A surprising role for the proteasome in the regulation of herpesvirus infection.
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Cysteine Endopeptidases↗
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Genital herpesvirus infection in a prepubertal girl.
An episode of acute vulvovaginitis which was found to be due to herpesvirus is described in an eight-year-old girl. The significance of such infections is discussed.
Child↗
Partial protection against Marek's disease in chickens immunized with glycoproteins gB purified from turkey-herpesvirus-infected cells by affinity chromatography coupled with monoclonal antibodies.
Glycoproteins gB of Marek's disease virus (MDV) and herpesvirus of turkeys (HVT) related to virus neutralization were purified from HVT-infected cells by affinity chromatography. Immunization of chickens with purified glycoproteins gB resulted in partial protection against MD. Neutralizing antibodies were detected in chickens immunized with HVT-gB.
Animals↗
Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.
Kaposi's sarcoma-associated herpesvirus (KSHV) was found in the bone marrow dendritic cells of multiple myeloma patients but not in malignant plasma cells or bone marrow dendritic cells from normal individuals or patients with other malignancies. In addition the virus was detected in the bone marrow dendritic cells from two out of eight patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor to myeloma. Viral interleukin-6, the human homolog of which is a growth factor for myeloma, was found to be transcribed in the myeloma bone marrow dendritic cells. KSHV may be required for transformation from MGUS to myeloma and perpetuate the growth of malignant plasma cells.
Blotting, Southern↗
Protection and therapy of experimental herpesvirus infections in mice with immunomodulating Propionibacterium avidum KP-40 and/or acyclovir.
Protection and therapy of NMRI mice with experimental herpes virus (HSV-1) encephalitis were investigated using heat-killed, lyophilized Propionibacterium avidum KP-40 (PA) and/or the herpes-specific antiviral substance acyclovir (ACL) as immunomodifier. Poly I:C as a potent macrophage activator was used as a reference compound for PA. Survival of experimental HSV-1 infections during 18 days following the inoculation of viruses was used for the evaluation of the effects of immunotherapy. The applied model of HSV-1 infection resulted in a mortality of about 87% of NMRI mice at 7-16 days following the inoculation of the virus. Treatment with ACL or Poly I:C at the day of HSV-1 infection resulted in a lowering of the mortality rate to about 40% (p < 0.05). PA applied 4 days before HSV-1 infection lowered the mortality rate to 27%, while treatment 2 days after infection was less effective and the mortality rate reached 44%, although still being significantly lower (p < 0.01) than in untreated controls. A combined treatment with ACL and PA on the day of HSV-1 infection protected 93% of animals against the development of clinically detectable herpesvirus encephalitis.
Acyclovir↗
Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma has a plasma cell gene expression profile.
Kaposi's sarcoma-associated herpesvirus is associated with three human tumors: Kaposi's sarcoma, and the B cell lymphomas, plasmablastic lymphoma associated with multicentric Castleman's disease, and primary effusion lymphoma (PEL). Epstein-Barr virus, the closest human relative of Kaposi's sarcoma-associated herpesvirus, mimics host B cell signaling pathways to direct B cell development toward a memory B cell phenotype. Epstein-Barr virus-associated B cell tumors are presumed to arise as a consequence of this virus-mediated B cell activation. The stage of B cell development represented by PEL, how this stage relates to tumor pathology, and how this information may be used to treat the disease are largely unknown. In this study we used gene expression profiling to order a range of B cell tumors by stage of development. PEL gene expression closely resembles that of malignant plasma cells, including the low expression of mature B cell genes. The unfolded protein response is partially activated in PEL, but is fully activated in plasma cell tumors, linking endoplasmic reticulum stress to plasma cell development through XBP-1. PEL cells can be defined by the overexpression of genes involved in inflammation, cell adhesion, and invasion, which may be responsible for their presentation in body cavities. Similar to malignant plasma cells, all PEL samples tested express the vitamin D receptor and are sensitive to the vitamin D analogue drug EB 1089 (Seocalcitol).
Calcitriol↗
Pathogenesis of ruminant herpesvirus infections.
Ruminants are hosts for members of both Alpha- and Gamma-herpesvirinae. A wide range of disease syndromes is associated with infections by these agents. The associated diseases reflect the biological nature of the causative viruses. Clinically, the symptoms may be mild and localized or include severe generalized disease, leading eventually to death. Much knowledge has been gained concerning the pathogenesis of some alpha-herpesviruses. Initially, these viruses replicate in epithelial cells at the portal of entry. The symptoms of the acute diseases are often associated with the destruction of those epithelial cells. However, as in the case of bovine herpesvirus 1 (BHV-1), the virus may spread in the infected host by viremia, gaining access to a broader range of tissues and organs, and causing a broader variety of diseases. Furthermore, many herpesviruses are capable of entering neuronal cells. There, they may replicate, which may lead to neuronal diseases, for example, encephalitis. In addition, the herpesviruses may establish latency in neuronal or lymphoid cells. During latency, apparently no viral antigens are synthesized but the genomes of the latent viruses are present in the nuclei of long living cells, such as, e.g., neurones of the ganglia corresponding to the sites of peripheral replication. Upon reactivation, the viruses re-establish the lytic cycle of replication. Shielded from the effectors of the immune system, they migrate back to the peripheral tissues where they are excreted and may be transmitted. Although a strong immune response is provoked during primary viral replication, these mechanisms help the herpesviruses to escape from immune surveillance during latency and to a lesser degree during reactivation. It has been observed that certain herpesviruses may behave differently upon infection of different hosts. Relatively little progress has been made concerning the understanding of the pathogenesis of ruminant herpesviruses but much has been learned about viral molecular biology. Many viral proteins have been identified and characterized and the technology to create recombinant viruses has been established. With these tools in our hands, it is now possible to address the really interesting questions concerning pathogenesis. We postulate that herpesviruses contain at least two sets of genes, a first set involved in gene expression and viral replication, and a second set responsible for functions, which may affect pathogenesis, latency, and virus/host interactions. Using recombinant virus technology, it will be possible in the future to design targeted deletions and gene transfers in ruminant herpesviruses in order to study the viral and host factors involved in pathogenesis on the molecular level.
Alphaherpesvirinae↗
Experimental pathogenesis of non-lethal herpesvirus infection and the establishment of latency.
In rabbits inoculated into the right scarified cornea with the Kupka strain of human Herpesvirus type 1 (HHV 1), healing of the keratitis occurred between days 8--12 post infection (p.i.). Viral particles were seen in nuclei and cytoplasm of corneal epithelium cells and in a few fibrocytes of corneal stroma. By immunofluorescence and electron microscopy, the virus was demonstrated in single neurons and satellite cells of the homolateral Gasserian ganglion since 24 hr p.i. From 20 hr to 8 days p.i., HHV 1 was found in ganglia of 7 out of 15 rabbits, while the explantation was positive in 10 out of 12 animals. In the course of latency, single HHV antigen-containing cells were seen in ganglia of 3 out of 7 rabbits and virus isolation attempts before explantation always were negative. Viral antigen was found in single ganglion cells only in 20% of rabbits with healed corneal lesions while the explanation of the ganglion tissue yielded HHV at an unchanged high frequency (92% of animals).
Animals↗
Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease.
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is linked to KS, primary effusion lymphomas (PEL), and a subset of multicentric Castleman's disease (MCD). Transcript mapping studies using PEL cell lines have allowed preliminary classification of viral gene expression into constitutive (class I) and inducible (class II/III) categories. To determine whether viral gene expression differs in vivo, we examined tissue sections of KSHV-infected disorders, using specific antibodies against proteins that are representative of the different expression classes of KSHV genes. ORF73/LANA appears to be a surrogate marker for KSHV infection because it is constitutively expressed in vitro and in vivo in all KSHV-infected cells. Expression of vIRF1, vIL6, and PF-8 proteins in the infected B cells of MCD lymph nodes reproduces the expression pattern observed in TPA-stimulated KSHV-infected B-cell lines. In contrast, the protein expression of the inducible viral genes that we tested in KS and PEL biopsies is restricted to PF-8 and vIL6, respectively. The tightly restricted expression of KSHV proteins in vivo differs from the dysregulated expression of inducible KSHV genes in vitro and suggests that viral gene expression in KSHV-infected cell lines does not accurately reflect what occurs in diseased tissues. These differences may be related to either cell-specific or immune restriction of viral replication.
Castleman Disease↗
Murine herpesvirus pathogenesis: a model for the analysis of molecular mechanisms of human gamma herpesvirus infections.
Murine herpes virus (MHV), a natural pathogen originally isolated from free-living rodents, constitutes the most amenable animal model for human gamma herpesviruses. Based on DNA sequence homology, this virus was classified as Murid Herpesvirus 4 to subfamily Gammaherpesvirinae. Pilot studies in our laboratory, using mice inoculated by the intranasal route, showed that MHV infects macrophages, B lymphocytes, lung alveolar as well as endothelial cells. From the lungs the virus spreads via the bloodstream to spleen and bone marrow and via the lymphatics to the mediastinal lymph nodes. Similarly to other gamma herpesviruses, MHV established life-long latency maintained in host B lymphocytes and macrophages. An IM-like syndrome (per analogy to EBV) may develop during acute MHV infection, in which the atypical T/CD8+ lymphocytes eliminate viral DNA carrying B cells expressing the M2 latency associated protein. During latency, the MHV LANA (a KSHV LANA homologue) maintains the latent viral genome, assuring its copying and partition to new carrier cells in the course of division of the maternal cell. The nonproductive latency is turned onto virus replication by means of Rta protein. The chronic lymphoproliferative syndrome of unclear pathogenesis, which occurs in a certain part of latent MHV carriers, is related to the expression of gamma herpesvirus common latency-associated genes such as v-cyclin and/or to that of a virus-specific (M11/bcl-2) gene. This review attempts to summarize our knowledge concerning the function of MHV genes (either gamma herpesvirus common or MHV specific) related to immune evasion, latency and lymphoproliferation when highlighting the unsolved problems and/or controversial opinions.
Animals↗
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, may be the infectious cause of KS. Its prevalence in the general population, on the basis of detection of the virus genome, is controversial. To investigate the seroprevalence, we measured antibodies to a recombinant capsid-related (lytic cycle) KSHV antigen and a latent antigen complex. METHODS: We selected potentially immunoreactive capsid-related proteins of KSHV by expressing them as recombinant proteins and testing them in western blot assays. We used a truncated recombinant protein encoded by KSHV open reading frame 65 (orf 65) to develop a diagnostic enzyme-linked immunosorbent assay (ELISA) and tested sera from HIV-infected individuals with KS, HIV-uninfected patients with "classic" KS, other HIV risk groups, and blood donors. We also compared the antibody response to this capsid-related protein to the response to latent antigen(s) in an immunofluorescence assay. FINDINGS: 77/92 (84%) sera from KS patients reacted with the KSHV orf 65 protein and 84/103 (81.5%) reacted with KSHV latent antigen(s). The dominant immunogenic region of orf 65 is within the carboxyterminal 80 aminoacids, a region with little sequence similarity to the related Epstein-Barr virus, suggesting that orf 65 is a KSHV specific antigen. Only three sera from patients with haemophilia (1/84) or from intravenous drug users (2/63) had KSHV specific antibodies in the orf 65 assay whereas none of these sera reacted with latent antigen. Antibodies to KSHV were also infrequently found in UK and US blood donors by either assay (UK, 3/174 with orf 65 and 4/150 with latent antigen; US, 6/117 with orf 65 and 0/117 with latent antigen). They were more common among HIV-infected gay men without KS (5/16 by orf 65 ELISA, 10/33 by IFA), HIV-uninfected STD clinic attenders (14/166 by IFA), and Ugandan HIV-uninfected controls (6/17 by orf 65 ELISA, 9/17 by IFA). Antibody reactivity to the orf 65 protein (ELISA) and to latent antigen(s) (IFA) was concordant in 89% of 462 sera tested but reactive blood donor sera were discordant in both assays. Four AIDS-KS sera were unreactive in both assays. INTERPRETATION: The distribution of antibodies to both a capsid-related recombinant protein and latent antigen(s) of KSHV strongly supports the view that infection with this virus is largely confined to individuals with, or at increased risk for, KS. However, infection with KSHV does occur, rarely, in the general UK and US population and is more common in Uganda. Antibodies to latent antigen(s) or to orf 65 encoded capsid protein will not detect all cases of KSHV infection, and a combination of several antigens will probably be required for accurate screening and confirmatory assays.
Adult↗
Experimental latent herpesvirus infection in rabbits, mice and hamsters: ultrastructure of the virus activation in explanted gasseric ganglia.
The frequency of latent infection as established in trigeminal ganglia of rabbits, mice and hamsters with human herpesvirus type 1 (HVH) was compared using two different virus strains. Explantation proved to be effective in reisolation of HVH from ganglion tissue, which did not yield infectious virus at time of its removal. After healing of acute keratitis, the latent infection in homolateral gasseric ganglia of rabbits was detected at a relatively high frequency (60-80 per cent) up to 120 days post infection (p.i.) in case of both virus strains. The activation rate was a little lower in hamsters. After inoculation of suckling and young mice with a sublethal dose of HVH by oral and nasal routes, approximately 40-100 per cent of the animals had virus in their gasseric ganglia during the acute period; 30-60 days later only 10-25 per cent had virus in the latent form. Immunofluorescent and electron microscopic examination of the explanted ganglion tissue showed the presence of HVH in neurons, neuronal satellites and Schwann cells. The nuclei of noneural cells contained numerous crystalline arrays. The possibility that pseudounipolar neurons of the regional sensoric ganglion are not the exclusive site of HVH latency is discussed.
Animals↗
Reactivation of Kaposi's sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein.
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), or human herpesvirus 8, is a lymphotropic virus strongly linked to several AIDS-related neoplasms. The primary reservoir of infection consists of latently infected B lymphocytes and possibly other mononuclear cells. Viral reactivation from latency and spread from this lymphoid reservoir is presumably required for development of nonlymphoid tumors like KS. Here we show that deregulated expression of a single viral gene, ORF 50, which encodes a transactivator able to selectively upregulate delayed-early viral genes, suffices to disrupt latency and induce the lytic gene cascade in latently infected B cells. The identification of this gene opens the way to studies of the physiologic mechanisms controlling reactvation of KSHV from latency.
B-Lymphocytes↗
Cutaneous herpesvirus infection in a mallard duck (Anas platyrhynchos).
Investigations of mortalities involving wild mallard ducks (Anas platyrhynchos) revealed the presence of a herpesvirus associated with skin lesions on the plantar surface of the foot web of one duck. Ultrastructurally, the paracrystalline arrays of viral core particles and unencapsidated nucleoids in the nucleus, and the enveloped viruses in cytoplasmic vacuoles are compatible with a herpesvirus. This appears to be the first report of cutaneous lesions in a mallard duck attributable to a herpesvirus. Whether this lesion is due to duck virus enteritis (DVE), suggesting that cutaneous shedding is possible, or due to another uncharacterized herpesvirus of ducks is unclear.
Animals↗
Prevalence of herpesvirus infection in British red deer and investigations of further disease outbreaks.
A serological survey of the prevalence of a new herpesvirus isolated from red deer (Cervus elaphus), tentatively designated herpesvirus of Cervidae type 1 (HVC-1), has shown that the virus is widespread in free-living and farmed red deer. Neutralising antibodies were detected in hill deer culled at three different locations in the north of Scotland, in farmed deer on five of eight Scottish farms and in four of 12 groups of English farmed or park deer. Fifty-eight of 145 (40 per cent) hill deer, 67 of 203 (33 per cent) Scottish farmed deer and 26 of 172 (14 per cent) English deer had antibody, the overall prevalence being 29 per cent. Further outbreaks of ocular disease in farmed red deer calves caused by HVC-1 were investigated. Deer sent to an auction from one farm were found after sale to have been incubating the disease and it was thus spread to seven deer farms. Despite a high incidence of clinical disease in the calves from the original farm, few in-contact deer showed clinical signs.
Animals↗
Comparative studies on experimental latent herpesvirus infections.
Two different models of virus persistence in laboratory animals, that of herpes simplex virus (HSV-1) and that of murine herpesvirus (MHV), are described. While HSV-1 is harboured in a nonproductive form in the regional sensory ganglion of rabbits and mice, the persistence of MHV in mouse lungs and spleen is of a productive (dynamic) type. Since cultivation of kidney and trigeminal ganglion fragments enhanced the MHV recovery rate, one may assume that MHV persisted in a static form too, at least in some of the latter tissues. In contrast to HSV, MHV is predominantly disseminated by hematogenous route. So far no evidence of neural transmission of MHV has been found.
Animals↗
Bovine recombinant interleukin-2 augments immunity and resistance to bovine herpesvirus infection.
The in vivo administration of bovine recombinant interleukin-2 (rIL-2) was evaluated in calves vaccinated and then challenged with bovine herpesvirus-1 (BHV-1). In Experiment 1, 24 calves were allotted to four groups: control; bovine rIL-2; BHV-1 vaccine (modified-live); and bovine rIL-2 + BHV-1 vaccine. Serum neutralizing antibody titers to BHV-1 were increased sixfold, and virus shedding was fourfold less in calves vaccinated and treated with rIL-2 (25 micrograms/kg, intramuscularly) when compared to calves that received vaccine only. Treatment with rIL-2 induced lymphokine-activated killer activity that was eliminated by pretreating effector cells with complement and a monoclonal antibody (B26A) specific for the sheep red blood cell receptor. The rIL-2 treatment in BHV-1-vaccinated calves increased the calves' ability to withstand a BHV-1 challenge. However, during treatment with rIL-2, calves developed diarrhea and mild fever that abated after IL-2 treatment was stopped. A second experiment was then conducted to determine a dose of rIL-2 that would enhance immunity to BHV-1 without causing adverse side effects. Twenty-five calves were allotted to five groups that received injections of rIL-2 at 0.0, 25.0, 2.5, 0.25, or 0.025 micrograms kg-1 day-1 for 5 days. All calves received a modified-live BHV-1 vaccine. Calves treated with 25.0 micrograms kg-1 day-1 showed similar adverse side effects as in the first experiment but all other calves were normal. Compared to control calves, those treated with 25.0, 2.5, and 0.25 micrograms kg-1 day-1 of rIL-2 had higher (P less than 0.05) serum antibody titers to BHV-1 and following challenge lower (P less than 0.05) BHV-1 titers in nasal secretions; additionally, clinical disease as evidenced by nasal and ocular discharge was less severe (P less than 0.05). In vitro cytotoxic responses against BHV-1-infected bovine kidney cells were increased (P less than 0.05) in calves treated with rIL-2 in a dose dependent manner. These data suggest that bovine rIL-2 at 2.5 to 0.25 micrograms/kg may be an effective adjuvant to immunization.
Adjuvants, Immunologic↗
Effect of cyclosporin A immunosuppression on primary lymphotropic herpesvirus infection in the guinea pig.
Female guinea pigs pretreated for 2 days with cyclosporin A (CsA), were then inoculated intranasally (IN) or intraperitoneally (IP) with a lymphotropic herpesvirus (GPHLV) and followed by 4 additional daily doses of CsA. Immunosuppressed animals did not show lymphocytosis and virus infectivity titers in their spleen, cervical lymph node and blood mononuclear cells were lower than those of oil-treated controls. While IN-inoculated CsA-treated animals expressed higher virus infectivity titer in their lungs compared to oil-treated controls, this difference was not seen in the IP-inoculated groups. At histopathology, lymphoid depletion was seen in all CsA-treated animals, but lymphocytic interstitial pneumonia was observed only in the lungs of IN-inoculated CsA-treated guinea pigs. Thus, CsA immunosuppression altered the pathogenesis of primary GPHLV infection with some notable differences attributed to the route of virus inoculation.
Administration, Intranasal↗