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. Study Design 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.

Prevalence of Neurotropic Viruses in Malignant Glioma and Their Onco-Modulatory Potential

“…Such relatively high frequencies of HHV-6A and HHV-6B in patients with HGG was not reflected in the present study, with the detection of only two positive cases out of 45 patients. This discrepancy cannot be explained by a low sensitivity of our detection method for this virus, as the realtime PCR used in the present study and the nested PCR used in the previous reports (42,43) have comparable sensitivities. However, nested PCR is a method that is prone to higher rates of contamination when compared to real-time PCR (44).…”

“…The two variants, HHV-6A and HHV-6B, are recognized as two distinct viruses (40). HHV-6 PCR positivity has been reported in 45% of patients with GBM (14/31) (41), whereas Crawford et al detected HHV-6 in 47% of patients from a large cohort of adult brain tumours using nested PCR (42), confirming their previous data in a series of paediatric primary brain tumours (43). Such relatively high frequencies of HHV-6A and HHV-6B in patients with HGG was not reflected in the present study, with the detection of only two positive cases out of 45 patients.…”

Past, present, and future perspectives on the diagnosis of Roseolovirus infections

“…Research-based methods of culture, serology, immunohistochemistry, and in situ hybridization are useful for identifying active infection and correlating with DNA viral load [50]. However, adaptation of these techniques to routine clinical diagnostics is limited by their complexity, long turn-around time, and variable sensitivity.…”

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

“…Studies in countries where HHV-6B is prevalent show that complications include childhood febrile status epilepticus, linked to hippocampus involvement and a risk factor for temporal lobe epilepsy development (Epstein et al, 2012), as well as cognitive dysfunction or fatal encephalitis in haematopoietic stem cell transplantation patients (Zerr, 2006;Zerr et al, 2011). By contrast, in these countries with childhood HHV-6B, HHV-6A appears to be an emergent infection and linked with distinct neuroinflammatory disease, either involving glial cells and demyelination as in multiple sclerosis, general encephalopathy or glial malignancy (glioma) (Akhyani et al, 2000;Alvarez-Lafuente et al, 2002;Ben-Fredj et al, 2013;Caselli et al, 2002;Cermelli et al, 2003;Chi et al, 2012;Crawford et al, 2009;Goodman et al, 2003;Kawabe et al, 2010;Virtanen et al, 2011;Yoshinari et al, 2007). Recent studies also link HHV-6A and HHV-6B with other inflammatory diseases including cardiovascular diseases (myocarditis and idiopathic-cardiomyopathy) (Bigalke et al, 2007;Krueger et al, 2008;Kühl et al, 2005a, b) and those in the thyroid (Hashimoto's thyroiditis, mainly HHV-6A) (Caselli et al, 2012).…”