Infection with human cytomegalovirus (HCMV) is a common and generally asymptomatic affection in childhood. Its role in
neuroblastoma (NB) patients has not yet been elucidated. As evidence grows that HCMV interacts with apoptotic signaling due to the interaction of HCMV gene products with cellular
proteins of apoptotic pathways, we used human NB cell line UKF-NB-2 persistently infected with HCMV strain AD169 to study the effects of long-term HCMV
infection on programmed cell death of
neuroectodermal tumor cells. The cells designated UKF-NB-2AD169 continued to produce infectious virus in successive subcultures over a period of more than 1 year. Up to 20% of cells expressed viral genes or produced infectious virus after initiation of
infection. UKF-NB-2AD169 cells were significantly less sensitive to the
cytotoxic agents cisplatinum and
etoposide than parental (noninfected) UKF-NB-2 cells. These effects were associated with decreased ability of UKF-NB-2AD169 cells to undergo apoptosis and continuous viral replication. UKF-NB-2AD169 cells showed increased levels of antiapoptosis Bcl-2
protein (up to 12-fold), whereas expression of p53 and c-myc was not changed. Treatment of UKF-NB-2AD169 cells with
ganciclovir, abolishing virus production, reestablished sensitivity to
chemotherapy, lowered Bcl-2 expression, and facilitated inducibility of apoptosis to the level of the parental cell line. The results demonstrate that persistent HCMV
infection confers resistance to
cytotoxic agents on
neuroectodermal tumor cells and protects from apoptosis, probably due to increased levels of Bcl-2
protein. Hence, it is conceivable that HCMV
infection before or during
tumorigenesis may contribute in some NB patients to failure of
therapy.