Multiple sclerosis (MS) is a heterogeneous disease that develops as an interplay between the immune system and environmental stimuli in genetically susceptible individuals. There is increasing evidence that viruses may play a role in MS pathogenesis acting as these environmental triggers. However, it is not known if any single virus is causal, or rather several viruses can act as triggers in disease development. Here, we review the association of different viruses to MS with an emphasis on two herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). These two agents have generated the most impact during recent years as possible co-factors in MS disease development. The strongest argument for association of EBV with MS comes from the link between symptomatic infectious mononucleosis and MS and from seroepidemiological studies. In contrast to EBV, HHV-6 has been found significantly more often in MS plaques than in MS normal appearing white matter or non-MS brains and HHV-6 re-activation has been reported during MS clinical relapses. In this review we also suggest new strategies, including the development of new infectious animal models of MS and antiviral MS clinical trials, to elucidate roles of different viruses in the pathogenesis of this disease. Furthermore, we introduce the idea of using unbiased sequence-independent pathogen discovery methodologies, such as next generation sequencing, to study MS brain tissue or body fluids for detection of known viral sequences or potential novel viral agents.

/pdf/viruses-and-multiple-sclerosis-63u2lectu8.pdf

Viruses and multiple sclerosis.

Objectives – To systematically review the published evidence for a relationship between human herpes virus 6 (HHV-6) and multiple sclerosis (MS). Materials and methods – The medical literature was searched using MEDLINE and the Cochrane database. Retrieved studies are presented according to the experimental technique(s) used. The studies are rated for quality using a priori defined criteria. Results – Twenty-eight studies were retrieved. A total of 12 different experimental techniques were used. Four of these techniques provided evidence for a relationship between HHV-6 and MS, but none were able to show a causative relationship. Conclusions – The available literature provides some support for a relationship between HHV-6 and MS. The limitations of the available studies and directions for future research are discussed.

Human herpes virus 6 and multiple sclerosis

After serial passage in the presence of increasing concentrations of ganciclovir (GCV) in vitro, a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC(50) of this mutant was 24-, 52- and 3-fold higher than that of the wild-type (wt) IC(50) in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type: an A-->G substitution of the U69 protein kinase (PK) gene resulted in an M(318)V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A(961)V amino acid substitution within the DNA polymerase. The M(318)V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M(460)V and M(460)I changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The M(318)V change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCV-resistant HCMV infection. These findings provide strong circumstantial evidence that the M(318)V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.

Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo.

Study Objective:To determine the extent and clinical significance of high-level penicillin-resistantEnterococcus faeciumat our institution. Design:Surveillance of clinical enterococcal iso...

High-Level Penicillin Resistance among Isolates of Enterococci

Human herpesvirus 6 (HHV–6) is one of many infectious agents that have been implicated in the pathogenesis of multiple sclerosis (MS). Intrathecal immunoglobulin (Ig) production with oligoclonal CSF bands are hallmarks of both MS and infections of the CNS. In neuroinfections the intrathecal Ig production is directed largely against the respective agent, while MS patients mount an intrathecal Ig production against different pathogens. In this study a total of 77 serum/CSF pairs were first analyzed for an intrathecal immune response against HHV–6. We found that 21% of the MS patients, but none of the control donors showed an intrathecal immunoglobulin (Ig) response against HHV–6 (p = 0.017). Patients with such an intrathecal Ig production had a significantly higher total amount of Ig (p = 0.007) and a higher cell number in the CSF (p = 0.03). In a second step, four of the MS–patients who showed a strong intrathecal Ig production against HHV–6 were examined for immune reactivity against other viruses (human herpesvirus type 1, measles virus, human cytomegalovirus, rubella virus, varicella zoster virus). All of these patients had an intrathecal Ig production against at least one other, unrelated virus. Together, our findings strongly argue that in the majority of MS patients without an intrathecal Ig response to HHV–6 (about 80 % in our study), this virus is not involved in the pathogenesis. In the other 20% the intrathecal Ig production to HHV–6 might reflect reactivation of HHV–6 or could be part of a polyspecific B cell activation.

Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of multiple sclerosis patients and might be linked to a polyspecific B–cell response

In the possible role for human herpesviruses (HHV) in the pathogenesis of multiple sclerosis (MS) neither clear distinction between the two variants of HHV-6, nor the involvement of HHV-7 have been described. Therefore, we quantitated HHV-6 variant specific and HHV-7 reacting antibodies in the CSF of 13 patients with MS or other neurological disorders by ELISA. Predominance in the positivity of IgG (67%) and IgM (44%) to HHV-6B over that of IgG (44%) with no detectable IgM to HHV-6A, and no antibodies to HHV-7 were found in the CSF of MS patients. None of these antibodies were found in the CSF of controls. This suggests that, intrathecal chronic active or primary HHV-6B infection might contribute to MS progression, while the local effects of HHV-6A and HHV-7 seem to be less important.

/pdf/a-pilot-study-on-the-antibodies-to-hhv-6-variants-and-hhv-7-3v20dxirv6.pdf

A pilot study on the antibodies to HHV-6 variants and HHV-7 in CSF of MS patients.

/pdf/pcr-detection-of-the-vana-gene-in-a-vancomycin-resistant-28talazzwz.pdf

PCR detection of the vanA gene in a vancomycin-resistant Enterococcus faecalis clinical isolate from Hungary

Prevalence of antibodies to variants HHV-6A and B as well as HHV-7, the time of primary infections are not know in Hungarian children Therefore, antibodies to these viruses were studied in 21 healthy children aged between 6 and 18 months Lymphoid cultures were infected with standard virus strains for indirect immunofluorescence IgM, IgG and high avidity IgG after 8M urea treatment were quantified in serial dilutions of sera It was established that, three of 13 boys had low level (1:20) IgG or IgM antibodies to HHV-6A, but all girls were negative With exception of one girl and one boy, all had antibodies to HHV-6B in different titres (1:20 to 1:640 by immunofluorescence), in 9 cases only IgM, in further 4 cases only low avidity IgG were detected Children studied gradually acquired symptom-free HHV-6B infection between age of 8 and 18 months Antibodies to HHV-7 were found in 3 boys and one girl before their age of 12 months, but the majority were infected after that age Approximately three quarters of children acquired either HHV-6B or HHV-7 before age of 18 months More than half of the children were infected with HHV-6B prior to HHV-7 Antibody level to HHV-6B was slightly higher in boys, while that to HHV-7 was higher in girls In Hungary, childhood infection with HHV-6A seems to be a very rare event Epidemiology of HHV-6B primary infection is similar to that of industrial countries, while that of HHV-7 resembles data of developing world: onset of antibodies occurs 1 or 2 years earlier than in the industrial nations

Emberi 6-os és 7-es típusú herpesvírusok elleni antitestek megjelenése magyarországi gyermekekben.

Molecular mechanisms of the action of b-lactam and glycopeptide antibiotics, as well as genetic background and phenotipical features of the resistance of staphylococci, streptococci and enterococci to these antibiotics are reviewed. Furthermore, susceptibility patterns concerning b-lactam and glycopeptide drugs of staphylococcal, streptococcal, as well as enterococcal strains isolated from clinical specimens at the Semmelweis University of Medicine, Budapest, Hungary between January 1997 and December 2000 are also presented.

/pdf/resistance-to-beta-lactams-and-glycopeptides-in-4hw1beax4v.pdf

Resistance to beta-lactams and glycopeptides in staphylococci and streptococci.

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.

Studies on the antibodies to human herpesvirus type 6 among Hungarian patients with asymptomatic HIV infection.

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