3,4',5-Trihydroxy-trans-stilbene (resveratrol) inhibits human cytomegalovirus replication and virus-induced cellular signaling.
Resveratrol is a polyphenolic natural product that is present in red wine and peanuts and has inhibitory activity against inflammation, heart disease, and cancer. Here we describe its inhibition of human cytomegalovirus replication (IC50 = 1-2 microM). At least 50-fold higher concentrations of compound were required to produce cytotoxicity against growing or stationary human embryonic lung fibroblasts. Mechanism of action studies determined that resveratrol blocked virus-induced activation of the epidermal growth factor receptor (EGFR) and phosphatidylinositol-3-kinase signal transduction as well as NF-kappaB and Sp1 transcription factor activation shortly following infection. Resveratrol prevented the appearance of immediate-early, early, and late viral proteins. Human cytomegalovirus DNA replication was reduced to undetectable levels by treatment with resveratrol, as were the second (late) phases of virus-induced phosphatidylinositol-3-kinase signaling and transcription factor activation. Resveratrol lost substantial antiviral activity when its addition was delayed until 4 h postinfection. Compound reversibility and preincubation studies were inconsistent with a virucidal mechanism of action. These data indicated that this compound likely operated during attachment and entry. We hypothesize that the primary molecular target for resveratrol may be blockage of epidermal growth factor receptor activation and its downstream effectors.
Lineberger Comprehensive Cancer Center, Rm 32-026, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
David L
DL
Evers
Xin
X
Wang
Shu-Mei
SM
Huong
David Y
DY
Huang
Eng-Shang
ES
Huang
D000998:Antiviral Agents / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000254:growth & development; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004279:DNA, Viral; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D013267:Stilbenes; D014764:Viral Proteins; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077185:Resveratrol