Antiviral activity of lovastatin against respiratory syncytial virus in vivo and in vitro

Respiratory syncytial virus (RSV) is an important human pathogen that can c ause severe and life-threatening respiratory infections in infants and immu nocompromised adults. We have recently shown that the RSV F glycoprotein, w hich mediates viral fusion, binds to RhoA. One of the steps in RhoA activat ion involves isoprenylation at the carboxy terminus of the protein by geran ylgeranyltransferase. This modification allows RhoA to be attached to phosp hatidyl serine on the inner leaflet of the plasma membrane. Treatment of mi ce with lovastatin, a drug that inhibits prenylation pathways in the cell b y directly inhibiting hydroxymethylglutaryl coenzyme A reductase, diminishe s RSV but not vaccinia virus replication when administered up to 24 h after RSV infection and decreases virus-induced weight loss and illness in mice. The inhibition of replication is not likely due to the inhibition of chole sterol biosynthesis, since gemfibrozil, another cholesterol-lowering agent, did not affect virus replication and serum cholesterol levels were not sig nificantly lowered by lovastatin within the time frame of the experiment. L ovastatin also reduces cell-to-cell fusion in cell culture and eliminates R SV replication in HEp-2 cells. These data indicate that lovastatin, more sp ecific isoprenylation inhibitors, or other pharmacological approaches for p reventing RhoA membrane localization should be considered for evaluation as a preventive antiviral therapy for selected groups of patients at high ris k for severe RSV disease, such as the institutionalized elderly and bone ma rrow or lung transplant recipients.