Luppi et al. (1993) demonstrated the pulsed-field gel electrophoresis HHV-6 integration to samples from two LD patients. Then, fluorescent ISH (FISH) on PBMCs from the patients in complete remission, showed integration of the HHV-6 genome in the distal part of the short arm of chromosome 17 (17p13) (Torelli et al., 1995). A possible deregulation of two human-known oncogenes, CRK and ABR could subsequently occur. FISH was also used to demonstrate integration of HHV-6 in the long arm of chromosome 1 (1q44) of leukaemic cells from an ALL (Daibata et al., 1998). The authors reported a surprising observation: the chromosomally integrated HHV-6 genome was transmitted in the same location (1q44) to one son and one granddaughter of that ALL patient, who are otherwise healthy. Another case localized HHV-6 to 22q13.
Thus, the high-viral load observed in some LD may be due to a chromosomal integration in some or even in all cells of those patients. However, viral integration seems to be rare, without any specific integration site. On the other hand, the detection of HHV-6 sequences integrated into host DNA of lymphoma cells does not prove the presence of a complete viral genome and does not indicate whether this chromosomally integrated HHV-6 genome has any role in the pathogenesis of HHV-6-positive LD.
HHV-6 may exert a role in cell proliferation by dysregulation of cytokine network
The hypothesis that HHV-6 may contribute to the development of LD by deregulation of cytokine control rather than by direct oncogenic involvement has been suggested. Recently, Takaku et al. (2005) studied the network of dynamic gene and protein interactions occurring during the infection of an adult T-cell leukaemia cell line by HHV-6B using a microarray and analysing the data by the Bayesian statistical framework. They reported the possible association between chemokine genes regulating the Th1/Th2 balance and genes regulating T-cell proliferation. Moreover, a gene encoding a TEC-family kinase, ITK, might be a putative modulator of the host immune response against HHV-6B infection.
An interesting approach consisted in the design of a computer model in order to simulate cell changes happening in LD and disturbances of the T-cell immune system (Krueger et al., 2003). The model uses the concept that these disturbances, identified as proliferation, differentiation and inhibition factors, may lead to hyperplastic, aplastic or neoplastic diseases. This computer model simulated acute and chronic persistent HHV-6 infections to study the influence of cytokines or chemokines in the Canale-Smith syndrome.
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