HHV-6 & Cancer

Lymphoma

Hodgkin’s disease

There have been numerous studies aimed at finding an association between HHV-6 and Hodgkin’s Disease (HD), and it has proven very difficult to conclude definitively on this subject due to the difference in assays and patients tested. However, a link between HHV-6 and the nodular sclerosis subtype of Hodgkin’s lymphoma (NSHL) has recently been reinforced by several groups. A study from Yale has identified HHV-6 in 86% of NSHL cases (Siddon 2012).  Researchers utilized several laboratory methods—including IHC, PCR, and FISH—to identify HHV-6 DNA in tissue samples from 31 lymph node cases of Hodgkin’s lymphoma.  In addition, the group also sought to localize the presence of HHV-6 DNA in particular HL cell types, and identified HHV-6 DNA via IHC in malignant Reed-Sternberg cells in nearly half of the cases.  This result, which is supported by previously published work by Lacroix et al and others, suggests that HHV-6 may play a direct role in the pathogenesis of NSHL.  The study is the most comprehensive and thorough investigation conducted on the association between HHV-6 & NHSL to date, and helps to clarify previously conflicting results published in the field.

Lacroix and colleagues found that HHV-6 is more frequently detected in the nodular sclerosis subset of HD: of 73 patients with nodular sclerosis, 39 (49%) were positive for both HHV-6 and EBV DNA, 25 (34%) had only HHV-6 and 8 (11%) had only EBV. However, of 10 cases of the mixed cellularity form of HD, 4 (40 %) had both viruses, 1 had HHV-6 only, 4 had EBV only, and 1 had neither (Lacroix 2007). Whether as-yet-uncharacterized proteins may be expressed in HD tissues remains to be explored.

Torelli et al 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 (AML, ALL, CLL)

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.

Gastrointestinal Cancer

A group from Finland’s Helsinki University Hospital has published preliminary evidence to suggest HHV-6B may be involved in the development of adenomatous gastrointestinal polyps.  In a series of immunocompetent patients with adenomas, polyp HHV-6B antigen expression from mucosal biopsies was more intense than in biopsies taken from patients receiving immunosuppressive drugs because of kidney transplantation or inflammatory bowel disease (Halme 2013).

In addition, a research team from Riga Stradins University in Latvia has reported that the activation of HHV-6B and HHV-7 in patients with gastrointestinal cancer may lead to a marked decrease in lymphocytes and worsening of immunosuppression.  Furthermore, a detailed analysis of viral interactions and specific cellular subpopulation levels among their cohort suggests an abnormal antiviral response that could lead to an accelerated progression of co-infections and worse outcomes in these patients (Sultanova 2013).

Cervical Cancer

It is well established that Human papillomaviruses (HPVs) are necessary, yet not sufficient, for the development of cervical cancer; and many essential cofactors have been implicated in the progression of this disease.  Some authors have suggested a role for several human herpesviruses—namely EBV and CMV—in the development of cervical cancer, particularly through co-infection with HPV and subsequent interaction with the HPV-16 genome (Szostek 2009). Multiple studies have detected HHV-6/HPV co-infection among samples from women with cervical cancer (Chen 1994, Tran-Thanh 2002).  In one study that primarily focused on new assay development, HHV-6B was detected in a patient who later developed cervical cancer (Li 2009). Chen et al have demonstrated that HHV-6 has HPV-transactivating capability, and HHV-6 co-infection leads to more rapid tumorgenesis (Chen 2004b).

In 2008, Broccolo et al found that the prevalence of HHV-6 DNA was significantly higher in high-grade squamous intraepithelial lesions (HSIL)—a known precursor to cervical cancer—compared to samples from healthy women (Broccolo 2008). In addition, co-presence of CMV and HHV-6 DNA was significantly higher in patients with SIL compared to controls. 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.  These findings suggest that HHV-6 alone or together with CMV may contribute to the development of cervical cancer.

CNS Tumors/Glioma

Investigators from Nanjing Medical University led by Dr. Kun Yao have found HHV-6 latent infection in glioma tissues, and have isolated a strain of HHV-6A from the glioma cyst, supporting earlier studies that suggest the involvement of HHV-6 in the pathogenesis of adult and pediatric gliomas (Chi 2012). Using nested PCR and immunohistochemistry, Dr. Yao’s team identified HHV-6 DNA and protein in tissue from 42.5% of gliomas compared to 7.7% of normal brain tissue. In addition, elevated levels of several cytokines that were specifically promoted by HHV-6 infection in astrocyte cultures were also observed in HHV-6-positive cyst fluid samples from glioma tissues.

An earlier paper by NINDS/NIH investigators (Crawford 2009) found that both early (p41) and late (gp116/64/54) HHV-6 viral antigens were detected three times more frequently in adult glial tumors compared to control brain tissues.  An additional study by this group utilized nested PCR, in situ hybridization (ISH), and IHC to detect HHV-6 in pediatric brain tumors, and demonstrated that HHV-6 viral antigens were significantly correlated with low grade-glioma tissues compared to controls (Crawford 2009b).

The authors note that “proinflammatory cytokines induced by HHV-6 infection might provide a chronic inflammatory environment that facilitates the development of glioma” by altering the properties of the infected cell and inducing proinflammatory cytokine secretion—as has been documented previously (Yoshikawa 2002). This suggests HHV-6 may directly facilitate the pathogenesis of glioma. In addition, the authors suggest that selective immunosuppression caused by HHV-6 infection can lead to the disruption of key immune activation pathways, perhaps further contributing to the pathogenesis of glioma.  Studies are currently underway to further characterize this neuro-ontological mechanism and the role of HHV-6 in the oncogenesis of glial tumors.  Some groups have also proposed that ciHHV-6 may play a role in the development of gliomas (Amirian 2012).

Key Papers: HHV-6 & Cancer