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J Virol, March 1998, p. 2316-2322, Vol. 72, No. 3
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Distinct Pathways for Tumor Necrosis Factor Alpha and Ceramides in Human Cytomegalovirus Infection

Justine Allan-Yorke,¹ Michel Record,² Claude de Préval,¹ Christian Davrinche,¹ and Jean-Luc Davignon^1,*

INSERM U.395¹ and INSERM U.326,² Toulouse, France

Received 28 August 1997/Accepted 14 November 1997

Human cytomegalovirus (HCMV) infection can be fatal to immunocompromised individuals. We have previously reported that gamma interferon and tumor necrosis factor alpha (TNF-) synergistically inhibit HCMV replication in vitro. Ceramides have been described as second messengers induced by TNF-. To investigate the mechanisms involved in the inhibition of HCMV by TNF-, in the present study we have analyzed ceramide production by U373 MG astrocytoma cells and the effects of TNF- versus ceramides on HCMV replication. Our results show that U373 MG cells did not produce ceramides upon incubation with TNF-. Moreover, long-chain ceramides induced by treatment with exogenous bacterial sphingomyelinase inhibited HCMV replication in synergy with TNF-. Surprisingly, short-chain permeant C6-ceramide increased viral replication. Our results show that the anti-HCMV activity of TNF- is independent of ceramides. In addition, our results suggest that TNF- and endogenous long-chain ceramides use separate pathways of cell signalling to inhibit HCMV replication, while permeant C6-ceramide appears to activate a third pathway leading to an opposite effect.

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^* Corresponding author. Mailing address: INSERM U.395, CHU Purpan, BP 3028, 31024 Toulouse CEDEX, France. Phone: (33) 5 62 74 83 76. Fax: (33) 5 61 31 97 52. E-mail: davignon{at}purpan.inserm.fr.

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