Herpes simplex virus type 1 (HSV‐1) is a ubiquitous and neurotropic pathogen and is the most common cause of acute sporadic encephalitis in humans. This virus is characterized by establishing a persistent latent infection in neurons of its hosts for life. The pathogenic mechanisms of HSV‐1 at the central nervous system (CNS) are not completely elucidated. Besides, evidences suggest that HSV‐1 establish latency in the CNS in humans and that this condition would not be harmless, especially in people whose immune system is declined. This trait has been strongly suggested as a risk factor for the development of neurodegenerative pathologies such as Alzheimer's disease. Currently, it is unclear whether a neuron, which undergoes viral reactivation and produces infectious particles, survives and resumes latency, loses functionality, or is killed. These data highlight the need for more studies at cellular and molecular levels to understand the strategies used by the virus and the host cells during both produc‐ tive and latent infection. The present chapter discusses the current investigations about HSV‐1 infection at the CNS and the potential risk of neuronal dysfunction and chronic neurological diseases.
Infection with herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) is extremely frequent in the human population, as well as recurrent reactivations due to lifelong infection. Infection and persistence of HSVs within healthy individuals likely results as a consequence of numerous molecular determinants evolved by these pathogens to escape both immediate and long-term host antiviral mechanisms. Indeed, HSVs harbor an arsenal of proteins that confer them stealth by negatively modulating immune function. Consequently, these viruses perpetuate within the host, altogether silently shedding onto other individuals. In this chapter, we discuss HSV determinants that interfere with cellular antiviral factors, as well as viral determinants that hamper innate and adaptive immune components intended to control such microbes. The identification of HSV evasion molecules that modulate the immune system, as well as the understanding of their mechanisms of action, should facilitate the design of novel prophylactic and therapeutic strategies to overcome infection and disease elicited by these viruses. This chapter is intended to provide an overview of the evasion mechanisms evolved by herpes simplex viruses to escape numerous host antiviral mediators.
The course of herpesvirus infection in human and animals is not so simple as it has been presumed on the analogy of other microbes at the beginning of virology era. Classification into acute and chronic infections, simple distinction of complete clinical and virological recovery or perishing of the host organism belong to the conventional views on the course and outcome of virus infections. But several other forms of existence of herpesviruses (HHVs) in the host are possible. Many diverse interactions between the macro-organism and herpesviruses have been discovered gradually. In spite of these new data, conventionally, the idea about one organism causing one well-characterized disease has remained in the mind of the majority of both many medical, veterinary professionals and the public. Nowadays we believe that we understand the pathomechanism of herpesviral diseases. Simply saying, this is not true, because, frequently we encounter new experimental evidence that cause surprise and contin‐ uously modify dogmas. The conventional way of our thinking on host-viral interaction is somewhat static, but the life-long flow of events between invading herpesviruses and the defensive organism is dynamic: several alternative ways on both sides might influence outcome. Furthermore, their bilateral interplay is modified by many intrinsic and extrinsic factors, consequently it is rather multilateral. This moment there are delicate methods to follow post-infection events at the molecular level. Beside structural polypeptides, herpesviruses encode a large number of proteins with enzymatic or regulatory functions. The exact way of regulating their activities by post-translational modifications, e.g. glycosylation or phosphor‐ ylation, is hardly explored. Events at sub-molecular level and energy flow during assembly of their structural components are almost unknown. Basic physics, not conventional virology could help supply knowledge in these matters. Data processing by computers analyses tens of thousands of data obtained in one model experiment or clinical cohorts including large number of patients, but in future we have to extrapolate their pathophysiological meaning to clinical relevance. It is
The herpesvirus family comprises several widespread infectious pathogens. They infect a variety of animal hosts, including humans and cause complex clinical outcomes. Recently, the possible correlation between genital infection by human herpesviruses (HHVs) and male infertility has attracted considerable attention. In this chaper, we investigated the mechanism of HHV-1-induced infertility in transgenic (Tg) rats and its possible correlation with infertility in human males. Ectopic expression of HHV-1 thymidine kinase (TK) in the testis of Tg rats increased male infertility. In addition, truncated TK proteins were found in postmeiotic spermatids of Tg rat testis, leading to progressive degeneration of germ cells and vacuolization of the seminiferous epithelium. These findings suggest the possibility that a similar process occurs within HHV-infected human germ cells.
Epstein-Barr virus (EBV) infection contributes to the development of different types of human malignancies, especially nasopharyngeal carcinoma. As a herpesvirus, EBV can establish two major modes of virus-cell interactions: a latent or a lytic infection. Latent infection is prevalent in the vast majority of malignant cells in EBV-related malignancies. Inducing a switch from latent to lytic infection in a substantial fraction of malignant cells has long been considered as a potentially interesting therapeutic approach. Therapeutic benefits are expected from (1) the cytotoxic or cytostatic effects of viral products expressed in the context of the lytic cycle; (2) expression of viral enzymes capable of metabolizing pro-drugs selectively inside these cells and (3) broadening the expression spectrum of antigenic viral proteins. In this chapter, addressing non EBV-specialized readers, we first summarize the main aspects of EBV biology with emphasis on the cellular mechanisms known to control latent and lytic infections. Then, we outline the basic principles and requirements of cytolytic EBV activation performed with a therapeutic intent. Finally, we review the main categories of pharmacological agents reported to be active in the switch from latent to lytic infection, including drugs used for conventional anti-tumour chemotherapy, histone-deacetylase inhibitors and various miscellaneous compounds.
Bovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle and cofactor for bovine respiratory disease, a polymicrobial disease. Acute infection of cattle leads to abundant expression of lytic cycle viral genes, high levels of virus shedding, and clinical symptoms. Following acute infection, lifelong latency is established in sensory neurons. Only the latency-related (LR) gene locus, which encodes at least two micro-RNAs and several proteins, is abundantly expressed in latently infected neurons. Increased corticosteroids, due to external stressors, disrupt the maintenance of latency and increase the incidence of reactivation from latency, which is crucial for virus transmission. For example, calves latently infected with BoHV-1 consistently reactivate from latency following a single intravenous (IV) injection of the synthetic corticosteroid dexamethasone. In contrast to wild-type BoHV-1, an LR-mutant virus that has three in-frame stop codons at the amino terminus of the first open reading frame in the LR gene (ORF2) does not reactivate from latency following dexamethasone treatment. The ability of dexamethasone to initiate BoHV-1 reactivation from latency in calves makes it an attractive model to identify early events that occur during reactivation from latency. Viral and cellular factors that regulate the BoHV-1 latency-reactivation cycle are discussed in this review.
This chapter is devoted to the topics of not yet marketed HSV vaccine, which is still in the focus of interest, especially from the point of immunotherapeutic use. To understand the principles of vaccination strategies (prophylactic and/or immunotherapeutic), the pathogenesis of herpes simplex virus 1 (HSV-1) and/or HSV-2 infections in animal models is briefly outlined. Even when both herpesviruses may spread via bloodstream, which is especially true in the immunocompromised host, the main route of their transmission is along peripheral nerves. Both viruses establish latency in ganglion cells, and after reactivation, they spread along axons back to the site of primary infection. Since neither the establishment of latency nor its reactivation can be fully controlled by virus-neutralizing antibodies, the outcome of immune response greatly depends on the activity of cytotoxic CD8+ T lymphocytes. The majority of important antigenic epitopes is located in envelope glycoproteins (such as gB, gD, gE, gC and gG) that are related to virus adsorption and penetration into susceptible cells. The HSV-1 and/or HSV-2 experimental vaccines designed so far were either purified virion products derived from infected cells (subunit vaccines), purified recombinant immunogenic herpes simplex virus HSV-coded proteins (especially gD), and/or attenuated live viruses lacking some of virulence tools (such as gH and/or gE). We bring a comprehensive overview of the efficacy of experimental HSV-1/HSV-2 vaccines and discuss our own data. In conclusion, we believe in the continued demand of HSV-1 and HSV-2 vaccines, at least for their immunotherapeutic use, suggesting unified evaluation criteria for clinical trials to reach consent at their interpretation.
The chapter aims at providing readers with the overview of the herpesvirus infection in bovines. It includes the detailed etiology of the infection, discussing the virus characteristics, virus structure, genome, viral proteins, types and subtypes of the virus. Then, the chapter discusses the transmission and pathogenesis of the virus, which are very important as they help to control the virus spread, viral latency and clinical signs observed in the affected animals. Later, the chapter discusses the diagnosis of herpesvirus infection in bovines to help the readers to gain knowledge about the techniques used earlier and nowadays for the diagnosis of the infection. Then, the chapter provides information on the procedures to be adopted for the prevention and control of the infection in bovines. Thus, the chapter provides complete information about the herpesvirus infection in bovines.
Apical periodontitis represents a chronic inflammation and destruction of periradicular tissue caused by polymicrobial infection of endodontic origin. The aim of this systematic review was to make an update on findings related to Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) presence in periapical pathoses and to correlate these findings with clinical, histopathological and radiographic features of periapical lesions. Methods were based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. A search was performed using PubMed, Web of Science and SCOPUS. Search key words included the following medical subjects heading terms: (periapical disease OR apical periodontitis OR periapical lesions OR periapical abscess) AND (viruses OR herpesvir*). A manual search involved references from articles retrieved for possible inclusion. The search, evaluation, and critical appraisal of articles were performed by two independent judges. Collected data were analyzed using the measures of descriptive statistics. The final review has included twenty nine articles related to herpesviral presence periapical pathoses. Qualitative analysis indicated that EBV HCMV, and HHV-8 were the most prevalent species in periapical pathoses. Our findings suggest that there is wide variety of herpesviruses detection rates in periapical pathoses in relation to their clinical, histopathological and radiographic features.
BACKGROUND:Many viral genes affect cytokine function within infected hosts, with interleukin 10 (IL-10) as a commonly targeted mediator. Epstein-Barr virus (EBV) encodes an IL-10 homologue (vIL-10) expressed during productive (lytic) infection and induces expression of cellular IL-10 (cIL-10) during latency. This study explored the role of vIL-10 in a murine gammaherpesvirus (MHV) model of viral infection.METHODS:The EBV vIL-10 gene was inserted into MHV-76, a strain which lacks the ability to induce cIL-10, by recombination in transfected mouse cells. Mice were infected intranasally with the recombinant, vIL-10-containing MHV-76 or control virus strains and assayed at various days post infection for lung virus titer, spleen cell number, percentage of latently infected spleen cells and ability to reactivate virus from spleen cells.RESULTS:Recombinant murine gammaherpesvirus expressing EBV vIL-10 rose to significantly higher titers in lungs and promoted an increase in spleen cell number in infected mice in comparison to MHV strains lacking the vIL-10 gene. However, vIL-10 expression did not alter the quantity of latent virus in the spleen or its ability to reactivate.CONCLUSIONS:In this mouse model of gammaherpesvirus infection, EBV vIL-10 appears to influence acute-phase pathogenicity. Given that EBV and MHV wild-type strains contain other genes that induce cIL-10 expression in latency (e.g. LMP-1 and M2, respectively), vIL-10 may have evolved to serve the specific role in acute infection of enlarging the permissive host cell population, perhaps to facilitate initial survival and dissemination of viral-infected cells.
Background Human cytomegalovirus (HCMV) infection is associated with cardiovascular disease (CVD) but the role of this virus in CVD progression remains unclear. We aimed to examine the HCMV serostatus in Russian patients (n = 90) who had undergone carotid endarterectomy (CEA) and controls (n = 82) as well as to determine the prevalence of HCMV immediate early (IE) and late (LA) antigens in carotid atherosclerotic plaques obtained from 89 patients. In addition, we sought to determine whether HCMV infection was associated with inflammatory activity in the plaque by quantifying infiltrating CD3 and CD68 positive cells and 5-LO immunoreactivity. Methods HCMV serology was assessed with ELISA and immunohistochemistry staining was performed to detect HCMV antigens, CD3, CD68 and 5-LO reactivity. The Fisher’s exact test was used to compare i) seroprevalence of HCMV IgG between patients and controls and ii) HCMV-positive or –negative to that of CD3, CD68 and 5-LO immunoreactive cells in plaque samples. The student- t test was performed to connote the significance level of mean optical density between patients and controls. Results The seroprevalence for HCMV IgG was high in both patients and controls (99% and 98%, respectively). Controls had significantly higher IgG titers for HCMV compared with patients (p = 0.0148). Strikingly, we found a high prevalence of HCMV antigens in atherosclerotic plaques; 57/89 (64%) and 47/87 (54%) were HCMV IE and LA positive, respectively. Most plaques had rather low HCMV reactivity with distinct areas of HCMV-positive cells mainly detected in shoulder regions of the plaques, but also in the area adjacent to the necrotic core and fibrous cap. In plaques, the cellular targets for HCMV infection appeared to be mainly macrophages/foam cells and smooth muscle cells. HCMV-positive plaques trended to be associated with increased numbers of CD68 positive macrophages and CD3 positive T cells, while 5-LO reactivity was high in both HCMV-positive and HCMV-negative plaques. Conclusions In Russian patients undergoing CEA, HCMV proteins are abundantly expressed in carotid plaques and may contribute to the inflammatory response in plaques via enhanced infiltration of CD68 and CD3 cells.
Congenital human cytomegalovirus (HCMV) infection, a leading cause of birth defects, is most often manifested as neurological disorders. The pathogenesis of HCMV-induced neurological disorders is, however, largely unresolved, primarily because of limited availability of model systems to analyze the effects of HCMV infection on neural cells.
BACKGROUND:Recently we identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway. Our previously characterized, novel mouse organ culture model of mouse CMV (mCMV)-induced tumorigenesis displays a number of histologic and molecular characteristics similar to human MEC.METHODS:Newborn mouse submandibular glands (SMGs) were incubated with 1 × 105 PFU/ml of lacZ-tagged mCMV RM427+ on day 0 for 24 hours and then cultured in virus-free media for a total of 6 or 12 days with or without EGFR/ERK inhibitors and/or aciclovir. SMGs were collected for histology, immunolocalization (pERK, FN, IL-6), viral distribution, or Western blot analysis (pERK).RESULTS:Here we report: (1) mouse SMG tumors soon exhibit an acquired resistance to EGFR/ERK pathway kinase inhibitors, alone or in combination; (2) long term tumor regression can only be sustained by concurrent inhibitor and antiviral treatment; (3) CMV-dependent, kinase inhibitor resistance is associated with overexpression of fibronectin and IL-6 proteins in abnormal stromal cells.CONCLUSIONS:Acquired resistance to kinase inhibitors is dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway, a phenomenon with important therapeutic implications for human MEC of salivary glands.
BACKGROUND:Diagnosis of cytomegalovirus (CMV) infection is challenging because of the high rate of asymptomatic infection and the low specificity of associated symptoms and signs. As a result, laboratory testing is an essential aid in making an accurate diagnosis. The presence of CMV IgM is indicative of primary CMV infection. In pregnancy, diagnosis of primary infection is important because primary maternal infection increases fetal infection risk substantially. Fetal infection can result in serious sequelae ranging from neurological deficits to death. Diagnosis among the immunocompromised is also critical for the timely initiation of therapy that can reduce morbidity and mortality risk.METHODS:The IMMULITE® 2000 CMV IgM assay qualitatively detects CMV IgM antibodies in human serum or plasma to aid in the diagnosis of current or recent CMV infection. To determine expected values in apparently healthy subjects, 136 samples were tested. Reproducibility, normal range, and method comparison studies were also performed to evaluate the assay's performance. The assay's reproducibility was evaluated across three sites. Seven hundred and eighteen (n = 718) individual patient serum samples, which included samples from CMV IgM-positive (n = 109, determined by the Abbott IMx CMV or the Diamedix CMV IgM assays), pregnant (n = 210), HIV-positive (n = 30), immunosuppressed (n = 102), and transplant patients (n = 17) and from patients with potentially cross-reacting conditions (n = 136) were evaluated in the method comparison study. The positive, negative, and overall agreement between the IMMULITE 2000 CMV IgM assay and the VIDAS CMV IgM assay (predicate assay) were determined.RESULTS:The assay demonstrated excellent reproducibility with a total CV of less than 10%. The positive, negative, and overall agreement between the IMMULITE 2000 assay and the VIDAS assay were > 95% for the method comparison samples. Among potentially cross-reactive samples, the overall agreement between the two assays was 96%. Similarly, among the immunocompromised and pregnant subjects, the overall agreement was ~96% and ~97%, respectively.CONCLUSIONS:The IMMULITE 2000 CMV IgM assay demonstrated excellent reproducibility, minimal cross-reactivity, and performance comparable to that of the VIDAS CMV IgM assay. It can aid in the diagnosis of acute CMV or recent CMV infection by qualitatively detecting the CMV IgM antibodies in human serum or plasma.
Background X-linked lymphoproliferative syndrome (XLP) is a rare inherited immunodeficiency by an extreme vulnerability to Epstein-Barr virus (EBV) infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP are now divided into type 1 (XLP-1) and type 2 (XLP-2), which are caused by mutations of SH2D1A/SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) genes, respectively. The diagnosis of XLP in individuals with EBV-associated HLH (EBV-HLH) is generally difficult because they show basically similar symptoms to sporadic EBV-HLH. Although EBV-infected cells in sporadic EBV-HLH are known to be mainly in CD8 + T cells, the cell-type of EBV-infected cells in EBV-HLH seen in XLP patients remains undetermined. Methods EBV-infected cells in two patients (XLP-1 and XLP-2) presenting EBV-HLH were evaluated by in EBER-1 in situ hybridization or quantitative PCR methods. Results Both XLP patients showed that the dominant population of EBV-infected cells was CD19 + B cells, whereas EBV-infected CD8 + T cells were very few. Conclusions In XLP-related EBV-HLH, EBV-infected cells appear to be predominantly B cells. B cell directed therapy such as rituximab may be a valuable option in the treatment of EBV-HLH in XLP patients.
Background Innate recognition is essential in the antiviral response against infection by herpes simplex virus (HSV). Chemokines are important for control of HSV via recruitment of natural killer cells, T lymphocytes, and antigen-presenting cells. We previously found that early HSV-1-mediated chemokine responses are not dependent on TLR2 and TLR9 in human macrophages. Here, we investigated the role of the recently identified innate IFN-inducible DNA receptor IFI16 during HSV-1 infection in human macrophages. Methods Peripheral blood mononuclear cells were purified from buffy coats and monocytes were differentiated to macrophages. Macrophages infected with HSV-1 were analyzed using siRNA-mediated knock-down of IFI16 by real-time PCR, ELISA, and Western blotting. Results We determined that both CXCL10 and CCL3 are induced independent of HSV-1 replication. IFI16 mediates CCL3 mRNA accumulation during early HSV-1 infection. In contrast, CXCL10 was induced independently of IFI16. Conclusions Our data provide the first evidence of HSV-1-induced innate immune responses via IFI16 in human primary macrophages. In addition, the data suggest that at least one additional unidentified receptor or innate sensing mechanism is involved in recognizing HSV-1 prior to viral replication.
Human alphaherpesviruses including herpes simplex viruses (HSV-1, HSV-2) and varicella zoster virus (VZV) establish persistent latent infection in sensory neurons for the life of the host. All three viruses have the potential to reactivate causing recurrent disease. Regardless of the homology between the different virus strains, the three viruses are characterized by varying pathologies. This review will highlight the differences in infection pattern, immune response, and pathogenesis associated with HSV-1 and VZV.
BACKGROUND:Mice infected with HSV-1 can develop lethal encephalitis or virus induced CNS demyelination. Multiple factors affect outcome including route of infection, virus and mouse strain. When infected with a sub-lethal dose of HSV-1 strain 2 via the oral mucosa, susceptible SJL/J, A/J, and PL/J mice develop demyelinating lesions throughout the brain. In contrast, lesions are restricted to the brainstem (BST) in moderately resistant BALB/c mice and are absent in resistant BL/6 mice. The reasons for the strain differences are unknown.METHODS:In this study, we combine histology, immunohistochemistry, and in-situ hybridization to investigate the relationship between virus and the development of lesions during the early stage (< 24 days PI) of demyelination in different strains of mice.RESULTS:Initially, viral DNA and antigen positive cells appear sequentially in non-contiguous areas throughout the brains of BALB/c, SJL/J, A/J, and PL/J mice but are restricted to an area of the BST of BL/6 mice. In SJL/J, A/J, and PL/J mice, this is followed by the development of 'focal' areas of virus infected neuronal and non-neuronal cells throughout the brain. The 'focal' areas follow a hierarchical order and co-localize with developing demyelinating lesions. When antigen is cleared, viral DNA positive cells can remain in areas of demyelination; consistent with a latent infection. In contrast, 'focal' areas are restricted to the BST of BALB/c mice and do not occur in BL/6 mice.CONCLUSIONS:The results of this study indicate that susceptible mouse strains, infected with HSV-1 via the oral mucosa, develop CNS demyelination during the first 24 days PI in several stages. These include: the initial spread of virus and infection of cells in non-contiguous areas throughout the brain, the development of 'focal' areas of virus infected neuronal and non-neuronal cells, the co-localization of 'focal' areas with developing demyelinating lesions, and latent infection in a number of the lesions. In contrast, the limited demyelination that develops in BALB/c and the lack of demyelination in BL/6 mice correlates with the limited or lack of 'focal' areas of virus infected neuronal and non-neuronal cells in these two strains.
BACKGROUND:Glioblastoma multiforme (GBM) represent the most aggressive brain tumor with a median overall survival of about 12-15 months. Over 90% of GBM tumors have recently been shown to be infected with human cytomegalovirus (HCMV). In this case-control study, we evaluated whether there was an association between the grade of HCMV infection and long-term survival (> 18 months) in GBM patients.MATERIAL AND METHODS:Brain tumor tissue sections from consecutive GBMs patients who survived more than 18 months (n = 40), and an equal number of GBM patients, matched to date of diagnosis and surgery, operated at Karolinska University Hospital in 2000-2005 were selected. HCMV infection grade was determined by estimation of the number of HCMV positive cells (scored negative or grade 1-4) in tumor tissue specimens. Using Chi-Square test and logistic regression analysis, we analyzed whether there was an association between long-term survival and HCMV low-grade infection or other clinical parameters known to be associated with prolonged survival of GBM patients; age under 50 years, radical surgery or low recursive partition analysis (RPA) subclass.RESULTS:HCMV infection was detected in tumor samples from 79 of 80 patients (99%). Among patients surviving > 18 months, HCMV infection grade 1 in the GBM tumor was predominant. A low grade HCMV infection was found in 19 patients, of these 16 survived > 18 months. Thus, 16 of 40 (40%) GBM patients who lived > 18 months had low-grade HCMV infection while only 3 of 40 (8%) GBM patients who lived < 18 months did (p .0006, Chi-Square test). Multiple logistic regression analyses yielded an odds ratio estimate of 6.604 with 95% confidence interval (1.36-32.1) (p .019) for low grade HCMV after adjustment for RPA class III and IV, radical surgery, age and gamma knife treatment.CONCLUSION:In conclusion, we found that low-grade HCMV infection was strongly associated with long-term survival in GBM patients.
