Suppressive effects of human herpesvirus 6 on in vitro colony formation of hematopoietic progenitor cells

Abstract

Human herpesvirus 6 (HHV-6) has been reported to be involved in bone marrow failure after bone marrow transplantation (BMT). To elucidate the role of HHV-6 in the marrow failure, we examined the comparative effect of two variants of HHV-6 (HHV-6A and HHV-6B) and human herpesvirus 7 (HHV-7) on in vitro colony formation of hematopoietic progenitor cells in methylcellulose semi-solid media. Progenitor cells prepared from cord blood mononuclear cells (CBMNCs) were infected with one of these viruses at various multiplicity of infection (MOI), and were subjected to methylcellulose colony assay. Formation of both granulocyte/macrophage (CFU-GM) and erythroid (BFU-E) colonies was MOI-dependently suppressed after infection with the Z29 strain of HHV-6B. Although HHV-6A suppressed the formation of BFU-E colonies as efficiently as HHV-6B, the former did not exhibit significant suppressive effect on the formation of CFU-GM colonies at an MOI 1. HHV-7 had no effect on hematopoietic colony formation at all. Based on frequent positivity of viral DNA in single colonies obtained from HHV-6-infected progenitor cells by polymerase chain reaction and in situ hybridization, direct effects of HHV-6 on the hematopoietic progenitor cells are suggested as the cause of the suppression rather than indirect effects via accessory cells of the bone marrow.

Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy

“…HHV-6 has been suspected of causing vascular endothelial damage in BMT recipients, a process that may lead to thrombotic microangiopathy, which is a major complication of BMT (273,389). Lastly, HHV-6 infection has been associated with bone marrow suppression (52,113), an observation that is supported by in vitro data on the suppressive effects of HHV-6 on proliferation of stromal cells of granulocyte/macrophage, erythroid, or megakaryocyte lineages (48,(187)(188)(189)212). A recent retrospective study by Boutolleau et al (42) in 78 stem cell transplant recipients found a correlation between HHV-6 viral load in PBMCs and delayed neutrophil engraftment, severe graft-versus-host disease, and classical HHV-6 manifestations, such as fever and rash.…”

Monitoring of human herpesviruses after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation

“…HHV-6 is shown to infect human haemopoietic progenitor cell lines (Ablashi et al, 1988), and to suppress proliferation and differentiation of multilineage haemopoietic progenitor cells in vitro (Knox & Carrigan, 1992;Isomura et al, 1997). In this study, delayed platelet engraftment was associated with HHV-6 status in terms of detection rate and the amount of viral DNA.…”

Human herpesvirus type 6 reactivation after haematopoietic stem cell transplantation

“…In vitro data showed that HHV6 can infect hematological progenitor cells and reduce colony formation, which may explain the delayed engraftment after HSCT. 24,25 For studies concerning children after HSCT, 3 studies have been published. 18,21,26 Now, significant associations of HHV6 reactivation with severe GvHD, delayed platelet engraftment, poor survival and non-relapse mortality (NRM) were found, but probably due to the low number of patients, the influence of HHV6 reactivation might even have been underestimated.…”