Article

Cholesterol biosynthesis modulation regulates Dengue viral replication

Novartis Institutes for Biomedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA.
Virology (Impact Factor: 3.28). 06/2009; 389(1-2):8-19. DOI: 10.1016/j.virol.2009.03.025
Source: PubMed

ABSTRACT We performed a focused siRNA screen in an A549 dengue type 2 New Guinea C subgenomic replicon cell line (Rluc-replicon) that contains a Renilla luciferase cassette. We found that siRNA mediated knock down of mevalonate diphospho decarboxylase (MVD) inhibited viral replication of the Rluc-replicon and DEN-2 NGC live virus replication in A549 cells. When the Rluc-replicon A459 cells were grown in delipidated media the replicon expression was suppressed and MVD knock down could further sensitize Renilla expression. Hymeglusin and zaragozic acid A could inhibit DEN-2 NGC live virus replication in K562 cells, while lovastatin could inhibit DEN-2 NGC live virus replication in human peripheral blood mononuclear cells. Renilla expression could be rescued in fluvastatin treated A549 Rluc-replicon cells after the addition of mevalonate, and partially restored with geranylgeranyl pyrophosphate, or farnesyl pyrophosphate. Our data suggest genetic and pharmacological modulation of cholesterol biosynthesis can regulate dengue virus replication.

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    • "Recently, it has been reported that apoptosis induction is mediated by PI3k/Akt pathway through Bcl-2 protein and requires the production of a subgenomic RNA [98]. In addition, Rotwell et al. [99] used RNAi screen in A549 cells (lung cells) found, that inhibition of the mevalonate decarboxylase protein expression decreased DENV replication , suggesting that the metabolism of lipids is involved in dengue infection. In agreement, autophagy, which is process that induces alterations in the lipid metabolism, has been reported to favor DENV infection [100] [101] [102]. "
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    • "Recently, it has been reported that apoptosis induction is mediated by PI3k/Akt pathway through Bcl-2 protein and requires the production of a subgenomic RNA [98]. In addition, Rotwell et al. [99] used RNAi screen in A549 cells (lung cells) found, that inhibition of the mevalonate decarboxylase protein expression decreased DENV replication , suggesting that the metabolism of lipids is involved in dengue infection. In agreement, autophagy, which is process that induces alterations in the lipid metabolism, has been reported to favor DENV infection [100] [101] [102]. "
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    • "Several (+) RNA viruses, such as hepatitis C virus (HCV), dengue, and West Nile virus, remodel the cellular cholesterol landscape to make intracellular host-cell membranes conducive for efficient genome replication (Rothwell et al., 2009; Wang et al., 2014). Enterovirus-induced rearrangements of secretory pathway membranes into the tubulovesicular RO structures may also depend on alterations in cholesterol homeostasis. "
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