Human Herpesvirus 6 and Malignancy: A Review

Abstract

In order to determine the role of human herpesvirus 6 (HHV-6) in human disease, several confounding factors, including methods of detection, types of controls, and the ubiquitous nature of the virus, must be considered. This is particularly problematic in the case of cancer, in which rates of detection vary greatly among studies. To determine what part, if any, HHV-6 plays in oncogenesis, a review of the literature was performed. There is evidence that HHV-6 is present in certain types of cancer; however, detection of the virus within tumor cells is insufficient for assigning a direct role of HHV-6 in tumorigenesis. Findings supportive of a causal role for a virus in cancer include presence of the virus in a large proportion of cases, presence of the virus in most tumor cells, and virus-induced in-vitro cell transformation. HHV-6, if not directly oncogenic, may act as a contributory factor that indirectly enhances tumor cell growth, in some cases by cooperation with other viruses. Another possibility is that HHV-6 may merely be an opportunistic virus that thrives in the immunodeficient tumor microenvironment. Although many studies have been carried out, it is still premature to definitively implicate HHV-6 in several human cancers. In some instances, evidence suggests that HHV-6 may cooperate with other viruses, including EBV, HPV, and HHV-8, in the development of cancer, and HHV-6 may have a role in such conditions as nodular sclerosis Hodgkin lymphoma, gastrointestinal cancer, glial tumors, and oral cancers. However, further studies will be required to determine the exact contributions of HHV-6 to tumorigenesis.

Keywords: HHV-6; HHV6; cancer; herpesvirus; human herpesvirus 6; malignant; oncogenic; transformation.

Figure 1

HHV-6 in nodular sclerosis Hodgkin lymphoma. (A) Presence of HHV-6 p41 by immunohistochemistry. Cytoplasmic staining of numerous large cells using a monoclonal antibody to HHV-6 p41 (3E3 clone). (B) HHV-6 U94 detection by immunohistochemistry. Staining with monoclonal antibody to HHV-6 U94 reveals positivity in the cytoplasm of numerous large cells. (C) Presence of HHV-6 by colorimetric in-situ hybridization with multiplex probe. HHV-6 DNA present in the nuclei of both small and large cells. From Eliassen et al. (112).

Figure 2

HHV-6A and HHV-6B genomic map. Representative coverage maps of HHV-6B Z29 and HHV-6A GS reference strains. Shotgun DNAsequencing reads from cultured virus were mapped to the NCBI HHV-6B and HHV-6A reference genomes, NC_000898 and NC_001664, respectively. The green stacked lines indicate the gene models for the respective viral species. (A) HHV-6B strain Z29 yielded a homogeneous 983-bp tandem repeat that was present at ~12.5 times higher coverage than the rest of the genome. Sequences at the 5 = and 3 = ends of the tandem repeat in strain Z29 are depicted and are different than those indicated previously (31). (B) HHV-6A strain GS yielded a heterogeneous 1,254-bp tandem repeat that was present at ~11.4 times higher coverage than the rest of the genome. Sequences at the 5 = and 3 = ends of the heterogeneous tandem repeat in strain GS are depicted. (C) ABI quantitative DNA material for HHV-6A GS and HHV-6B Z29 also demonstrated similar origin tandem repeats with additional loci with copy number differences in the GS strain. Long-distance rearrangements between U12 to U20, U73 to R3, U86 to U95, and the U91-to-U100/DR intergenic region are represented by curved dashed lines, and the estimated viral subpopulation containing the respective deletion is indicated by the percentage. From Greninger et al. (111).

Figure 3

Potential mechanisms of HHV-6A-associated oncogenesis and oncomodulation. Several HHV-6A-mediated changes may contribute to disruption of apoptosis, cellular transformation, invasion, and proliferation pathways, and transactivation of other viruses may contribute to their oncogenic activity. EBV, Epstein-Barr virus; HERV, human endogenous retrovirus; HPV, human papillomavirus; HIV-1, human immunodeficiency virus-1; MVB, microvesicular bodies; Treg, regulatory T cell.

Figure 4

Potential mechanisms of HHV-6B-associated oncogenesis and oncomodulation. Several HHV-6B-mediated changes may contribute to disruption of apoptosis, cellular transformation, invasion, and proliferation pathways, and transactivation of other viruses may contribute to their oncogenic activity. In addition, HHV-6B-infected cells may promote cellular growth in neighboring uninfected cells through a presently unknown mechanism. MVB, microvesicular bodies.