|Budget Amount *help
¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1998 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1997 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Human herpesvirus 6 (HHV-6), HHV-7 and KSHV (HHV-8) are new human herpesviruses which have been recently isolated. In the present study, the pathogenesis of these herpesvirus infections was investigated focusing on the functional alteration of virus-infected CD4+T lymphocytes. Results obtained from the series of the present study are as follows :
1. HHV-6 infection of CD4+T lymphocytes resulted in their apoptosis. The degree of apoptosis increased when HHV-6-inoculated cells were cultured in the presence of TNF-a and anti-Fas antibody. HHV-6 induces apoptosis in CD4^+T cells by indirect mechanisms, as reported recently in HIV-1 infection.
2. We examined the susceptibility to HHV-7 infection of various CD4-negative cell lines into which the cDNA for CD4 was transferred using an adenovirus vector. Out of 13 cell lines transduced with Adex1CACD4, 4 cell lines showed high susceptibility to HHV-7 infection. These data suggest strongly that CD4 is a major component of the binding receptor for
3. Two novel Ph chromosome-positive myeloid cell lines, SAS4l3 and SAS527, which possess different hematologic characteristics and show distinct susceptibility to infection of HHV-6, have been established. TPA-treatment of SAS527 which was latently infected with HHV-6B resulted in reactivation of HHV-6. These novel cell lines should be useful for studying the mechanisms of HHV-6- induced hematopoietic failure and HHV-6 latency and reactivation.
4. Although CXCR4 and CCR5 appeared not to be the coreceptors for these viruses, marked down-regulation of CXCR4, but not CCR5, was detected in HHV-6 and HHV-7-infected cells. Down-regulation of CXCR4 resulted in impairment of chemotaxis and a decreased level of elevation of the intracellular Ca^<2+> concentration in response to SDF-1. Northern blot analysis of mRNAs extracted from HHV-6- and HHV-7-infected CD4^+T lymphocytes demonstrated a markedly decreased level of CXCR4 gene transcription, but post-transcriptional stability of CXCR4 mRNA was not significantly altered. Less