Human herpesvirus-6 (HHV-6) has been proposed to be associated with B- cell lymphoma and other lymphoproliferative disorders especially in immunosuppressed settings. The virus (GS strain) was first isolated in 1986 from patients with AIDS and other lymphoproliferative disorders. To elucidate its role in human malignancies, we examined its transforming potential. Using our established assay system for gene transfer and transformation, we first reported that HHV-6 genome (170 kb, GS isolate) and two subgenomic clones pZVH14 (8.7 kb insert) and pZVB70 (21 kb insert) could transform NIH 3T3 cells to tumorigenicity. Two other HHV-6 isolates, Z-29 (CDC isolate from AIDS patient) and GD (isolated from chronic fatigue syndrome) were tested for transforming activity to understand whether it is a common property with HHV-6. Like GS isolate, genomic DNAs of GD and Z-29 isolates also transformed 3T3 cells to tumorigenicity. Restriction digestion of the viral DNAs indicated distinct difference between Z-29 and GS or GD isolates and a minor difference between GS and GD. Z-29 DNA seemed to be more tumorigenic than GS or GD DNA. We are currently performing the molecular biological analysis of the tumors to identify the gene sequences involved in transformation and whether a common transforming gene exists in these isolates. We also investigated whether HHV-6 can transform human cells to establish its relationship to human malignancies. We found that the same two subgenomic clones pZVH14 and pZVB70 that could transform NIH 3T3 cells, were also capable of tumorigenic conversion of human epidermal keratinocyte cell line (RHEK-1). Southern blot analysis indicated the presence of pZVH14 DNAs in the transformed and tumor cells. Chromosome analysis identified the tumors to be of human origin. Tumor cells showed some chromosomal aberrations. Tumors were diagnosed as poorly differentiated carcinomas by histological analysis. Further studies are in progress to map the transforming genes and to identify the mechanism of transformation.
