We obtained 7,566 peripheral blood mononuclear cell (PBMC) samples from 2,332 individuals and screened them for human herpesvirus infection. We identified five individuals who persistently harbored high copy numbers of human herpesvirus 6 (HHV-6) DNA in their PBMCs. HHV-6 DNA was also detected in other somatic tissues of these individuals. Five additional cases were identified among their family members. For two of these families, chromosomally integrated HHV-6 DNA (CIHHV-6) was detected in the PBMCs by fluorescence in situ hybridization. The prevalence of CIHHV-6 among all the subjects was 0.21%. The HHV-6 DNA was variant B in four families and variant A in one family. Antibodies to immediate early antigen and glycoprotein B were detected in 57 and 14% of individuals with CIHHV-6 and in 0 and 60% of healthy volunteers without CIHHV-6, respectively. HHV-6 could not be isolated from PBMCs with CIHHV-6. These cases shared no clinical features, and included three healthy individuals. Our data suggest that CIHHV-6 is rare but detectable in the general population and that hereditary transmission is one of the routes of HHV-6 transmission.

Summary:Human herpesvirus 6 (HHV-6) infection and disease are serious complications of allogeneic hematopoietic stem cell transplantation (allo-SCT). Ganciclovir (GCV) is effective against HHV-6 in vitro but the antiviral susceptibility of HHV-6 has not been well characterized in vivo. We retrospectively compared the HHV-6 reactivation rate in pediatric allo-SCT recipients with and without GCV prophylaxis. The HHV-6 reactivation rate at 3 weeks after allo-SCT in patients without prophylactic GCV administration was significantly higher than that in those receiving prophylactic GCV (11/28 vs 0/13, P Ͻ 0.01). Five of 36 patients without prophylactic GCV showed clinical manifestations including skin rash, interstitial pneumonitis, persistent thrombocytopenia, enterocolitis and thrombotic microangiopathy, respectively. HHV-6-associated symptoms were observed in one of the 13 patients receiving prophylactic GCV. This patient showed fever, diarrhea and graft rejection concomitantly with a sudden increase of HHV-6 DNA copy number. Patients who received GCV for treatment of HHV-6 infection showed an improvement in symptoms and/or decrease of HHV-6 copy number. Thus, GCV is effective for treating HHV-6 disease after allo-SCT in vivo.

Human herpesvirus 6 (HHV-6) encodes a viral chemokine and chemokine receptors that may modify the functions of monocytes/macrophages (MO/M phi) during productive HHV-6 infection. The interactions between HHV-6 and MO/M phi during acute infection, however, remain poorly understood. In this study, we investigated the tropism of HHV-6 in peripheral blood mononuclear cells (PBMCs) during acute infection. We detected 637 +/- 273 copies of viral DNA in 10(4) MO/M phi. in contrast, in 10(4) CD4+ T cells, which have been reported to be viral carriers during the acute infection of HHV-6, we found only 115 +/- 42 copies of viral DNA. Consistent with these data, virus was isolated from MO/M phi an order of magnitude more frequently than from CD4+ T cells. Viral mRNA U79/80, which indicates viral replication, was detectable in the MO/M phi. In addition, the mRNAs that encode viral chemokine receptors U12 and U51, which may modify the function of MO/M phi, were expressed in the cells. Therefore, productively infected MO/M phi may be the dominant cell population that is responsible for HHV-6 viremia during acute HHV-6 infection. The strong interaction of HHV-6 with MO/M phi may be partly responsible for the pathogenesis of this virus.

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Human herpesvirus 6 (HHV-6) infection in recipients of cord blood stem cell transplants (CBSCTs) was estimated by semiquantitative and real-time quantitative polymerase chain reaction (PCR) and reverse-transcription PCR. Of the CBSCT recipients, 7 (70%) of 10 had active HHV-6 infection after transplantation, and all 7 were inferred from their age to have already had a primary infection. Because HHV-6 DNA is seldom detected in cord blood, these cases were considered likely to represent reactivation. In contrast, the 3 patients without HHV-6 infection were all believed to be naive regarding HHV-6 primary infection because of their age and the results of PCR assays given before the transplantation procedure. The incidence of HHV-6 infection after transplantation was significantly higher (P < .05) than after bone marrow (BM) transplantation and peripheral blood stem cell (PBSC) transplantation, when recipients without primary HHV-6 infection prior to transplantation were excluded (CBSCT, 100%; BMT/PBSCT, 56.3%). Real-time PCR revealed a higher level of viral DNA in the peripheral blood mononuclear cells from CBSCT recipients than from BMT/PBSCT recipients or patients with exanthem subitum (P < .05). HHV-6 mRNA of the U79/80gene was also detected by reverse-transcription PCR in all analyzed patients with HHV-6 infection. Its detection was correlated with the emergence of viral DNA in the plasma and symptoms such as fever and rash. Thus, HHV-6 infection was more frequent and the viral load was higher in CBSCT recipients with prior primary infection.