No Association Between Human Herpesvirus Type 8 Infection and multiple Myeloma

Human herpesvirus type 8 (HHV-8) is a human herpesvirus that is associated with Kaposi's sarcoma (KS), Castemans disease, and a rare form of body cavity lymphoma ( 1 , 2 ). Recently, Retting et al. ( 3 ) have also demonstrated the presence of HHV-8 in cultured bone marrow stromal dendritic cells from 15 of 15 samples obtained from patients with multiple myeloma and in two of eight samples from patients with monoclonal gammaopathy of undetermined significance (MGUS). However, the virus was not found not in malignant plasma cells. Therefore, the researchers believed that the virus might cause the bone marrow cancer by infecting nonmalignant cells, possibly through alteration in the bone marrow microenvironment and production of viral interleukin 6 ( 3 ). Since then, other investigators have evaluated the possible link between HHV-8 and multiple myeloma through either serologic assays or polymerase chain reaction (PCR)-based experimental designs. None of these investigators could confirm this association, but one group ( 4 ) did detect HHV-8 in 18 of 20 acetone-fixed and paraffin-embedded bone marrow biopsy samples tested. We have demonstrated ( 5 ) the presence of HHV-8 by PCR in biologic samples of human immunodeficiency virus-positive and -negative individuals in western Sicily, an area with one of the highest incidence rates of classical KS in developed countries, suggesting that HHV-8 is widespread in the general population ( 5 ). Therefore, to establish the possible association between HHV-8 and plasma cell dyscrasias, we used a nested PCR to amplify the HHV-8 KS330 sequence (a 233-base-pair herpesvirus-like DNA sequence). We extracted DNA from peripheral blood mononuclear cells (PBMCs), bone marrow aspirates, and bone marrow stromal cells isolated from 20 patients with multiple myeloma and two patients with MGUS as described ( 5 ). PBMCs and bone marrow mononuclear cells were separated by Ficoll-Hypaque density sedimentation from EDTA-treated blood samples and fresh bone marrow aspirates. Bone marrow mononuclear cells were used to establish long-term bone marrow stromal cell cultures as described ( 3 ). An immunofluorescence assay, using body-cavity-based lymphoma-1 cells, that detects antibodies against latent and lytic antigens of HHV-8 was also performed to investigate the presence of antibodies to HHV-8 in patients with multiple myeloma and MGUS. Table 1 shows that none of the 22 patients had HHV-8 DNA sequences in PBMCs, in bone marrow aspirates, or in dendritic stromal cells. Antibodies to HHV-8 antigens were detected in four of 22 patients. This seroprevalence rate is similar to that found in our earlier studies ( 6 ) on a general population of the same age from western Sicily. Although HHV-8 infection may be detected in patients with multiple myeloma, as a consequence of the spread of the virus in our area, we did not find any evidence of its presence in cultured bone marrow dendritic stromal cells. Therefore, the lack of any virologic association and the lack of increased rate of multiple myeloma in our geographic area ( 7 ) do not support the hypothesis that HHV-8 plays a direct role in the pathogenesis of multiple myeloma.