The antisense oligonucleotide ISIS 2922 prevents cytomegalovirus-induced upregulation of IL-8 and ICAM-1 in cultured human fibroblasts

Human cytomegalovirus (HCMV) infection is associated with excessive proinfl ammatory immune responses such as cytokine/chemokine production or upregula tion of adhesion molecules on the host cells. It is assumed that these feat ures of HCMV-related immunopathology can not be treated effectively with cu rrently available anti HCMV drugs. In the present study the efficacy of gan ciclovir (GCV), foscarnet (PFA), cidofovir (HPMPC), and ISIS 2922, an antis ense oligonucleotide complementary to HCMV immediate-early (IE) mRNA, was i nvestigated on HCMV-induced secretion and functional activity of the C-X-C chemokine IL-8 and the expression of the intercellular adhesion molecule-1 (ICAM-1). As compared with mock-infected cells IL-8 production was increase d up to 9-fold and ICAM-1 expression up to 4-fold in HCMV-infected fibrobla sts. Treatment of infected cells with GCV (40 mu M), PFA (200 mu M) or HPMP C (2 mu M) suppressed completely virus replication as demonstrated by quant ification of late (L) antigen expression and infectious virus production. T hese drugs, however, failed to inhibit IE antigen expression and did not pr event HCMV-induced upregulation of IL-8 and ICAM-1. In contrast, ISIS 2922 (1 mu M) suppressed both IE and L antigen expression by 99% and inhibited i nfectious virus production by 10(4)-fold. Moreover, ISIS 2922 significantly suppressed HCMV-induced upregulation of both IL-8 and ICAM-1 expression on the transcriptional and on the protein level. Our results indicate that IS IS 2922 but not inhibitors of HCMV DNA prevents HCMV-induced upregulation o f IL-8 and ICAM-1, both hallmarks of inflammatory processes. Thus, inhibiti on of HCMV IE expression with ISIS 2922 may be an important strategy for th e treatment of HCMV-related immunopathogenesis. J. Med Virol. 60:373-323, 2 000. (C) 2000 Wiley-Liss, Inc.