ORF36 protein kinase of Kaposi's sarcoma herpes simplex virus activates the c-Jun N-terminal kinase signaling pathway.

alpha-, beta-, and gamma-Herpesviruses encode putative viral protein kinases. The herpes simplex virus UL13, varicella-zoster virus ORF47, and Epstein-Barr virus BGLF4 genes all show protein kinase domains in their protein sequences. Mutational analysis of these herpes simplex viruses demonstrated that the viral kinase is important for optimal virus growth. Previous studies have shown that ORF36 of Kaposi's sarcoma herpes simplex virus (KSHV) has protein kinase activity and is autophosphorylated on serine. The gene for ORF36 is expressed during lytic growth of the virus and has been classified as a late gene. Inspection of the ORF36 sequence indicated potential motifs that could be involved in activation of cellular transcription factors. To analyze the function of ORF36, the cDNA for this viral gene was tagged with the FLAG epitope and inserted into an expression vector for mammalian cells. Transfection experiments in 293T and SLK cells demonstrated that expression of ORF36 resulted in phosphorylation of the c-Jun N-terminal kinase. Autophosphorylation of ORF36 is important for JNK activation because a mutation in the predicted catalytic domain of ORF36 blocked its ability to phosphorylate JNK. Western blot analysis, using phosphospecific antibodies, revealed that mitogen-activated kinases MKK4 and MKK7 were phosphorylated by ORF36 but not by the kinase-negative mutant. Binding experiments in transfected cells also demonstrated that both the wild type and kinase-negative mutant of ORF36 form a complex with JNK, MKK4, and MKK7. In addition, using a tetracycline-inducible Rta BCBL-1 cell line (TREx BCBL1-Rta), JNK was phosphorylated during lytic replication, and inhibition of JNK activation blocked late viral gene expression but not early viral gene expression. In summary, these studies demonstrate that KSHV ORF36 activates the JNK pathway; thus this cell signaling pathway may function in the KSHV life cycle by regulating viral and/or cellular transcription.

Anti-herpes chemotherapy

With the increasing number of immunocompromised patients over the last two decades, disease pattern caused by Herpesviridae has changed. More virulent, more severe, herpes simplex virus diseases are more frequently treated and consequently the drug-resistant herpes simplex virus mutants have arisen in the clinic. All these events justify to explore future directions in drug development and herpesviral research as antisens strategy or immunotherapy.

Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia.

BACKGROUND: Cognitive deficits are a characteristic feature of schizophrenia and contribute to the profound disabilities associated with this illness. Some of the cognitive deficits that occur in individuals with schizophrenia are similar to those found in individuals who have recovered from central nervous system infections with human herpes simplex viruses. METHODS: We measured cognitive functioning and serologic evidence of infection with human herpes simplex viruses in 229 outpatients with schizophrenia. We evaluated cognitive functioning with the Repeatable Battery for the Assessment of Neuropsychological Status. For each patient, serum IgG class antibodies with specificities for the following potentially neurotropic human herpes simplex viruses were measured by means of a solid-phase immunoassay: herpes simplex viruses 1 and 2, cytomegalovirus, Epstein-Barr virus, human herpes simplex virus 6, and varicella-zoster virus. We determined the association between serologic evidence of herpes simplex viruses infection and cognitive functioning by univariate and multivariate analyses, including demographic and clinical factors associated with cognitive functioning. RESULTS: We found that serologic evidence of infection with herpes simplex virus 1 is an independent predictor of cognitive dysfunction in individuals with schizophrenia. Discriminant function analysis indicated that much of the difference in cognitive functioning could be attributed to immediate memory. We found no significant association between cognitive dysfunction and serologic evidence of infection with other human herpes simplex viruses. CONCLUSION: Serologic evidence of herpes simplex virus 1 infection is associated with cognitive impairment in schizophrenia.

Clinical course of patients with serologic evidence of recurrent genital herpes simplex presenting with signs and symptoms of first episode disease.

BACKGROUND AND OBJECTIVES: The care of patients with first episode and recurrent genital herpes simplex differs with respect to therapy and source partner evaluation. Of 498 persons who presented with what appeared by history and symptoms to be a first episode of Genital Herpes, we identified 41 who had serologic evidence of remotely acquired herpes simplex virus 2 (HSV-2) infection. GOALS: To define the natural history of these individuals with previously unrecognized HSV-2 and to evaluate if any clinical or historical features could differentiate these people from persons with true first episode infection. STUDY DESIGN: Observational cohort study. RESULTS: Clinical overlap existed in the frequency of local symptoms, fever, and size of genital lesions between those with remotely acquired versus recently acquired Genital Herpes. The frequency of new sexual partners and recent sexual history were also similar in the two groups. However, on follow-up, the lesions of persons with remotely acquired HSV-2 healed more rapidly and subsequently recurred less frequently than those of true primary HSV-2. CONCLUSIONS: Even in a referral clinic with experienced clinicians, almost 10% of persons who are judged to have first episode genital herpes simplex have evidence of remotely acquired HSV-2, suggesting that clinical differentiation of first episode genital herpes simplex from previously acquired infection is difficult. Type-specific serologic testing assists the clinician in correctly classifying the infection and determining the potential source partner.

Neurologic manifestations of varicella herpes zoster infection

BACKGROUND: The aim of the present study was to analyze the clinical characteristics and fluid alterations in neurologic infection by varicella herpes zoster virus in hospitalized patients. METHODS: A retrospective study of the cases with neurologic involvement by the varicella herpes zoster virus in patients admitted in the authors' hospital from March 1991 to March 1993 was carried out. RESULTS: Our of the 14 patients studied with neurologic involvement by the varicella herpes zoster virus, 10 were males (71%) with a mean age of 38 years (range: 13-83 years). Only 4 patients (28%) presented a base disease (diabetes mellitus in 2 cases and HIV infection in another 2). In 10 cases (71%) the appearance of cutaneous lesions was prior to neurologic manifestations (between 1 and 30 days before neurologic clinical manifestations). All the patients presented hyperthermia at some time. The most common symptoms were: headache, vomiting, confusion and/or neck stiffness, with meningitis, encephalitis and neurologic foci and mixed pictures. In 4 cases (28%) the cephalorhachidian fluid did not present analytical changes suggestive of viral meningitis. All the patients underwent i.v. Acyclovir treatment at a dosis of 10-15 mg/kg/8 h with good evolution, with no deaths being observed. In 3 out of the 6 cases presenting neurologic foci the evolution was slow with sequelae following treatment completion. CONCLUSIONS: Neurologic involvement by the varicella herpes zoster virus does not clinically defer from other neutrotropic virus. Fluid alterations were compatible with benign lymphocytary meningitis although some cases of encephalitis showed normal LCR. Taking into account that none of the patients herein reported died and considering the mortality associated with meningitis or encephalitis by varicella herpes zoster referred in the literature in untreated patients, the authors believe that the use of Acyclovir is obligatory in these cases.

Interrelationship between ultraviolet light and recurrent herpes simplex infections in man.

In humans, epicutaneous application of a universally sensitizing dose (2000 micrograms) of dinitrochlorobenzene (DNCB) to skin exposed to 4 consecutive daily doses (144 mJ/cm2) of ultraviolet-B radiation (UVB) induces contact hypersensitivity (CH) in approximately 56% of normal, adult individuals (UVB-resistant--UVB-R), but not in the remaining 44% (UVB-susceptible--UVB-S). In patients with biopsy proven basal/squamous cell cancer, the frequency of the UVB-S trait exceeds 90%, indicating that this phenotype may be a risk factor for sunlight-induced skin cancer. Since many patients with recurrent Herpes Labialis complain that lip lesions are precipitated by acute sun exposure, we wondered whether the UVB-S trait might be associated with this recurrent disease. A group of 31 volunteers was selected, each with a history of numerous episodes of labialis secondary to reactivated herpes simplex virus-1 infection. Subjects were questioned carefully concerning factors, including sun exposure, thought to be important in precipitating lip lesions. Each individual was then subjected to the UVB plus DNCB protocol. When forearm skin of these individuals was assayed for CH after 30 days, 20 (65%) proved to be UVB-S (approximately 1.5 times the expected frequency), while the remainder displayed vigorous DNCB-specific CH. A strong history of sun-induced recurrent herpes simplex labialis did not predict the UVB phenotype. A subset of these subjects was exposed to 2 MEDs of UVB to their faces. None of the UVB-R subjects developed recurrent Herpes Labialis while 6 of 8 UVB-S subjects developed recurrent lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Alphaherpes virus proteins related to herpes simplex virus type 1 ICP0 affect cellular structures and proteins.

The herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0 interacts with several cellular proteins and induces the proteasome-dependent degradation of others during infection. In this study we show that ICP0 is required for the proteasome-dependent degradation of the ND10 protein Sp100 and, as with the other target proteins, the ICP0 RING finger domain is essential. Further, comparison of the kinetics and ICP0 domain requirements for the degradation of PMI and Sp100 suggests that a common mechanism is involved. Homologues of ICP0 are encoded by other members of the alphaherpes virus family. These proteins show strong sequence homology to ICP0 within the RING finger domain but limited similarity elsewhere. Using transfection assays, we have shown that all the ICP0 homologues that we tested have significant effects on the immunofluorescence staining character of at least one of the proteins destabilized by ICP0, and by using a recombinant virus, we found that the equine herpes simplex virus ICP0 homologue induced the proteasome-dependent degradation of endogenous CENP-C and modified forms of PML and Sp100. However, in contrast to ICP0, the homologue proteins had no effect on the distribution of the ubiquitin-specific protease USP7 within the cell, consistent with their lack of a USP7 binding domain. We also found that ICP0 by itself could induce the abrogation of SUMO-1 conjugation and then the proteasome-dependent degradation of unmodified exogenous PML in transfected cells, thus demonstrating that other HSV-1 proteins are not required. Surprisingly, the ICP0 homologues were unable to cause these effects. Overall, these data suggest that the members of the ICP0 family of proteins may act via a similar mechanism or pathway involving their RING finger domain but that their intrinsic activities and effects on endogenous and exogenous proteins differ in detail.

Herpes Simplex virus type 1 is the prevailing cause of genital herpes simplex in the Tel Aviv area, Israel.

BACKGROUND AND GOAL: The changing epidemiology of genital herpes simplex with the increasing importance of herpes simplex virus (HSV) type 1 prompted a study on the relative prevalence of HSV-1 and HSV-2 among cases of genital herpes simplex in the Tel Aviv area, Israel. STUDY DESIGN: A retrospective laboratory-based study of positive genital and nongenital herpes simplex cultures performed at the Beilinson Medical Center between 1993 and 2002. Data regarding the number of isolates of each type and the age and sex of patients with genital lesions were retrieved from the database. Cultures were performed using Vero cells, and positive results were confirmed and typed by immunofluorescence. RESULTS: A total of 285 positive genital cultures and 659 positive nongenital cultures were recorded. HSV-1 was identified in 189 (66.3%) of the positive genital specimens and in 656 (99.55%) of the nongenital specimens. HSV-1 was isolated in 174 of 262 (66.4%) female subjects and 15 of 23 (65.2%) male subjects. The proportion of HSV-1 genital isolates was 72.7% in patients 15 to 24 years of age, 62% in those 25 to 44 years, and 46% in those aged 45 years or older. Overall, the annual isolation rate of genital HSV-1 has not changed markedly over the years. CONCLUSION: Herpes Simplex virus type 1 has clearly been the predominant HSV type isolated from genital specimens in the Tel Aviv area over the last decade.

Clinical and genetic risk factors of herpes zoster in patients with systemic lupus erythematosus.

OBJECTIVE: The aim of this study was to determine the clinical and genetic risk factors that influence herpes zoster occurrence in patients with systemic lupus erythematosus (SLE). METHODS: Three hundred three SLE patients meeting the American College of Rheumatology criteria were enrolled in this study. Herpes zoster was diagnosed when classic grouped vesicles were noted. Medical records were reviewed retrospectively to collect clinical information. For Fc gamma receptor IIa (FcgammaRIIa) and FcgammaRIIIa genotyping, polymerase chain reaction (PCR) using allele-specific primers was performed. The PCR sequence-specific oligonucleotide probe method was utilized in human HLA-DRB1 genotyping. RESULTS: Forty-two cases (13.9%) of zoster occurred among 303 SLE patients. The incidence of zoster in patients with SLE was 32.5/1,000 patients per year. Patients who developed zoster had higher rates of lupus nephritis (P=0.018) and positive anti-Sm antibody (P=0.019). However, FcgammaRIIa and FcgammaRIIIa polymorphism and the HLA-DRB1 genotype did not influence herpes zoster occurrence. CONCLUSION: Systemic lupus erythematosus patients with lupus nephritis or anti-Sm antibody are at higher risk of herpes zoster. FcgammaRIIa (H/R131), FcgammaRIIIa (F/V176), and HLA-DRB1 genetic polymorphisms did not influence the occurrence of herpes zoster in these patients.

The risk and prognosis of cancer after hospitalisation for herpes zoster: a population-based follow-up study.

We examined the risk of cancer and survival in a cohort of patients hospitalised with herpes zoster between 1977 and 1996, drawn from the Danish National Registry of Patients. Through linkage with the Danish Cancer Registry, we compared the observed number of cancers with the expected number on the basis of national age-, gender-, and site-specific incidence rates. The survival of herpes zoster patients with cancer was compared with that of non-Herpes Zoster patients with cancer. Among the 10 588 patients hospitalised with herpes zoster whom we identified, 1427 cancers were observed compared with 1239 expected (relative risk=1.2, 95% confidence interval 1.1-1.2). The risk was substantially elevated during the first year of follow-up, mainly for haematological cancer. Patients with cancer within 1 year of follow-up had a higher prevalence of distant metastases than controls, although the mortality was similar. For those with haematological cancer, however, the mortality was higher for herpes zoster patients than for controls. Haematological cancer following hospitalisation for herpes zoster has a poorer prognosis than in non-Herpes Zoster patients.