PRODUCTIVE HHV-6 INFECTION IN DIFFERENTIATED U937 CELLS - ROLE OF TNF-ALPHA IN REGULATION OF HHV-6

This study characterizes the effect of differentiation on the resistan ce of the human monocytic cell line U937 to human herpes virus type 6 (HHV-6). The use of monocytic cell line has the advantage of avoiding genetic variations among different donors. The HHV-6 infection was com pared in undifferentiated U937 cells and U937 cells differentiated wit h a combination of vitamin D3 and retinoic acid. Undifferentiated U937 cells were highly resistant to HHV-6 infection. Differentiation of U9 37 cells was accompanied by an increase in permissiveness for HHV-6 de monstrated in terms of extracellular virus production and viral antige n positive immunofluorescent cells. Tumor necrosis factor alpha (TNF a lpha) appears to be an essential mediator during the first line defenc es of the host against viruses, even though its role during viral infe ction remains controversial. For this reason we examined the behaviour of TNF alpha in differentiated U937 upon HHV-6 infection. No basal pr oduction of TNF alpha was found in culture supernatants, while HHV-6 i nfection up-regulated TNF alpha release. The addition of human recombi nant-TNF alpha to HHV-6 infected cells induced a marked cytotoxic effe ct accompanied by an increased release of extracellular virus, whereas it did not affect viral replication, as shown by the unmodified perce ntage of antigen positive cells. In conclusion, TNF alpha acts as a so luble mediator of cytotoxicity against HHV-6 infected U937 cells, but it fails to induce an antiviral state.