Borna disease virus and human disease

Abstract

The biology of Borna disease virus (BDV) strongly supports the likelihood of human infection with BDV or a variant of BDV. Thus far, the evidence supporting BDV infection in humans has initiated much controversy among basic and clinical scientists; only time and additional research will support or refute the hypothesis of human BDV infection. Until an assay of acceptable specificity and sensitivity has been developed, validated, and used to document human BDV infection, scientists cannot reasonably begin to associate BDV infection with specific disease syndromes. Clinical studies seeking causal associations between BDV infection and specific diseases must ensure the proper identification of the BDV infection status of patients and control subjects by using a validated, highly sensitive, and highly specific assay (or series of assays). For clinical studies, a highly sensitive "screening" test followed by a highly specific confirmatory test will be of significant benefit. Although it is possible to formulate hypotheses about the clinical outcomes of human BDV infection based on animal model work, to date no human disease has been causally linked to human BDV infection. Scientists all over the world are actively pursuing these issues, and with continuing advances in clinical and basic BDV research, the answers cannot be far away.

FIG. 1

BDV genome and gene products. Figure courtesy of Patrick Lai, Salem-Teikyo University, Salem, W.V.

FIG. 2

(A and B) OL cells mock infected or persistently infected with HuP2br were immunohistochemically stained with polyclonal rabbit anti-BDV p40 and then with fluorescein isothiocyanate-conjugated goat anti-rabbit IgG (A) and were subjected to in situ hybridization using antisense digoxigenin-conjugated riboprobe directed to BDV p40 region and then stained with fluorescent-labeled anti-digoxigenin Ig (B). (C) Newborn gerbils were mock infected or infected with HuP2Br. The sections prepared from the cerebral cortex (frontal lobe) of the gerbils on day 30 postinfection were subjected to in situ hybridization using antisense riboprobe directed to the BDV p40 region. Figure courtesy of Kazuyoshi Ikuta, Osaka University, Osaka, Japan.

FIG. 2

(A and B) OL cells mock infected or persistently infected with HuP2br were immunohistochemically stained with polyclonal rabbit anti-BDV p40 and then with fluorescein isothiocyanate-conjugated goat anti-rabbit IgG (A) and were subjected to in situ hybridization using antisense digoxigenin-conjugated riboprobe directed to BDV p40 region and then stained with fluorescent-labeled anti-digoxigenin Ig (B). (C) Newborn gerbils were mock infected or infected with HuP2Br. The sections prepared from the cerebral cortex (frontal lobe) of the gerbils on day 30 postinfection were subjected to in situ hybridization using antisense riboprobe directed to the BDV p40 region. Figure courtesy of Kazuyoshi Ikuta, Osaka University, Osaka, Japan.

FIG. 3

Expression of BDV N (p40) antigen and BDV RNA in autopsy tissue from the human brain. (A) For detection of viral antigen, hippocampal sections from brains of representative patients with hippocampal sclerosis (HS) or Alzheimer's disease (AD), immunolabeled with either a rabbit anti-BDV N serum or an anti-GFAP antibody, were used. (B) For detection of viral nucleic acid, RNA was isolated from frozen brain samples of hippocampal sclerosis or Alzheimer's disease patients and analyzed by RT-PCR using specific primers to amplify a 528-nucleotide segment of the BDV N ORF. An aliquot of cDNA from each sample was also used to amplify glyceraldehyde-3-phosphate dehydrogenase (GAPDH) sequences by RT-PCR as a control of RNA quality. The BDV specificity of the PCR products was confirmed by Southern blot hybridization using a BDV N probe internal to the predicted PCR product. Figure courtesy of Juan Carlos de la Torre, Scripps Research Institute, La Jolla, Calif.

FIG. 3

Expression of BDV N (p40) antigen and BDV RNA in autopsy tissue from the human brain. (A) For detection of viral antigen, hippocampal sections from brains of representative patients with hippocampal sclerosis (HS) or Alzheimer's disease (AD), immunolabeled with either a rabbit anti-BDV N serum or an anti-GFAP antibody, were used. (B) For detection of viral nucleic acid, RNA was isolated from frozen brain samples of hippocampal sclerosis or Alzheimer's disease patients and analyzed by RT-PCR using specific primers to amplify a 528-nucleotide segment of the BDV N ORF. An aliquot of cDNA from each sample was also used to amplify glyceraldehyde-3-phosphate dehydrogenase (GAPDH) sequences by RT-PCR as a control of RNA quality. The BDV specificity of the PCR products was confirmed by Southern blot hybridization using a BDV N probe internal to the predicted PCR product. Figure courtesy of Juan Carlos de la Torre, Scripps Research Institute, La Jolla, Calif.