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 proinflammatory immune responses such as cytokine/chemokine production or upregulation of adhesion molecules on the host cells. It is assumed that these features of HCMV-related immunopathology can not be treated effectively with currently available anti HCMV drugs. In the present study the efficacy of ganciclovir (GCV), foscarnet (PFA), cidofovir (HPMPC), and ISIS 2922, an antisense oligonucleotide complementary to HCMV immediate-early (IE) mRNA, was investigated 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 increased up to 9-fold and ICAM-1 expression up to 4-fold in HCMV-infected fibroblasts. Treatment of infected cells with GCV (40 microM), PFA (200 microM) or HPMPC (2 microM) suppressed completely virus replication as demonstrated by quantification of late (L) antigen expression and infectious virus production. These drugs, however, failed to inhibit IE antigen expression and did not prevent HCMV-induced upregulation of IL-8 and ICAM-1. In contrast, ISIS 2922 (1 microM) suppressed both IE and L antigen expression by 99% and inhibited infectious 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 ISIS 2922 but not inhibitors of HCMV DNA prevents HCMV-induced upregulation of IL-8 and ICAM-1, both hallmarks of inflammatory processes. Thus, inhibition of HCMV IE expression with ISIS 2922 may be an important strategy for the treatment of HCMV-related immunopathogenesis.
Cinatl
J
J
Zentrum der Hygiene, Institut für Medizinische Virologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. cinatl@em.uni-frankfurt.de
Kotchetkov
R
R
Weimer
E
E
Blaheta
R A
RA
Scholz
M
M
Vogel
J U
JU
Gümbel
H O
HO
Doerr
H W
HW
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D000077404:Cidofovir; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D017245:Foscarnet / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013873:Thionucleotides / Q000494:pharmacology*; D015854:Up-Regulation
D000998:Antiviral Agents; D016209:Interleukin-8; D016376:Oligonucleotides, Antisense; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; D017245:Foscarnet; D003596:Cytosine; D000077404:Cidofovir; D015774:Ganciclovir; C091346:fomivirsen