Human herpesvirus 6 infection after allogeneic stem cell transplantation

Abstract

Human herpesvirus 6 (HHV-6) is a lymphotropic virus mainly infecting T lymphocytes but also other types of cells. Seroepidemiological studies have shown that more than 90% of individuals older than 2 years are seropositive for HHV-6. There are two variants (A and B) of HHV-6, and variant B has been much more often coupled to diseases than variant A. The prevalence of the two variants is still not known since the serological responses cannot be differentiated by currently available methods.

We used PCR on leukocytes and a T-lymphocyte proliferation assay for studies of variants A and B in a group of healthy adults. All individuals were HHV-6 seropositive by an immunofluorescence assay. HHV-6 DNA was detected in 16%. Almost all of the HHV-6 DNA detected belonged to variant B. Furthermore, 58% of the healthy adults responded to variant B in the lymphocyte stimulation assay, while only 25% responded to variant A. The results indicate that infection with HHV-6 variant B is more common than with variant A.

Allogeneic stem cell transplantation (allo-SCT) can cure patients with hematological malignancies and genetic diseases. However, treatment-related mortality remains a significant problem. Before this study started, the knowledge of HHV-6's role after allo-SCT was very limited. HHV-6 infection had been suggested to be associated with encephalitis, interstitial pneumonitis, bone marrow suppression, and acute graft-versus host disease in preliminary studies.

By using PCR, we confirmed that HHV-6 variant B infection was associated with delayed stem cell engraftment, while no relation to acute GVHD was noticed. The role of HHV-6 infection in central nervous system (CNS) disease after allo-SCT was investigated by PCR on cerebrospinal fluid. In this study, HHV-6 infection was found to be the cause of 50% of patients with, until then, unexplained CNS symptoms after allo-SCT. HHV-6 DNA was detected in cerebrospinal fluid from less than 1% of patients who were immunocompromised, but who had no CNS symptoms.

Studies on other human herpesviruses have shown that an active viral infection is followed by recovery of lymphocyte proliferation response after allo-SCT. Lymphocyte proliferation responses to HHV-6 after allo-SCT were studied. Persistent detection of HHV-6 DNA in peripheral blood cells was found to correlate inversely with the ability to respond to HHV-6 antigen stimulation. Moreover, none of the patients with HHV-6 disease showed a positive lymphocyte proliferation response despite having persistent HHV-6 DNAemia. It was shown that almost all the patients with persistent HHV-6 DNAemia had low lymphocyte counts.

HHV-6 infection is cytotoxic to T lymphocytes, and can also inhibit hematopoietic stem cells in vitro and in vivo. Thus, our data provided the first in vivo evidence that HHV-6 may inhibit the immune function after allo-SCT, thereby possibly also contributing to development of other infectious pathogens such as CMV. Recovery of an effective immune function is crucial to control CMV infection. We found that most patients with persistent HHV-6 infection were unable to respond to CMV antigen stimulation. These patients needed more courses of antiviral therapy in order to control CMV infection due to persistent CMV DNAemia. HHV-6 infection was found to be common after allogeneic SCT and our studies indicate that it is an important pathogen in this patient population.