Lovastatin Delays Infection and Increases Survival Rates in AG129 Mice Infected with Dengue Virus Serotype 2

Abstract

BackgroundIt has been reported that treatment of DENV-infected cultures with Lovastatin (LOV), can affect viral assembly. The objective of this study was to evaluate the effect of LOV on the survival rate and viremia levels of DENV-2-infected AG129 mice.Methodology/Principal FindingsMice were inoculated with 1×106 plaque-forming units (PFU/ml) of DENV-2 and treated with LOV (200 mg/kg/day). Pre-treatment with one or three doses of LOV increased the survival rate compared to untreated mice (7.3 and 7.1 days, respectively, compared to 4.8 days). Viremia levels also decreased by 21.8% compared to untreated mice, but only in the group administered three doses prior to inoculation. When LOV was administered after viral inoculation, the survival rate increased (7.3 days in the group treated at 24 hpi, 6.8 days in the group treated at 48 hpi and 6.5 days in the group treated with two doses) compared to the untreated group (4.8 days). Interestingly, the serum viral titer increased by 24.6% in mice treated at 48 hpi with a single dose of LOV and by 21.7% in mice treated with two doses (at 24 and 48 hpi) of LOV compared to untreated mice. Finally histopathological changes in the liver and spleen in infected and untreated mice included massive extramedullary erythropoiesis foci and inflammatory filtration, and these characteristics were decreased or absent in LOV-treated mice.Conclusions/SignificanceOur results suggest that the effect of LOV on viremia depends on the timing of treatment and on the number of doses administered. We observed a significant increase in the survival rate in both schemes due to a delay in the progression of the disease. However, the results obtained in the post-treatment scheme must be handled carefully because this treatment scheme increases viremia and we do not know how this increase could affect disease progression in humans.

Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library

“…A clinical trial tested the efficacy of the treatment of Dengue-infected patients with Lovastatin 31 , since the endothelial stabilizing effects of statins could decrease Dengue-related vasculopathy. Although Lovastatin anti-flaviviral activity was already reported in hepatitis C virus 32 and Dengue virus 33, 34 , no evidence of a beneficial effect on any of the clinical manifestations or on Dengue viremia was found. In addition, Lovastatin was reported to attenuate nervous injury in animal model of Guillain-Barré syndrome 35 .…”

Coupling of replication and assembly in flaviviruses

“…When the cholesterol biosynthesis inhibitor, lovastatin, was used ER membrane biogenesis remained unaffected. However, production of infectious DENV particles was abrogated suggesting that cholesterol has additional functions in replication [51,65]. Furthermore, increased levels of cholesterol were induced in the early stages of DENV infection and an increase in LDL particle uptake and HMG-COA reductase activity was seen [58].…”

Flavivirus modulation of cellular metabolism

“…Virtually all of the processes discussed in this review have been targeted for anti-flaviviral efficacy in cell culture (32). Inhibition of cholesterol biosynthesis has anti-flaviviral properties (15, 20, 24, 25, 29). Similarly inhibitor of fatty acid synthesis are anti-flaviviral (10, 23, 26, 29, 30), in addition to downstream lipid synthetic enzymes (15, 19, 31).…”