Prevalence of HHV‐6 integrated chromosomally among children treated for acute lymphoblastic or myeloid leukemia in the Czech Republic

Abstract

Chromosomal integration of human herpesvirus 6 (HHV-6) is a novel situation found in a small percentage of individuals. While active HHV-6 infection is treatable using antivirals, the abnormally high level of HHV-6 DNA found in chromosomal integration of HHV-6 (CI-HHV-6) is not affected by such drugs. Stored DNA samples taken originally for detection of fusion genes and minimal residual disease from 339 pediatric patients treated for leukemia in the Czech Republic between the years 1995-2007 were tested retrospectively. Using real-time quantitative PCR technology, the quantity of HHV-6 DNA detected was normalized to 100,000 human genome equivalents as assessed by quantitation of the albumin gene. HHV-6 DNA was detected in 107 samples from 91 patients (26.8%). In the majority of samples (99) only a minute level of normalized viral copies (NVCs) (median 1.84 NVCs) was detected. A high viral load of approximately 100,000 NVCs was detected in 5 patients (1.5%; median 140,150 NVCs), in all of whom were confirmed subsequently CI-HHV-6 by a detection of HHV-6 DNA in hair follicles or in the nails. In all but one patient with HHV-6 variant B, variant A of the virus was detected. None of the patients with CI-HHV-6 had complications attributable to HHV-6 infection. The prevalence of CI-HHV-6 in childhood leukemia does not differ from that published for other patients or healthy populations. Where high levels of HHV-6 DNA are present, CI-HHV-6 should be confirmed as soon as possible so that potentially toxic but ineffective antiviral treatment can be stopped.

Prevalence of Human Herpesvirus-6 Chromosomal Integration (CIHHV-6) in Italian Solid Organ and Allogeneic Stem Cell Transplant Patients

“…These patients were supposed to represent cases of CIHHV-6 in a following paper by Clark et al (13), but the appropriate screening to confirm the viral integration was never performed. (10,13,14,19,20 …”

“…This phenomenon features a high viral copy number either in whole blood (>6 log 10 HHV-6 copies/mL) or sera (>3.5 log 10 copies/mL) or other body sites (>4 log 10 copies/hair follicle or/mL of cerebrospinal fluid), as a consequence of inheritance of viral sequences through the germ line and their retainance in every nucleated cell (7). The prevalence of CIHHV-6 has been resulted 0.21% in healthy subjects from Japan and ranging from 0.8% to 3% in the general population from United Kingdom, while it is 1.5% in children treated for acute leukemias in the Czech Republic (8)(9)(10). Although the integrated viral genome may be transcriptionally active, to date, no replication has been reported either in vitro or in vivo (11).…”

Herpesviruses and Chromosomal Integration

“…The first reports date to the early to mid-1990s, when Luppi et al made the first demonstration of the presence of a partial and possibly full-length integrated HHV-6 genome in the DNA of freshly isolated peripheral blood mononuclear cells (PBMCs) (66,68,94). Subsequent work by researchers around the world give estimates of the prevalence of CIHHV-6 in the world population of approximately 1%, with no apparent disease association, although the number of cases reported remains limited: 1.5% of Czech Republic childhood leukemia patients (43), 0.9% of the Italian transplant population (78), 0.8% of United Kingdom blood donors (up to 2.9% of hospital patients) (59), 1.6% of patients with suspected encephalitis in the United Kingdom (found in the cerebrospinal fluid) (102), and 0.21% of the general Japanese population (90). Both HHV-6 variants A and B have the ability to integrate the human genome.…”

U20 Is Responsible for Human Herpesvirus 6B Inhibition of Tumor Necrosis Factor Receptor-Dependent Signaling and Apoptosis

“…In addition, evidence exists for an association between HHV-6B and mesial temporal lobe epilepsy (10,11). A number of studies have associated HHV-6A or -6B with different T-and B-cell lymphomas (20,21), although evidence for a direct role of the viruses is complicated by their ubiquitous nature and ability to integrate chromosomally (14). Possibly, HHV-6A or -6B might act as a cofactor in certain oncogenic diseases by promoting replication of other viruses, thereby helping the double-infected cells to evade the immune system (8).…”