title: Detection of human herpesvirus-6 variants in pediatric brain tumors: association of viral antigen in low grade gliomas.
abstract: BACKGROUND
  Human herpesvirus-6 (HHV-6) has been associated with a diverse spectrum of central nervous system (CNS) diseases and reported glial tropism.
  
  
  OBJECTIVE
  To determine if HHV-6 is present in a series of pediatric brain tumors.
  
  
  METHODS
  Pediatric gliomas from 88 untreated patients represented in a tissue microarray (TMA) were screened for HHV-6 by nested polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemistry (IHC) and compared to non-glial tumors (N=22) and control brain (N=32). Results were correlated with tumor grade and overall survival.
  
  
  RESULTS
  HHV-6 U57 was detected by nested PCR in 68/120 (57%) tumors and 7/32 (22%) age-matched non-tumor brain (P=0.001). HHV-6 U31 was positive in 73/120 (61%) tumors and 11/32 (34%) controls (P=0.019). Seventy-two percent (43/60) of tumors were HHV-6 Variant A. HHV-6 U57 was confirmed by ISH in 83/150 (54%) tumors and 10/32 (31%) controls (P=0.021), revealing a non-lymphocytic origin of HHV-6. HHV-6A/B gp116/64/54 late antigen was detected by IHC in 50/124 (40%) tumors and 6/32 (18%) controls (P=0.013). Interestingly, 58% of low grade gliomas (N=67) were IHC positive compared to 19% of high grade gliomas (N=21, P=0.002) and 25% of non-gliomas (N=36, P=0.001). HHV-6A/B gp116/64/54 antigen co-localized with glial fibrillary acidic protein, confirming the astrocytic origin of antigen. Overall, there was no primary association between HHV-6A/B gp116/64/54 antigen detection and survival (P=0.861).
  
  
  CONCLUSIONS
  We provide the first reported series of HHV-6 detection in pediatric brain tumors. The predominance of HHV-6 in glial tumors warrants further investigation into potential neurooncologic disease mechanisms.
authors.affiliation: The Department of Neurology, Children's National Medical Center, The George Washington University, Washington, DC, United States. jrcrawford@ucsd.edu
authors.forename: John R
authors.initials: JR
authors.lastname: Crawford
authors.forename: Maria R
authors.initials: MR
authors.lastname: Santi
authors.forename: Halldora K
authors.initials: HK
authors.lastname: Thorarinsdottir
authors.forename: Robert
authors.initials: R
authors.lastname: Cornelison
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Rushing
authors.forename: Huizhen
authors.initials: H
authors.lastname: Zhang
authors.forename: Karen
authors.initials: K
authors.lastname: Yao
authors.forename: Steven
authors.initials: S
authors.lastname: Jacobson
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: Macdonald
mesh_terms: D000293:Adolescent; D000956:Antigens, Viral / Q000032:analysis; D001932:Brain Neoplasms / Q000209:etiology / Q000473:pathology / Q000821:virology*; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000032:analysis; D005910:Glioma / Q000209:etiology / Q000473:pathology / Q000821:virology*; D015654:Herpesvirus 6, Human / Q000302:isolation & purification*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007223:Infant; D016133:Polymerase Chain Reaction / Q000379:methods; D019349:Roseolovirus Infections / Q000150:complications*; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D000956:Antigens, Viral; D004279:DNA, Viral