EBV, another herpesvirus frequently associated with HD, is not distributed equally among the different subtypes of EBV-positive HD; 70% of mixed cellularity, >95% of lymphocyte depleted, 10-40% of nodular sclerosis, and almost absent from lymphocyte-predominant HD subtypes. In addition, HD cases associated with EBV occurred most frequently in children or in elderly people. Previous epidemiological studies suggested multiple etiologies for HD and led to the hypothesis of an infectious viral non-EBV etiology for cases occurring in young adults. It was therefore interesting to look for the presence of HHV-6 sequences according to HD subtype.
Torelli et al. (1992) described three HHV-6-positive HD, belonging to the nodular-sclerosis-lymphocyte-depletion subgroup, which occurred in young women (27-, 28- and 31-years old). Similarly, different authors obtained the highest prevalence and highest mean copy for the scleronodular subtype of HD (Table 1). In a large study conducted on 86 adult HD patients, we obtained a high prevalence (83.6%) of HHV-6 in scleronodular HD (unpublished data). However, scleronod-ular subtype is the most frequent in HD patients examined. In the same study, the mean age of scleronodular HD patients positive for HHV-6 and negative for EBV, was 29.5 years, whereas 45 years if HHV-6 negative and EBV positive. Therefore, HHV-6 seems to be more predominant in scleronodular HD and much more in young adults, arguing a potential role for this virus in the etiology of HD in this context. Clark et al. (1990) found an association of increased HHV-6 seropositivity and geometric mean titre ratio with HD among young adults lacking social contact in the family group, suggesting that those patients were exposed late to HHV-6.
Some cases of HD are associated with EBV, especially cases of mixed cellularity occurring in children and in elderly people. Although HHV-6 and EBV infect different cells, they can be present in the same HD tissue. Using two different realtime PCRs (one for HHV-6 and one for EBV), we found 68.2% of HD patients positive for both viruses in their lymph nodes. In this case, EBV was often weakly present compared to HHV-6 (unpublished data). Identical findings have also been reported by others (Torelli et al., 1992; Valente et al., 1996).
HHV-6 is present in different cell types and also in RS cells
Cells harbouring HHV-6 were studied in positive lymphoid lesions by ISH and/or immunohistochemistry (IHC) (Valente et al., 1996; Luppi et al., 1998): elevated number of cells carrying HHV-6 was found in cases of HD not yet in reactive lymphoid hyperplasia. Virus-infected cells were identified primarily as lympho-histiocytic cells, less frequently as Hodgkin's and RS cells. In some studies, HHV-6 positive-cells appeared small and lymphoid in appearance (Krueger et al., 1989). In other studies, RS or HD cells expressing HHV-6 non-structural and/or structural antigens were detected with monoclonal antibodies (MAbs) in up to 20% of HD patients. In our experience, not all, but at least 30-50% of lymph nodes from HHV-6 positive HD exhibit RS cells expressing HHV-6 structural antigens (HHV-6A or -B gp116/54/64) as determined by the use of MAbs. In these specimens and also in other HHV-6-positive lymph nodes, HHV-6 is also detected in lymph-ocytes-plasmocytes and in histiocytic cells (unpublished data). This phenomenon is also described for EBV, which, when present, may be localized in RS cells and also in lymphocytes.
The objective of these studies was to determine if HHV-6 can be detected in uninvolved tumour tissues and therefore be considered as a simple passenger, or if it is restricted to tumour cells and can be proposed as an etiological agent of HD. Unfortunately, biology is often much more complex and questions are still open. Does HHV-6 present in RS cells play a role in the cell transformation? Does HHV-6 present in the ''cell environment" act as a transactivator, for example? Or is HHV-6 just a passenger?
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