Inferred father-to-son transmission of herpes simplex virus results in near-perfect preservation of viral genome identity and in vivo phenotypes.

High throughout sequencing has provided an unprecedented view of the circulating diversity of all classes of human herpesviruses. For herpes simplex virus 1 (HSV-1), we and others have previously published data demonstrating sequence diversity between hosts. However the extent of variation during transmission events, or in one host over years of chronic infection, remain unknown. Here we present an initial example of full characterization of viruses isolated from a father to son transmission event. The likely occasion of transmission occurred 17 years before the strains were isolated, enabling a first view of the degree of virus conservation after decades of recurrences, including transmission and adaptation to a new host. We have characterized the pathogenicity of these strains in a mouse ocular model of infection, and sequenced the full viral genomes. Surprisingly, we find that these two viruses have preserved their phenotype and genotype nearly perfectly during inferred transmission from father to son, and during nearly two decades of episodes of recurrent disease in each human host. Given the close genetic relationship of these two hosts, it remains to be seen whether or not this conservation of sequence will occur during non-familial transmission events.

Queratouveítis herpética bilateral en paciente inmunocompetente / Bilateral herpetic keratouveitis in an immunocompetent patient

CASO CLÍNICO: Se presenta el caso de un varón inmunocompetente que acude a nuestro servicio con escleritis adyacente a limbo y queratitis intersticial en ojo izquierdo. A los pocos días se observa nueva úlcera de aspecto dendritiforme en ojo derecho y empeoramiento bilateral progresivo hasta presentar uveítis granulomatosa en ambos ojos. En el estudio etiológico destacan títulos positivos de IgM para virus herpes simple en suero. DISCUSIÓN: Ante un cuadro de queratouveítis bilateral de tórpida evolución con tratamiento convencional, es necesario descartar el origen herpético debido a las diferentes presentaciones de este virus

CASE REPORT: We report the case of an immunocompetent male who presented with a limbal-adjacent scleritis and interstitial keratitis in the left eye. A few days later a new dendritiform ulcer in his right eye and bilateral progressive worsening with granulomatous uveitis in both eyes were observed. A thorough review of systems revealed positive serum IgM titles for herpes simplex virus. DISCUSSION: In the context of a bilateral keratouveitis refractory to conventional treatment it is mandatory to rule out the herpetic origin based on the different forms of clinical presentation of this virus

[Ping-pong transmission of herpes simplex virus 1 following corneal transplantation]. / Ping-Pong-Transmission von Herpes-simplex-Virus 1 nach Hornhauttransplantation.

BACKGROUND: Primary corneal graft failure (PCGF) after penetrating keratoplasty (PKP) despite good endothelial cell count of the transplant in organ culture rarely occurs in young patients. A herpes simplex virus type I (HSV-1) infection (transmission through the donor or reactivation by the patient) can lead to PCGF. METHODS: We report on a 43-year-old man with pellucid marginal corneal degeneration and neurodermitis, who was underwent penetrating keratoplasty (PKP) on the left eye after acute corneal hydrops in both eyes. A repeat keratoplasty (re-PKP) had to be performed 15 days after the first PKP due to a primary graft failure. A re-re-PKP with simultaneous amniotic membrane transplantation (as a patch) and partial lateral tarsorrhaphy became necessary 4 months after the re-PKP due to melting on the edge of the graft with persistent epithelial defects. RESULTS: After intensive cooperation between ophthalmologists and pathologists the histopathological findings showed keratocytes which reacted immunohistochemically positive for HSV-1 antigens in the deep corneal stroma of both corneal grafts. The excised own cornea of the patient was histopathologically negative but the DNA-PCR for HSV-1 was weakly positive. After adequate topical and systemic antiviral therapy the third graft has remained clear for 12 months. CONCLUSION: In cases of PCGF after normal risk corneal transplantation the possibility of HSV infection should always be considered. After confirmation of the diagnosis with the help of the immunohistochemical tests and/or PCR, an adequate treatment with antiviral medication (acyclovir tablets 2 × 400 mg for more than 1 year) should be administered to the patient after repeat PKP.

A case series: herpes simplex virus as an occupational hazard.

STATEMENT OF THE PROBLEM: Herpes labialis infections are common and present a serious risk to the dental team. PURPOSE OF THE STUDY: The purpose is to make dentists aware of the risks involved with treatment of patients with active herpes labialis. In addition, evidence-based risk-management strategies are presented. METHODS AND MATERIALS: The incidence and natural history of herpes simplex virus type 1 (HSV-1) are reviewed. Four previously unreported case histories are presented to illustrate the impact common sequelae of HSV-1 can have on the dental team. The differences between HSV-1 and the blood-borne diseases which are the focus of universal precautions are discussed. In particular, the highly contagious, highly transmissible nature of HSV-1 and its transmission through aerosols are highlighted. Finally, the need to include protection against aerosols in the profession's understanding of universal precautions is noted. RESULTS: The authors suggest limiting the treatment of patients with active lesions to urgent care only, and treating active HSV-1 lesions to reduce time of healing. For four common clinical situations involving HSV-1 infections, evidence-based methods for protecting the dental team and the patient from cross-contamination are also presented. CONCLUSION: While it is clear that the treatment of patients with active herpes labialis lesions increases risk of cross-infection, there are good protocols for controlling this risk. CLINICAL SIGNIFICANCE: By bringing common vectors of cross-infection to light and providing evidence-based protocols for preventing them, this article provides practitioners with positive steps that can be taken for controlling the risk of spreading herpes infections to the dental team.

Characterization of a UL49-null mutant: VP22 of herpes simplex virus type 1 facilitates viral spread in cultured cells and the mouse cornea.

Herpes simplex virus type 1 (HSV-1) virions, like those of all herpesviruses, contain a proteinaceous layer termed the tegument that lies between the nucleocapsid and viral envelope. The HSV-1 tegument is composed of at least 20 different viral proteins of various stoichiometries. VP22, the product of the U(L)49 gene, is one of the most abundant tegument proteins and is conserved among the alphaherpesviruses. Although a number of interesting biological properties have been attributed to VP22, its role in HSV-1 infection is not well understood. In the present study we have generated both a U(L)49-null virus and its genetic repair and characterized their growth in both cultured cells and the mouse cornea. While single-step growth analyses indicated that VP22 is dispensable for virus replication at high multiplicities of infection (MOIs), analyses of plaque morphology and intra- and extracellular multistep growth identified a role for VP22 in viral spread during HSV-1 infection at low MOIs. Specifically, VP22 was not required for either virion infectivity or cell-cell spread but was required for accumulation of extracellular virus to wild-type levels. We found that the absence of VP22 also affected virion composition. Intracellular virions generated by the U(L)49-null virus contained reduced amounts of ICP0 and glycoproteins E and D compared to those generated by the wild-type and U(L)49-repaired viruses. In addition, viral spread in the mouse cornea was significantly reduced upon infection with the U(L)49-null virus compared to infection with the wild-type and U(L)49-repaired viruses, identifying a role for VP22 in viral spread in vivo as well as in vitro.

Herpes simplex virus: an occupational hazard in dentistry.

Approximately 70% of the population in the western world become infected with the herpes simplex virus type 1 (HSV-1) by the second decade of life. This review discusses the role of the HSV-1 as a potential occupational hazard for dental workers, focusing on herpes labialis, herpetic whitlow and keratitis. The risks associated with the dental treatment of patients with HSV-1, both from the perspective of the clinician and the patient are presented. Procedures for minimising the impact of HSV-1 within the dental practice, in particular infection control, delivery of treatment and patient education, are addressed. The management options for recurrent herpes labialis are also reviewed.

Herpes simplex virus DNA in corneal transplants: prospective study of 38 recipients.

Herpes simplex virus (HSV) infection of the eye can induce epithelial and stromal keratitis and may also lead to postoperative endothelial failure in keratoplasty. Clinical symptoms and/or virus culture of corneal scrapings most frequently provide the basis for diagnosis of ocular HSV infection, and although HSV DNA has been shown to be present in the cornea, its role in success or failure of corneal grafts remains unclear. In this study, a PCR assay was used to detect HSV DNA in corneal buttons of 38 corneal graft recipients and in donor scleral remnants, retaining one-half of each sample for subsequent viral isolation. Recipients were followed up clinically for a period of 6 months after keratoplasty. All recipients but three were found to be HSV seropositive. Eight recipient corneal buttons contained detectable HSV DNA (7 HSV-1, 1 HSV-2, the latter case confirmed by viral culture). Two donor corneas were found positive for HSV-1 DNA, with negative cultures, and endothelial graft failure occurred in one of the matching recipients after 4 months. One recipient with no history of herpes contracted herpetic keratitis 4 months after keratoplasty, even though the corneal button and donor scleral remnants contained no detectable HSV DNA. The study confirms previous observations of HSV DNA in the corneal tissue of HSV seropositive patients apparently unrelated to any clinical manifestation of herpes infection. However, as demonstrated by culture, HSV remains infectious and may therefore induce donor-to-host infection in corneal recipients.

Reactivation and donor-host transmission of herpes simplex virus after corneal transplantation.

PURPOSE: To review our previous studies regarding herpes simplex virus type 1 (HSV-1) corneal latency in the rabbit lamellar keratoplasty (LK) and penetrating keratoplasty (PKP) models. METHODS: Rabbits latently infected with HSV- I received allografts from naive rabbits, and naive rabbits received grafts from rabbits latently infected with HSV-1. In rabbits undergoing LK, viral shedding in tear film and the occurrence of herpetic lesions were investigated for 7 days after operation. In rabbits undergoing PKP, latency-associated transcript (LAT)-positive and -negative HSV- I mutants were used to establish latency. Ninety days after PKP, reactivation of HSV-1 was induced by transcorneal iontophoresis of epinephrine. Viral shedding was then assessed by tear-film swabbing. Donor corneal buttons, recipient corneal rims, and corresponding trigeminal ganglia were analyzed for HSV DNA concentration and viral transcription. RESULTS: In rabbits undergoing LK, the occurrence of positive tear-film cultures and number of days on which corneal epithelial lesions were observed were significantly higher in the operated eyes of latently infected rabbits as compared with controls. In rabbits undergoing PKP, HSV- I could transmit between host and donor tissues both in anterograde and retrograde fashion. LAT-positive virus had a significantly greater ability to transmit. Higher concentrations of HSV DNA detected in cornea and trigeminal ganglia correlated with active viral transcription and higher percentage of viral shedding. CONCLUSION: Corneas from latently infected rabbits contain HSV-1 DNA that can replicate and transmit after induced reactivation. Our studies provide further evidence for corneal latency of this virus.

Herpes simplex virus 1 transmission through corneal transplantation.

Genetic characterisation of herpes simplex virus type 1 (HSV-1) DNA isolated from a donor cornea before and after corneal transplantation demonstrated the transmission of HSV-1 through transplantation. This study is the first to provide conclusive evidence for the transmission of HSV-1 by penetrating keratoplasty with subsequent reactivation of donor-derived HSV-1 in the transplanted cornea.

Herpes simplex virus epidemiology and ocular importance.

PURPOSE: To review the changing epidemiology of herpes simplex disease and correlate it with the epidemiology of ocular herpes simplex disease. METHOD: A review of pertinent reports in the world literature about the epidemiology of herpes simplex and specifically about ocular herpes simplex. RESULTS: In developed countries, many individuals are reaching adolescence and adulthood without prior herpesvirus infection. Herpes simplex genital infection is increasing at a rapid rate in sexually active adolescents and adults, with about one in six adults now infected in the United States. Similar statistics are confirmatory worldwide in developed countries. Active herpes simplex infection is a risk factor for acquisition of human immunodeficiency virus. The Herpetic Eye Disease Study, as well as prior studies from Moorfields Eye Hospital and the Mayo Clinic in Rochester, Minnesota, provides us with the epidemiology of ocular herpes simplex. Recent studies suggest an older age of onset and perhaps overall more severe ocular disease as compared with the older literature. CONCLUSIONS: Herpes simplex is a significant health concern at present with genital infections increasing in epidemic proportions. This is also reflected in a rise in the incidence of neonatal herpes. Herpes simplex virus type 1 (HSV-1) infection is being acquired for the first time in an older age group. A significant and increasing proportion of genital herpes is caused by HSV-1. Serologic studies are no longer as useful in distinguishing orofacial herpes from genital herpes. More acute retinal necrosis syndrome cases are associated with HSV-2. Speculation about the future of ocular herpes is made based on this changing epidemiology.

Corneal donor infection by herpes simplex virus: herpes simplex virus DNA in donor corneas.

Three corneoscleral discs (from two donors) underwent subtotal endothelial loss during routine "long-term" organ culture storage. Laboratory studies of these corneas revealed evidence of herpes simplex virus (HSV) infection. The fellow cornea from one of the donors had been issued for transplant to a patient with keratoconus. Deterioration of the graft was noted 5 days after surgery; the disc was removed at 2 months and was shown to be infected with HSV. In an experiment designed to simulate initial "cleansing" of donor globes, 0.1% polyvinylpyrolidone-iodine protected cells from infection with HSV. It was concluded that the detection of HSV in these corneas could not be explained by external contamination of the ocular surface. Furthermore, culture of conjunctival and pharangeal swabs taken from 47 consecutive donors confirmed that HSV is rarely isolated at or around the time of death. Five pairs of donor corneas destined for use in transplantation were selected at random and investigated for the presence of HSV. HSV DNA was detected by polymerase chain reaction (PCR) in tissue from two of the corneal donors. Sequential stepwise sectioning suggested that HSV DNA when present was distributed in discrete foci within the cornea. These observations suggest that HSV infection may be a cause of severe endothelial loss during corneal organ culture and possibly provide an explanation for some "failures" of corneal grafting.

Non-traumatic acquisition of herpes simplex virus infection through the eye.

Primary ocular herpes is usually seen as a follicular conjunctivitis and blepharitis, with or without involvement of the cornea. It is unknown, however, to what extent asymptomatic and/or subclinical primary disease occurs, and whether primary ocular herpes follows direct droplet spread to the eye. Previous models of murine ocular herpes have used trauma (scarification) to introduce virus into the cornea, producing disease which results in significant corneal scarring. To mimic a likely route of infection in humans, a droplet containing virus was placed on the mouse eye and clinical disease recorded. At least 1 month after inoculation, serum was assayed for neutralising antibodies and the cornea, iris, and trigeminal ganglion were investigated for evidence of herpes simplex virus type 1, by cocultivation and the polymerase chain reaction. Some animals showed a severe ulcerative blepharitis with little to no involvement of the cornea, while disease was undetectable in others. The development of disease depended on the dose and strain of virus and age of the animal, with older mice appearing more resistant. Virus was isolated from the trigeminal ganglion of younger animals inoculated with higher doses of virus, after 21 days in culture, suggesting that latency had been established. Neutralising antibodies were present in most mice irrespective of the presence of recognisable clinical disease. Using primers for the thymidine kinase and glycoprotein C regions of the viral genome, herpes simplex virus type 1 DNA was found in the cornea, iris, and trigeminal ganglion of most animals and showed a good correlation with the presence of neutralising antibodies. It would thus appear that herpes simplex virus type 1 is able to accede into the cornea, iris, and trigeminal ganglion following nontraumatic application of virus onto the mouse eye. This model mimics primary ocular disease in humans and may be useful for studies on recurrent disease and the spread of ocular herpes.

Anterograde transport of HSV-1 and HSV-2 in the visual system.

The anterograde spread of herpesvirus in the visual system subsequent to retinitis has been observed clinically. We compared the ability of two well-studied Herpes simplex virus (HSV) strains to be transported in the anterograde direction in the hamster visual system: strain McIntyre, representing HSV-1, and strain 186, representing HSV-2. Intravitreal injection of HSV-2 labeled more retinorecipient neurons than did HSV-1, suggesting important type differences in the ability of HSV to infect retinorecipient neurons after intravitreal injection. The most likely explanation for our results is that HSV-2 is more efficiently adsorbed than HSV-1 in the retinal ganglion cells. Our results also suggest that HSV may be useful as an anterograde transneuronal tracer for neuroanatomical studies of the visual system.

Transmission of herpes simplex virus infection via lacrimal canaliculi.

We analyzed the differentiation of two strains isolated from the conjunctiva and rhinorrhea of a patient with herpetic keratitis by the restriction endonuclease digestion method of herpes simplex virus (HSV) DNA. As a result two strains were identified as the same one. This result suggests that HSV contained in tears flows into the nasal cavity via the lacrimal canaliculi.