HHV-6 in Cancer

HHV-6 induced immune dysregulation puts patients with chronic active infections at risk for autoimmune disease and certain lymphoproliferative disorders. Both beta herpesviruses (cytomegalovirus, HHV-6 and HHV-7) and gamma herpesviruses (Epstein Barr Virus and HHV-8) have been recently identified as risk factors for some types of cancer.  EBV has been implicated in several types of lymphoma, nasopharyngeal and gastric carcinomas. HHV-8 has been implicated in Kaposi’s sarcoma, multicentric Castleman’s disease, and body cavity B-cell lymphoma or PEL. Beta herpesviruses may serve as a possible cofactor in certain tumors. A recent study (Chun Lu, 2005) found that Kaposi’s sarcoma does not develop without a co-infection of HHV-6. There has been some suggestive evidence for CMV or HHV-6 contributing to the development of cervical cancer and Hodgkin's disease (Chen 1994).

HHV-6 is frequently present in patients with various lymphoproliferative disorders including acute lymphoblastic leukemia, multiple myeloma, Hodgkin's disease, T-cell lymphoma,  and myeloproliferative syndromes. HHV-6 was first discovered in six cases of lymphoproliferative disorders, three of which were cancer related: cutaneous T-cell lymphoma, immunoblastic lymphoma, and acute lymphocytic leukaemia (Salahuddin 1986). The possible link between HHV-6 and the genesis of some B cell tumors was raised in a study of over 50 pathologically defined tissues in which viral sequences were detected in three lymphomas of B cell derivation (Josephs 1988). Shortly thereafter, HHV-6 specific DNA sequences were also isolated from two patients with non-Hodgkin’s lymphoma (Jarrett RF 1988). Based on later studies reported by numerous teams, it seems that HHV-6 can be detected in more than one third of Hodgkin’s biopsies which would suggest that it might be associated with a subset of patients with the disorder. Within the subtypes of Hodgkin’s disease, HHV-6 was found most frequently in scleronodular Hodgkin’s disease in young adults, thus it is possible that HHV-6 plays a role in the etiology of this condition. In most cases the detection of HHV-6 in Hodgkin’s disease samples was of the B variant which is not surprising given the greater lymphotropism of HHV-6B compared to HHV-6A. HHV-6 sequences have also been detected in high copy numbers in the lymph nodes of patients with non-endemic European Burkitt’s lymphoma (Iyengar et al., 1991). Additionally, HHV-6 has been linked to oral cancer (Yadav 1994). Further studies are required, however, to elucidate the causal relationship to the pathogenesis of such diseases. It is difficult to study the disease associations in tissue by PCR given the high level of HHV-6 latent virus in the cells.
 
HHV-6 may also contribute to cancer circuitously through immune suppression. HHV-6 can directly infect CD4+ T-cells and induce apoptosis. HHV-6 can also infect thymic epithelial cells, hematopoietic stem cells, and natural killer cells, which are critical for immune maturation and protection against cancer and viral infections. Thus active HHV-6 infection can contribute to the pathologic effects of other viral infections (Krueger 1990, Schonnbeck 1991).
 
Kashanki (1997) found that HHV-6 genes have malignant transforming activity and the “ORF-1 oncogene” binds to p53, the tumor suppressor protein and inactivates it. This is not proof that an active HHV-6 infection leads to oncogenesis but it raises the level of suspicion. In addition, there exist apparently other mechanisms such as of genomic transactivation (e.g. by NF-κB activation) by HHV-6 that can enhance the pathogenesis of diseases by various causes (Gies 1998).