Lymphoma
Hodgkin’s disease:
EBV now is generally acknowledged to be a cause of Hodgkin’s disease (HD). Some have also suggested a role for HHV-6 in HD. An etiologic role for HHV-6 is possible for the nodular sclerosis subtype of HD. Lacroix and colleagues found that HHV-6 more frequently in the nodular sclerosis form of HD: of 73 patients with nodular sclerosis, 39 (49%) had both HHV-6 and EBV DNA, 25 (34%) had only HHV-6 and 8 (11%) had only EBV. In contrast, of 10 cases of the mixed cellularity form of HC, 4 (40 %) had both viruses, 1 had HHV-6 only, 4 had EBV only, and 1 had neither (Lacroix 2007). HHV-6+/EBV- patients were younger than the EBV+/HHV-6- patients and 92% of the HHV-6+ lymph nodes contained variant B. (Lacroix 2007). Whether as-yet-uncharacterized proteins may be expressed in HD tissues remains to be explored.
Torelli reported finding HHV-6 sequences by PCR in 3/25 cases of Hodgkin’s disease, all nodular sclerosis type, and in none of 41 cases of non-Hodgkin’s lymphoma (Torelli 1991). Krueger and colleagues performed immunohistochemical studies of tumors from 103 patients with HD, and found HD tissue sections to be frequently infected by both EBV and HHV-6. However, Luppi et al., (Luppi 1998) examined a large series of HD cases in which HHV-6 DNA was found by both PCR and Southern blot analysis, and did not detect either latent or lytic HHV-6 antigens in either neoplastic cells, and detected only limited expression in Reed-Sternberg cells.
Non-Hodgkin’s lymphomas:
Luppi et al., (Luppi 1993), reported finding a higher frequency of HHV-6 DNA in a well characterized series of patients with angioimmunoblastic T cell lymphoma (AITL), a subtype of T-cell non-Hodgkin’s lymphoma, compared with other lymphoma subtypes and controls. These findings have been confirmed by Zhou et al., (Zhou 2007) showing a clear association between histological progression of AITL and the detectable copy number of both EBV and HHV-6 B in the AITL lesional tissue. While this increased viral load could reflect a role for HHV-6 in the pathogenesis and progression of AITL, it also could be the consequence of increasing dysfunction of the immune system during lymphoma progression. Immunohistochemical studies have so far failed to demonstrate HHV-6 antigens in the CD4 positive T cells (the likely proliferating elements) within AITL lesions.
Leukemia
Persistent IL-2 regulated HHV-6 infection of adult T-cell leukemia cells causes T cell leukemia to progress more rapidly (Ojima 2005), but in vivo studies have not yet confirmed a pathogenetic role for HHV-6 in this disease. Studies of the role of HHV-6 in acute leukemia are mixed. HHV-6 antibody titers may be higher in patients with acute myeloid leukemia (AML) but not with acute lymphoblastic leukemia (ALL) (Gentile 1999). Salonen et al found that 40% of children with leukemia had IgM antibodies to HHV-6 compared to 7.7% of reference subjects. (Salonen 2002). However, molecular studies have so far failed to show a higher rate of HHV-6 DNA in children with ALL compared with healthy subjects (Barozzi 1995). Although a recent report found higher rates of seropositivity to human cytomegalovirus (HCMV) among patients with B cell chronic lymphocytic leukemia (CLL) than among healthy control subjects, the same was not true for seropositivity to HHV-6 (or EBV and HHV-7) (Steininger 2009). In conclusion, with the possible exception of adult T-cell leukemia, available data do not lend support to a role for HHV-6 in human acute leukemias.
Carcinoma
In 2008, Broccolo et al suggested that HHV-6 infection alone or together with CMV infection may increase the risk of developing squamous intraepithelial lesions (SIL’s) and eventually cervical carcinoma/cancer in women (Broccolo 2008). In a study to determine the prevalence of EBV in adenocarcinomas and squamous-cell lung carcinomas (Gomez-Roman 2009), HHV-6 was reported as the only viral agent present in two cases of adenocarcinomas.
CNS Tumors/Glioma
The definitive role of herpesviruses in brain tumors is still unclear and controversial. CMV, a betaherpesvirus structurally similar to HHV-6, has been reported in malignant gliomas (Mitchell 2008). In 2009, Crawford et al published two studies (Crawford 2009) that identified the presence of HHV-6 in both adult and pediatric glial brain tumors (gliomas). Studies are currently underway to further characterize this neuroontological mechanism and the role of HHV-6 in the oncogenesis of glial tumors.
Does HHV-6 play an indirect role in malignancies?
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, Schonnebeck 1991).
Kashanchi (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.
Download a copy of The HHV-6 Foundation’s 2011 ASH Meeting Brochure, which has a collection of select abstracts and information on HHV-6′s role in hematological issues such as Hematopoietic Stem Cell Transplantation, Cognitive Dysfunction, GVHD, and more.
Key Papers: HHV-6 & Cancer
