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Antimicrobial Agents and Chemotherapy, April 2001, p. 1231-1237, Vol. 45, No. 4
Departments of Microbiology and
Immunology1 and
Medicine,2 Vanderbilt University
School of Medicine, Nashville, Tennessee 37232
Received 24 August 2000/Returned for modification 13 November
2000/Accepted 24 January 2001
Respiratory syncytial virus (RSV) is an important human pathogen
that can cause severe and life-threatening respiratory infections in
infants and immunocompromised adults. We have recently shown that the
RSV F glycoprotein, which mediates viral fusion, binds to RhoA. One of
the steps in RhoA activation involves isoprenylation at the carboxy
terminus of the protein by geranylgeranyltransferase. This modification
allows RhoA to be attached to phosphatidyl serine on the inner leaflet
of the plasma membrane. Treatment of mice with lovastatin, a drug that
inhibits prenylation pathways in the cell by directly inhibiting
hydroxymethylglutaryl coenzyme A reductase, diminishes 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
cholesterol biosynthesis, since gemfibrozil, another
cholesterol-lowering agent, did not affect virus replication and serum
cholesterol levels were not significantly lowered by lovastatin within
the time frame of the experiment. Lovastatin also reduces cell-to-cell fusion in cell culture and eliminates RSV replication in HEp-2 cells.
These data indicate that lovastatin, more specific isoprenylation inhibitors, or other pharmacological approaches for preventing RhoA
membrane localization should be considered for evaluation as a
preventive antiviral therapy for selected groups of patients at high
risk for severe RSV disease, such as the institutionalized elderly and
bone marrow or lung transplant recipients.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.4.1231-1237.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Antiviral Activity of Lovastatin against
Respiratory Syncytial Virus In Vivo and In Vitro
*
Corresponding author. Mailing address: A-4103 MCN,
Vanderbilt University School of Medicine, 1161 21st Ave. South,
Nashville, TN 37232-2582. Phone: (615) 343-3717. Fax: (615)
322-8222. E-mail: bgraham{at}mail.nih.gov.
Antimicrobial Agents and Chemotherapy, April 2001, p. 1231-1237, Vol. 45, No. 4
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.4.1231-1237.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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