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 resistance 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 compared in undifferentiated U937 cells and U937 cells differentiated with a combination of vitamin D3 and retinoic acid. Undifferentiated U937 cells were highly resistant to HHV-6 infection. Differentiation of U937 cells was accompanied by an increase in permissiveness for HHV-6 demonstrated in terms of extracellular virus production and viral antigen positive immunofluorescent cells. Tumor necrosis factor α (TNFα) appears to be an essential mediator during the first line defences of the host against viruses, even though its role during viral infection remains controversial. For this reason we examined the behaviour of TNFα in differentiated U937 upon HHV-6 infection. No basal production of TNFα was found in culture supernatants, while HHV-6 infection up-regulated TNFα release. The addition of human recombinant-TNFα to HHV-6 infected cells induced a marked cytotoxic effect accompanied by an increased release of extracellular virus, whereas it did not affect viral replication, as shown by the unmodified percentage of antigen positive cells. In conclusion, TNFα acts as a soluble mediator of cytotoxicity against HHV-6 infected U937 cells, but it fails to induce an antiviral state.