Genetic Relationship of Borna Disease Virus Isolates

The infection of humans with Borna disease virus (BDV) is still a matter of debate. In a recent publication, we described a BDV (RW98) isolated from the blood of a psychiatric patient. The RNA of this virus differed more than 5% from that of the widely used strain He/80, which was supposed to represent our laboratory virus. Here, we show that the virus used in our laboratory was not He/80 and, furthermore, that RW98 has sequence identity to the laboratory strain. We also present data that BDV-specific nucleic acid detected in blood of the donor of the presumed RW98 isolate and one other patient differs from all known BDV-p24 sequences, arguing for the existence of BDV sequences in man.     

Detection by Radioligand Assay of Antibodies against Borna Disease Virus in Patients with Various Psychiatric Disorders

Using a radioligand assay, which preserves the natural form of the antigen, antibodies against Borna disease virus nucleoprotein and phosphoprotein were detected in 11 and 19 sera of 171 psychiatric patients, respectively. Compared with results by Western blotting, three and nine sera were concordantly positive, respectively. The four sera showing the highest levels of antibodies by radioligand assay were all negative by Western blotting; however, dilution and inhibition tests supported the positive results. Our results suggest the importance of conformational structure to detect human anti-Borna disease virus antibodies.     

Self Antigen Prognostic for Human Immunodeficiency Virus Disease Progression

We have recently found that an extracellular protein, α₁ proteinase inhibitor (α₁PI; α₁ antitrypsin), is required for in vitro human immunodeficiency virus (HIV) infectivity outcome. We show here in a study of HIV-seropositive patients that decreased viral load is significantly correlated with decreased circulating α₁PI. In the asymptomatic category of HIV disease, 100% of patients manifest deficient levels of active α₁PI, a condition known to lead to degenerative lung diseases and a dramatically reduced life span. Further, HIV-associated α₁PI deficiency is correlated with circulating anti-α₁PI immunoglobulin G. These results suggest that preventing HIV-associated α₁PI deficiency may provide a strategic target for preventing HIV-associated pathophysiology.     

Neuropeptide Y up-regulation in cerebrocortical neurons after Borna Disease Virus infection is unrelated to brain inflammation in rats

Neuropeptides participate in the pathophysiology of cerebral inflammatory diseases. We analyzed the involvement of neuropeptide Y (NPY) in rat brain infected with Borna Disease Virus (BDV). NPY expressing cerebrocortical neurons were increased during the acute stage of BDV-induced encephalitis. The increase was resistant to immunosuppression by systemic dexamethasone, which greatly reduced inflammatory reactions in the brain. This indicates that the increase of cerebrocortical NPY expression is not causally related to inflammation. As cerebral NPY is known to be increased during experimental seizures and to have anticonvulsive actions, we propose that NPY up-regulated during BDV encephalitis limits seizures known to be associated with Borna Disease.     

Influence of immunosuppressive treatment on Borna Disease in rabbits

Summary A total of 72 Borna Disease virus infected rabbits were treated with different concentrations of cyclophosphamide, glucocorticoids or both in combination. Comparison with untreated, infected rabbits showed a drastic alteration in the clinical picture, a considerable prolongation of the survival time, and differences in weight and body temperature during the course of the disease. The immunosuppressed animals had no or low amounts of antibodies in the serum and cerebrospinal fluid, but they harbored infectious virus and high amounts of specific antigen in the brain. A quotient of the relative amount of antibodies and antigen never exceeded 0.20 and was significantly lower than in untreated rabbits. Immunohistologically, differences in location and distribution of antigen as compared to positive untreated animals could not be detected. In the immunosuppressed animals perivascular infiltrates were not observed in the different regions of the brain.With 4 Figures     

Persistent Borna Disease Virus (BDV) infection activates microglia prior to a detectable loss of granule cells in the hippocampus

Neonatal Borna Disease Virus (BDV) infection in rats leads to a neuronal loss in the cortex, hippocampus and cerebellum. Since BDV is a non-lytic infection in vitro, it has been suggested that activated microglia could contribute to neuronal damage. It is also conceivable that BDV-induced cell death triggers activation of microglia to remove cell debris. Although an overall temporal association between neuronal loss and microgliosis has been demonstrated in BDV-infected rats, it remains unclear if microgliosis precedes or results from neuronal damage. We investigated the timing of microglia activation and neuronal elimination in the dentate gyrus (DG) of the hippocampus. We found a significant increase in the number of ED1+ microglia cells as early as 10 days post infection (dpi) while a detectable loss of granule cells of the DG was not seen until 30 dpi. The data demonstrate for the first time that a non-lytic persistent virus infection of neurons activates microglia long before any measurable neuronal loss.     

Disturbance of the Cortical Cholinergic Innervation in Borna Disease Prior to Encephalitis

Rats experimentally infected with the highly neurotropic Borna disease virus (BDV) display a wide variety of dysfunction such as learning deficiencies and behavioral abnormalities. Prior to the onset of encephalitis alterations of one of the major cortical neurotransmitters, acetylcholine, were monitored immunohistochemically by light and electron microscopy of its synthesizing enzyme choline acetyltransferase (ChAT). We found a progressing decrease in the number of ChAT-positive fibers, starting with discrete changes at day 6 post infection (p.i.) and ending with a nearly complete loss of cholinergic fibers, especially in the hippocampus and neocortex, suggesting a massive disturbance of the cholinergic innervation by day 15 p.i. The fiber pathways (e.g., fimbria-fornix) connecting the basal forebrain with these target areas in the cortex displayed axon spheroids which are often linked to axonal transport dysfunction. No evidence for significant cellular destruction was seen in the brain, including the cells of origin of these axons in the basal forebrain. We conclude that the motor, mood, learning and memory disabilities in BDV-infected rats are likely to result, in part, from cortical cholinergic denervation. The present study gives new insights into the pathogenesis of neurological disease caused by a noncytopathogenic virus.     

Patients Presenting with Advanced Human Immunodeficiency Virus Disease: Epidemiological Features by Age Group

We explored factors influencing presentation with advanced human immunodeficiency virus (HIV) disease by age group. Data were derived from a city-wide cross-sectional survey of 759 HIV-infected adults living in Seoul, Korea. The significance of each observed factor was assessed via multivariate logistic regression. Of subjects aged 20-34 years, lower educational level had a positive influence on presentation with advanced HIV disease (adjusted odds ratio [aOR], 2.43; 95% confidence interval [CI], 1.36-4.34); those recently diagnosed with HIV were more likely to be presented with advanced HIV disease (aOR, 3.17; 95% CI, 0.99-10.2). Of the subjects aged 35-49 years, those w ith advanced HIV disease were more likely to have been diagnosed during health check-ups (aOR, 2.91; 95% CI, 1.15-7.32) or via clinical manifestations (aOR, 3.61; 95% CI, 1.39-9.36). Of the subjects aged ≥ 50 years, presentation with advanced HIV disease was significantly more common in older subjects (aOR per increment of 5 years, 2.06; 95% CI, 1.32-3.23) and less common among individuals diagnosed with HIV in 2000-2006 (aOR, 0.18; 95% CI, 0.04-0.83). In conclusion, a lower educational level in younger subjects and more advanced age in older subjects positively influence the presentation of advanced HIV disease.     

Human Immunodeficiency Virus Type 1 Disease Progression, CCR5 Genotype, and Specific Immune Responses

The correlation among the presence of a 32-bp deletion in the CC-chemokine receptor 5 (CCR5) gene, disease progression, and human immunodeficiency virus type 1 (HIV-1)-specific immune responses was analyzed for a cohort of 79 Caucasian HIV-1-infected patients. The CCR5 genotype (CCR5/CCR5 = wild type/wild type or Δ32CCR5/CCR5 = 32-bp deletion/wild type) in peripheral blood mononuclear cells was determined by PCR, followed by sequencing of both wild-type and Δ32CCR5 gene fragments. HIV-1-specific humoral responses to gp41 and V3_MN peptides were determined by enzyme immunoassays. The prevalence of the Δ32CCR5 allele was lower among 37 patients with rapid progression (progression to AIDS or to a CD4 cell count of <200 × 10⁶/liter in less than 9 years; P < 0.01) compared to that for 42 patients with slow progression (no AIDS and CD4 cell count of >200 × 10⁶/liter after at least 9 years from infection) or to that for 25 non-HIV-1-infected Swedish blood donors (P < 0.05). No differences were observed in the wild-type CCR5 sequences between the different groups of patients. For three analyzed patients, the 32-bp Δ32CCR5 gene deletions were identical. The antibody titers against gp41 and a V3_MN peptide in patients with the Δ32CCR5/CCR5 genotype were not significantly different from those in pair-matched CCR5/CCR5 controls. However, in 13 analyzed patients, a stronger serum neutralizing activity was associated with the Δ32CCR5/CCR5 genotype. Thus, a CCR5/CCR5 genotype correlates with a shortened AIDS-free HIV-1 infection period and possibly with a worse neutralizing activity, without an evident influence on the antibody response to two major antigenic regions of HIV-1 envelope.     

Immunomodulatory Effects of Newcastle Disease Virus AF2240 Strain on Human Peripheral Blood Mononuclear Cells

Immunotherapy has raised the attention of many scientists because it hold promise to be an attractive therapeutic strategy to treat a number of disorders. In this study, the immunomodulatory effects of low titers of Newcastle disease virus (NDV) AF2240 on human peripheral blood mononuclear cells (PBMC) were analyzed. We evaluated cytokine secretion and PBMC activation by cell proliferation assay, immunophenotyping and enzyme linked immunosorbent assay. The proliferation of the human PBMC was measured to be 28.5% and 36.5% upon treatment with 8 hemaglutinin unit (HAU) and 2 HAU of NDV respectively. Interestingly, the percentage of cells with activating markers CD16 and CD56 were increased significantly. Furthermore, the intracellular perforin and granzyme levels were also increased upon virus infection. Human PBMC treated with NDV titer 8 HAU was found to stimulate the highest level of cytokine production including interferon-γ, interleukin-2 and interleukin-12. The release of these proteins contributes to the antitumor effect of PBMC against MCF-7 breast cancer cells. Based on the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay, activated human PBMC showed high cytolytic efficiency towards human breast tumor cells. In summary, NDV was able to stimulate PBMC proliferation, cytokine secretion and cytolytic activity.