importance of HVEM and nectin-1 in mediating HSV infection in vivo was demonstrated by the use of KO mice. HSV-2 vaginal infection was completely prevented in HVEM/nectin-1 double-KO mice. Interestingly, the absence of HVEM alone was not protective in the vaginal model of HSV-2 infe...

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Section: Hsv-2 Causes Severe Disease In Both Wt and Hvem Ko Mice Follmentioning

confidence: 93%

Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes

Karaba

Kopp

Longnecker

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The phenotypes produced by HSV-1 infection in mouse models are affected by the strain of virus and mouse as well as the gender and age of the animals (17,27,29,44). Our previous studies have shown that replication of the reporter virus and wild-type strain KOS are essentially identical in cultured Vero cells and outbred CD-1 mice (39,40).…”

Section: Discussionmentioning

confidence: 99%

Bioluminescence Imaging Reveals Systemic Dissemination of Herpes Simplex Virus Type 1 in the Absence of Interferon Receptors

Luker

Prior

Song

et al. 2003

J Virol

112

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Herpes simplex virus type 1 (HSV-1) can produce disseminated, systemic infection in neonates and patients with AIDS or other immunocompromising diseases, resulting in significant morbidity and mortality in spite of antiviral therapy. Components of host immunity that normally limit HSV-1 to localized epithelial and neuronal infection remain incompletely defined. We used in vivo bioluminescence imaging to determine effects of type I and II interferons (IFNs) on replication and tropism of HSV-1 infection in mice with genetic deficiency of type I, type II, or both type I and II IFN receptors. Following footpad or ocular infection of mice lacking type I IFN receptors, HSV-1 spread to parenchymal organs, including lung, liver, spleen, and regional lymph nodes, but mice survived. Deletion of type I and II IFN receptors produced quantitatively greatest and most widespread dissemination of virus to visceral organs and the nervous system, and these mice invariably died after ocular or footpad infection. Type II receptor knockout and wild-type mice had comparable viral replication and localization, with no systemic spread of HSV-1 or lethality. Therefore, while isolated deficiency of type II IFN receptors did not affect pathogenesis, loss of these receptors in combination with genetic deletion of type I receptors had a profound effect on susceptibility to HSV-1. These data demonstrate different effects of type I and II IFNs in limiting systemic dissemination of HSV-1 and further validate the use of bioluminescence imaging for studies of viral pathogenesis.

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“…Given that the increased virulence of HSV-1 strains such as McKrae correlates with an increased resistance to IFN-␣/␤ (56), it would be of interest to determine if the virulence of HSV-1 strain McKrae maps to the interferon resistance locus of HSV-1 that is formed by the adjacent ICP0 and ICP34.5 genes (20,36,37). Although there are some data to support this hypothesis (42), a rigorous analysis remains to be done.…”

Section: Discussionmentioning

confidence: 99%

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

Halford

Balliet

Gebhardt

2004

J Virol

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It is often stated that individuals of a species can differ significantly in their innate resistance to infection with herpes simplex virus type 1 (HSV-1). Three decades ago Lopez reported that C57BL/6 mice could survive a 5,000-fold-higher inoculum of HSV-1 given intraperitoneally than mice of the A or BALB/c strain (Nature 258:152-153, 1975). Susceptible strains of mice died of encephalitis-like symptoms, suggesting that viral spread to the central nervous system was the cause of death. Although Lopez's study documented that C57BL/6 mice were resistant to the development of HSV-1 encephalitis and mortality, the resistance of C57BL/6 mice to other steps of the HSV-1 infection process was not assessed. The results of the present study extend these observations to clarify the difference between resistance to (i) HSV-1 pathogenesis, (ii) HSV-1 replication, (iii) HSV-1 spread, and (iv) the establishment of latent HSV-1 infection. Although C57BL/6 mice are more resistant to HSV-1 pathogenesis than BALB/c mice, the results of the present study establish that HSV-1 enters, replicates, spreads, and establishes latent infections with virtually identical efficiencies in C57BL/6 and BALB/c mice. These observations raise questions about the validity of the inference that differences in natural resistance are relevant in explaining what differentiates humans with recurrent herpetic disease from the vast majority of asymptomatic carriers of HSV-1 and HSV-2.

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Herpes simplex virus type 1 mutants containing the KOS strain ICP34.5 gene in place of the McKrae ICP34.5 gene have McKrae-like spontaneous reactivation but non-McKrae-like virulence

Abstract: Herpes simplex virus type 1 (HSV-1) strain McKrae is neurovirulent in rabbits infected

Cited by 28 publications

References 25 publications

Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes

Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes

Bioluminescence Imaging Reveals Systemic Dissemination of Herpes Simplex Virus Type 1 in the Absence of Interferon Receptors

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

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