Simultaneous Guillain-Barrè syndrome and active human herpesvirus 6 infection in the central nervous system.
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Central Nervous System Diseases↗
Biomedical subjects
D Di Luca
Publications and source records attributed to D Di Luca.
A combined bovine herpesvirus 1 gB-gD DNA vaccine induces immune response in mice.
Although DNA vaccines have several advantages over conventional vaccines, antibody production and protection are often not adequate, particularly in single plasmid vaccine formulations. Here we assessed the potential for a combined vaccine based on plasmids encoding the membrane-anchored or secreted forms of bovine herpesvirus type 1 (BHV-1) glycoprotein B and D (gB and gD) to induce neutralizing and cell mediated immune responses in mice. Animals were injected by intramuscular, subcutaneous and intranasal routes. Mice immunized with the combined vaccine containing the secreted forms of BHV-1 glycoproteins developed higher titers of anti-BHV-1 neutralizing antibodies, compared to wild type gB/gD combined plasmids and to single plasmid injected groups. Cellular immunity was also developed in mice immunized with combined vaccines, whereas low or no response were observed in single plasmid injected animals. The data suggest the potential use of this combined vaccine in in vivo trials of calves, in order to evaluate its protective efficacy.
Administration, Intranasal↗
Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease.
The presence and the replicative state of human herpesvirus 6 (HHV-6) were evaluated in clinical samples from multiple sclerosis (MS) patients at the first time of MS diagnosis. HHV-6 variant B was present in peripheral blood mononuclear cells of 5/32 (15%) patients, but persisted with a latent infection. Viral sequences were present also in cerebrospinal fluid (CSF), both free in the liquid (7/32, 22%) and latent in the cellular fraction (3/32, 9%), as shown by analysis of viral transcription. In these cases, variant A was detected. HHV-6 DNA sequences present in the CSF were associated to mature viral particles. In fact, in vitro infectious assays of CSF showed the presence of replication-competent virions. These results show that about 20% of MS patients have active foci of HHV-6 variant A infection in the early stages of the disease and suggest that viral replication takes place within the central nervous system.
Central Nervous System Diseases↗
Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients.
Orthotopic liver transplantation (OLT) is the only effective therapeutic modality in severe acute hepatic failure (AHF). The scarcity of organs for transplantation leads to an urgent necessity for temporary liver support treatments in AHF patients. A hepatocyte-based bioartificial liver (BAL) is under investigation with the main purpose to serve as bridging treatment until a liver becomes available for OLT, or to promote spontaneous liver regeneration. We developed a novel radial-flow bioreactor (RFB) for three-dimensional, high-density hepatocyte culture and an integrated pumping apparatus in which, after plasmapheresis, the patient's plasma is recirculated through the hepatocyte-filled RFB. Two hundred thirty grams of freshly isolated porcine hepatocytes were loaded into the RFB for clinical liver support treatment. The BAL system was used 8 times in supporting 7 AHF patients in grade III-IV coma, all waiting for an urgent OLT Three patients with no history of previous liver diseases were affected by fulminant hepatic failure (FHF) due to hepatitis B virus, 3 by primary non-function (PNF) of the transplanted liver, and one by AHF due to previous abdominal trauma and liver surgery. Six out of 7 patients underwent OLT following BAL treatment(s), which lasted 6-24 hours. All patients tolerated the procedures well, as shown by an improvement in the level of encephalopathy, a decrease in serum ammonia, transaminases and an amelioration of the prothrombin time, with full neurological recovery after OLT Our initial clinical experience confirms the safety of this BAL configuration and suggests its clinical efficacy as a temporary liver support system in AHF patients.
Adolescent↗
Human herpesvirus 7 is latent in gastric mucosa.
Chronic gastritis is associated frequently with persistent infection by Helicobacter pylori. However, not all patients with chronic gastritis have evidence of H. pylori infection, suggesting that other factors might contribute to the development of gastritis. The present study was undertaken to evaluate a possible etiologic role of human herpesvirus 7 (HHV-7). HHV-7 DNA was detected in about 80% of gastric biopsies, both in healthy mucosa from individuals without evidence of inflammation and in biopsies from patients with histologically confirmed chronic gastric inflammation. HHV-7 was present also in H. pylori negative samples, was associated specifically with gastric tissue and not with residual blood within the mucosa, and was present with high viral loads. HHV-7 DNA persisted in several patients also after remission of gastric inflammation and the viral presence did not correlate with specific symptoms. Analysis by RT-PCR showed that HHV-7 is transcriptionally inactive in chronic gastritis lesions. These observations show that gastric tissue represents a site of HHV-7 latent infection and a potential reservoir for viral reactivation.
Biopsy↗
PCR in meningoencephalitis diagnosis.
Polymerase chain reaction (PCR) detection of a stretch of nucleic acid sequence of microbial origin from a clinical sample is not always diagnostic of disease unless the identified agent is a strict pathogen or its growth is documented. We describe here a case of acute meningoencephalitis in a 21-y-old man, in whom no pathogen was isolated by traditional bacterial or viral culture. Standard DNA PCR performed on the cerebrospinal fluid (CSF) identified the presence of 3 infectious agents: HHV-6, HHV-7 and Mycoplasma pneumoniae. Additional PCRs performed on CSF fractions along with gene transcript analysis proved the bystander role of the 2 herpesviruses and indicated M. pneumoniae as the relevant replicating agent, most likely playing to be a pathogenic role. Until this useful analysis becomes routine, clinicians should deal carefully with DNA PCR results, especially when assessing the aetiological role of agents, such as herpesviruses, which are known to undergo latency.
Acute Disease↗
Human herpesvirus 6 infects and replicates in aortic endothelium.
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Aorta↗
Human herpesvirus 6 is latent in peripheral blood of patients with relapsing-remitting multiple sclerosis.
Studies of the association between HHV-6 and multiple sclerosis are hindered by the difficulty in discriminating between latent and active infection. A follow up study was undertaken of patients with multiple sclerosis, searching peripheral blood mononuclear cells for molecular markers associated with HHV-6 latency and lytic replication. The results show that HHV-6 is latent and did not support systemic infection in patients with multiple sclerosis. Likewise, patients with multiple sclerosis did not show any evidence of active infection with other human herpesviruses HHV-7 and HHV-8.
Adolescent↗
U94 of human herpesvirus 6 is expressed in latently infected peripheral blood mononuclear cells and blocks viral gene expression in transformed lymphocytes in culture.
Human herpesvirus 6 (HHV-6) like other herpesviruses, expresses sequentially immediate early (IE), early, and late genes during lytic infection. Evidence of ability to establish latent infection has not been available, but by analogy with other herpesviruses it could be expected that IE genes that regulate and transactivate late genes would not be expressed. We report that peripheral blood mononuclear cells of healthy individuals infected with HHV-6 express the U94 gene, transcribed under IE conditions. Transcription of other IE genes (U16/17, U39, U42, U81, U89/90, U91) was not detected. To verify that U94 may play a role in the maintenance of the latent state, we derived lymphoid cell lines that stably expressed U94. HHV-6 was able to infect these cells, but viral replication was restricted. No cytopathic effect developed. Furthermore, viral transcripts were present in the first days postinfection and declined thereafter. A similar decline in the level of intracellular viral DNA also was observed. These findings are consistent with the hypothesis that the U94 gene product of HHV-6 regulates viral gene expression and enables the establishment and/or maintenance of latent infection in lymphoid cells.
Cell Transformation, Viral↗
Studies on the antibodies to human herpesvirus type 6 among Hungarian patients with asymptomatic HIV infection.
The occurrence and the possible role in promoting HIV infection by human herpesvirus type 6 (HHV-6) have not yet been revealed in Hungary. In different groups of patients, serum titre of IgM and IgG antibodies, as well as avidity of IgG were quantitated by indirect immunofluorescence and an enzyme-linked immunosorbent assay, using isolate U1102 of HHV-6 variant A as antigen. In 60% of HIV-seronegative adult controls, high avidity IgG antibodies were found in low titre suggesting childhood infection. In HIV-seronegative persons with high risk behaviour for HIV-infection, both IgM and low avidity IgG were frequently found in higher titre, representing either primary or frequent reinfections, or reactivation of latent HHV-6. In asymptomatic HIV-seropositive patients, high titre of high avidity IgG antibodies was predominant, proving virus infection in the near past. These results indicate the contribution of HHV-6 to immunosuppression prior to AIDS, predisposing the organism to HIV infection.
Adult↗
Persistence of human herpesvirus 7 in normal tissues detected by expression of a structural antigen.
Human herpesvirus 7 (HHV-7) infection in histologically normal human tissues was investigated by immunohistochemical detection of the 85-kDa tegument phosphoprotein (pp85) encoded by the U14 gene. So far, two cell types were recognized as sites of HHV-7 infection in vivo: CD4+ T lymphocytes, believed to be the site of latent infection, and epithelial cells of salivary glands, the site of productive infection and viral shedding. Unexpectedly, cells expressing the HHV-7 structural antigen were detectable in lungs, skin, and mammary glands. Morphologically and phenotypically, they were distinct from lymphocytes. Liver, kidney, and tonsils were positive, although the number of HHV-7-positive cells was low. Large intestine, spleen, and brain were negative. Different from the current notion of the state of HHV-7 in humans, the results show that a variety of tissues harbor cells at a late stage of infection and suggest that HHV-7 causes a persistent rather than a true latent infection.
Antigens, Viral↗
Temporal mapping of transcripts in herpesvirus 6 variants.
To define the molecular features characteristic of the early stages of infection of lymphocytes with human herpesvirus 6 (HHV-6) variant A or B, we studied the temporal regulation of expression of selected sets of viral genes. Thus, U42, U94, U89-U90, U73, and U39 are alpha genes since their transcripts (i) were made in the presence of inhibitors of protein synthesis and (ii) were detected 3 h after infection of untreated cells. U41, U53, U31, and U19 are beta genes since their expression is inhibited by cycloheximide but not by phosphonoacetate, an inhibitor of DNA synthesis. U100 is a gamma gene since its spliced transcript encoding the structural glycoprotein gp82/105 was first detected 16 h after infection of untreated cells but could not be detected in cells treated with phosphonoacetate. HHV-6 variants differ in the transcription patterns of their genes. U16-U17 originates a splice transcript and is regulated as alpha in HHV-6B and as beta in HHV-6A. U91 generates two transcripts, amplified as 476- and 374-bp PCR fragments. The 476-bp fragment is alpha in HHV-6A-infected cells but beta in HHV-6B-infected cells. Conversely, the 374-bp fragment is beta in HHV-6A-infected cells and alpha in HHV-6B-infected cells. Furthermore, the spliced product of U18-U19-U20 (526 bp) is beta in HHV-6A-infected cells, but only a partially spliced form (1.9 kb) was detected at late stages of infection in HHV-6B. HHV-6 transcription was also studied in nonproductive lymphoid cells, and the same transcription pattern detected during lytic infection was observed. Also, HHV-6 variants maintain the differences in U91, U16-17, and U18-U19-U20. We conclude that, as expected from the sequencing data, gene expression is generally similar in HHV-6 variants. However, transcription of selected genes in HHV-6A and HHV-6B differs with respect to temporal regulation and splicing pattern. Furthermore, the identification of viral functions expressed during the different stages of lytic replication suggests that reverse transcription-PCR for HHV-6 genes is a useful diagnostic approach to differentiate between latent and productive HHV-6 infection.
Cell Line↗
Human herpesvirus 6 in human immunodeficiency virus-infected individuals: association with early histologic phases of lymphadenopathy syndrome but not with malignant lymphoproliferative disorders.
Preliminary evidence suggested that human herpesvirus-6 (HHV-6) may act as a cofactor in acquired immunodeficiency syndrome (AIDS) and may contribute to the pathogenesis of lymphoproliferative disorders occurring in individuals infected with the human immunodeficiency virus (HIV). To understand better the biological and clinical significance of HHV-6 infection in the context of HIV-related immunosuppression, the polymerase chain reaction was used to study the frequency and variant distribution of HHV-6 in peripheral blood mononucleated cells (PBMCs) from HIV-seropositive individuals, either asymptomatic or with lymphadenopathy syndrome (LAS) or with overt AIDS. Non-neoplastic and malignant lymphoproliferative disorders from both HIV-infected and HIV-seronegative patients were also investigated using the same series of samples for the presence of Epstein-Barr virus (EBV). When compared with healthy blood donors (12/42, 29%), HHV-6 prevalence in PBMCs showed a progressive decline in HIV-seropositive individuals with asymptomatic HIV infection (3/26, 11%) and in patients with LAS (1/13, 8%) and a significant reduction in patients with overt AIDS (1/20, 20%; P = 0.02). The decrease correlated with the number of CD4+ cells at the time of examination. In addition, HHV-6 DNA sequences were significantly more prevalent in LAS biopsies (13/20, 65%) than in HIV-unrelated reactive lymphadenopathies (2/10, 20%; P = 0.02) and the presence of HHV-6 sequences correlated closely with a histologic pattern of follicular hyperplasia (13/16, 81%; P = 0.003). Strikingly, HHV-6 prevalence decreased in PBMCs of LAS patients, suggesting that the likelihood of interactions between HHV-6 and HIV varies in different body districts. In particular, the demonstration that all HHV-6-carrying LAS samples were also positive for HIV infection suggests that LAS lymph nodes constitute one of the sites where biologically relevant interactions between the two viruses might occur. Also, the prevalence of EBV was higher in LAS (14/20, 70%) than in non-neoplastic lymph nodes from HIV-seronegative individuals (4/10, 40%), although the difference was not statistically significant. EBV was associated strongly with HIV-related malignant lymphoproliferative disorders, being detected in 100% of patients with Hodgkin's disease (HD) and 53% of B-cell non-Hodgkin's lymphomas (NHL). In contrast, the prevalence of HHV-6 DNA in HD and B-cell NHL arisen in HIV-infected patients (30% and 6% respectively) was remarkably lower and similar to that observed in lymphoproliferative disorders from HIV-seronegative patients. Finally, as observed in healthy individuals, HHV-6 variant B was more prevalent than variant A in benign and malignant lymphoproliferative disorders from bot HIV-infected and HIV-seronegative patients. These results suggest that the interactions between HHV-6 and HIV could be different in the various phases of HIV disease and in different districts; HHV-6 has probably no direct role in the pathogenesis of HIV-associated B-cell NHL and HD cases, and behave differently from EBV; and HIV-related immunosuppression does not alter the distribution of HHV-6 variants in these tissues, as observed in the case of EBV.
AIDS-Related Complex↗
Human herpesvirus 8 is present in the lymphoid system of healthy persons and can reactivate in the course of AIDS.
In this study the prevalence of human herpesvirus (HHV) 8 DNA was determined in biopsies from persons with lymphoproliferative disorders and in peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus (HIV)-seronegative and HIV-infected persons. The results show that HHV-8 is present in 10% of biopsies from HIV-seronegative persons: HHV-8 is detected with similar prevalence values in HIV-infected patients with lymphoproliferative diseases, but the virus load is higher. HHV-8 was also found in PBMC. The presence of monoclonal Epstein-Barr virus (EBV) genomes in malignant lymphoproliferations was only infrequently associated with HHV-8 infection. Therefore, HHV-8 is fairly common in the population, and the lymphoid system could represent a reservoir of latently infected cells from which the virus may reactivate in conditions of immunodepression; furthermore, HHV-8 and EBV do not seem to act in conjunction in lymphomagenesis.
AIDS-Related Opportunistic Infections↗
B cell clonality in gastric lymphoid tissues of patients with Sjögren's syndrome.
OBJECTIVE: To determine the prevalence of mucosa associated lymphoid tissue (MALT) in the stomach and of a possible antigen driven proliferation, in patients with Sjögren's syndrome (SS). METHODS: Twenty one patients with primary SS and 80 dyspeptic controls underwent upper endoscopy. Lymphoid tissue and Helicobacter pylori were assessed by histopathological analysis. Epstein-Barr virus (EBV) or human herpes virus-6 (HHV-6) genome were studied by polymerase chain reaction (PCR) DNA amplification. Two PCR VDJ procedures were used to detect immunoglobulin heavy chain (IgH) gene rearrangement. RESULTS: Organised MALT was found in 33.3% of the patients, compared with 21.5% of the controls (NS). H pylori infection was seen in 71% of patients and 63% of controls. Genomic EBV or HHV-6 was found in a minor portion of SS gastric tissues. B cell expansion was detected in nine of the 21 patients. Infectious agents in the stomach might have contributed to B cell clonality only in 55.5% of the cases. No strict relationship was found between lymphoid follicles and clonality. CONCLUSION: Lymphoid accumulation in the gastric mucosa is common in Sjögren's syndrome, but full evidence for an antigen driven B cell expansion could not be demonstrated. Only a portion of those with clonal B cell expansion had evidence of an infectious agent. Other unknown infectious agents or factors related to the underlying disease (autoantigen) and its tissue environment may have a further role as possible causes of B clonal expansion in the gastric mucosa.
Adult↗
Transcriptional activation of human immunodeficiency virus type 1 by herpesvirus infection: an in vivo footprinting study.
The process of transcriptional activation directed by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) was investigated by in vivo footprinting using ligation-mediated polymerase chain reaction in a human epithelial cell line infected with human herpes simplex virus type 1 (HSV-1) or human herpes virus 6 (HHV-6). Infection with both viruses induces a remarkable enhancement in LTR-mediated gene expression that correlates with a change in the pattern of protein binding to the downstream kappa B site of the enhancer region. In HHV-6 infected cells, this change in the genomic footprinting pattern is concomitant with the induction of specific enhancer-binding proteins in the nucleus. The similarity of these events to those detected in other previously investigated experimental systems suggests that the LTR enhancer region is the ultimate target for the induction of the HIV-1 transcriptional response upon stimuli acting through different upstream pathways.
Animals↗
Role of IFN gamma on TNF alpha, IL-1 beta and IL-6 release during HHV-6 infection.
The release of monokines such as Tumor Necrosis Factor a (TNF alpha), Interleukin-1 beta (IL-1 beta) and Interleukin-6 (IL-6) by activated monocytes/macrophages is an important step in the immune as well as in the inflammatory response. In this study the production of TNF alpha, IL-1 beta and IL-6 by human monocytes (HM) and peripheral blood mononuclear cells (PBMC) was evaluated after HHV-6 infection. Our results demonstrate that HHV-6 can selectively regulate monokine synthesis, in a time-dependent manner. Moreover, we observed a different response closely related to the cellular population (HM or PBMC) examined. The hypothesis we evaluated was that IFN gamma is an important factor triggering the activation of HHV-6 infected human monocytes, to release monokines.
Adjuvants, Immunologic↗
Distribution of HHV-6 variants in human tissues.
Human herpesvirus (HHV)-6 strains segregate into two variants (HHV-6A and HHV-6B), closely related to each other but clearly and easily distinguishable. These two HHV-6 variants differ in their ability to grow in T-cell lines, have distinctive patterns of DNA restriction fragments, and show specific reactivities with some monoclonal antibodies. The degree of DNA homology between variants ranges from 97% in the most conserved region to 75% in the immediate early region 1. HHV-6B is the etiologic agent of exanthema subitum but HHV-6A has not yet been clearly associated with any human pathology. HHV-6 sequences are frequently detected by the polymerase chain reaction (PCR) in healthy and pathological tissues. HHV-6B is more prevalent in peripheral blood mononuclear cells and in lymphatic tissue. The prevalence of HHV-6A may be greater in some pathological conditions such as Kaposi's sarcoma, and in skin biopsies. Results so far available support the hypothesis that HHV-6 variants may have different epidemiologies.
Exanthema Subitum↗