Defective rotavirus particle assembly in lovastatin-treated MA104 cells

Mohan, Ketha V. K.; Müller, Jacqueline; Atreya, Chintamani D.

doi:10.1007/s00705-008-0261-0

Cited by 23 publications

(25 citation statements)

References 31 publications

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“…The cholesterol synthesis pathway facilitates the replication of diverse RNA and DNA viruses in vitro (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), similar to what was observed for MHV68 ( Fig. 1 and 2).…”

Section: Discussionsupporting

confidence: 80%

“…Statins are prescribed to ϳ12.5% of the adult population in the United States. Interestingly, statins decrease the replication of several RNA and DNA viruses in tissue culture (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). In some cases, statin-mediated attenuation of endogenous cholesterol synthesis is thought to interfere with viral entry or decrease the abundance of intracellular membranes that serve as platforms for viral replication and assembly/maturation.…”

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confidence: 99%

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Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Lange

Darrah

Vonderhaar

et al. 2016

J Virol

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The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents. IMPORTANCEStatins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S. population. Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity. I ntracellular cholesterol is acquired via two major mechanisms: internalization of exogenous cholesterol via the low-density lipoprotein receptor (LDLR) and endogenous cholesterol synthesis. The latter mechanism (Fig. 1A) operates in all cell types and is positively regulated by sterol regulatory element-binding protein 2 (Srebp2). Srebp2, a transcription factor synthesized as an inactive membrane-associated precursor, is cleaved by Golgi apparatus-specific proteases under conditions of low cholesterol to release an active product (1). This active cleaved product induces expression of most enzymes involved in cholesterol synthesis, including the rate-limiting enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) (2). Active Srebp2 also increases the expression of LDLR to promote the acquisition of exogenous cholesterol. Due to the critical role of cholesterol for cell viability, genetic disruption of Srebp2 leads to early embryonic lethality (3).Elevated plasma cholesterol levels are a potent risk factor for atherosclerosis, and the targeting of the cholesterol synth...

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Lange

Darrah

Vonderhaar

et al. 2016

J Virol

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“…For example, cholesterol depletion by lovastatin, an inhibitor of cholesterol biosynthesis, was shown to reduce rotavirus replication in MA104 cells (31). Likewise, drugs that disperse lipid droplets by promoting lipolysis were shown to interfere with rotavirus particle or viroplasm formation (7).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Bile Acids and Synthetic Farnesoid X Receptor Agonists on Rotavirus Replication

Kim

Chang

2011

J Virol

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Rotaviruses (group A rotaviruses) are the most important cause of severe gastroenteritis in infants and children worldwide. Currently, an antiviral drug is not available and information on therapeutic targets for antiviral development is limited for rotavirus infection. Previously, it was shown that lipid homeostasis is important in rotavirus replication. Since farnesoid X receptor (FXR) and its natural ligands bile acids (such as chenodeoxycholic acid [CDCA]) play major roles in cholesterol and lipid homeostasis, we examined the effects of bile acids and synthetic FXR agonists on rotavirus replication in association with cellular lipid levels. In a mouse model of rotavirus infection, effects of oral administration of CDCA on fecal rotavirus shedding were investigated. The results demonstrate the following. First, the intracellular contents of triglycerides were significantly increased by rotavirus infection. Second, CDCA, deoxycholic acid (DCA), and other synthetic FXR agonists, such as GW4064, significantly reduced rotavirus replication in cell culture in a dose-dependent manner. The reduction of virus replication correlated positively with activation of the FXR pathway and reduction of cellular triglyceride contents (r 2 ‫؍‬ 0.95). Third, oral administration of CDCA significantly reduced fecal virus shedding in mice (P < 0.05). We conclude that bile acids and FXR agonists play important roles in the suppression of rotavirus replication. The inhibition mechanism is proposed to be the downregulation of lipid synthesis induced by rotavirus infection.

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“…In concordance with these results, we found a reduction in infectious viral particles released in the supernatant. Mohan et al [28] recently found an increase in intracellular viral protein in MA104 cells infected with rotavirus and subsequently treated with LOV. Moreover, they observed an increase in the number of 'empty-looking' particles seen by electron microscopy in supernatants from these cells, which suggests a defect in virus assembly.…”

Section: Discussionmentioning

confidence: 99%

“…Studies using cultured cells have demonstrated inhibitory effects of statins on the replication of RNA and DNA viruses, including respiratory syncytial virus [25] , hepatitis C virus [26] , human immunodeficiency virus [27] , rotavirus [28] , and cytomegalovirus [29] . In some cases, including hepatitis C and human immunodeficiency viral infection, their activity has been assessed in infected patients, demonstrating a decrease in the severity of infection [27,30] .…”

mentioning

confidence: 99%

Statins Reduce Dengue Virus Production via Decreased Virion Assembly

2011

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Background: Most of the effects of statins can be explained by pleiotropic effects independent of their lowering of serum cholesterol; in some cases, these effects have been shown to be a result of the role of statins in the prenylation of cellular proteins, some of which are involved in the life cycle of animal viruses. This study evaluated the potential antiviral activity of lovastatin (LOV) against dengue virus (DENV) infection of epithelial and endothelial cells (VERO cells, epithelial cells derived from African green monkey kidney, and HMEC-1 cells, human dermal microvascular endothelial cells). Methods: To evaluate its potential antiviral effects, LOV was used before, during and after inoculation of cell cultures with DENV. Results: Before and after viral inoculation, LOV caused a reduction in virus yield (80% for HMECs and 25% for VERO cells). However, with LOV treatment after inoculation induced a marked increase (2- to 9-fold) in viral-positive RNA while the amount of viral protein increased only by 13–23%. A moderate reduction (1 log unit) in viral titer occurred concurrent with the increase in DENV genomic RNA and protein within the cells. Conclusions: According to our results, LOV appears to have a greater effect on viral assembly than on replication, resulting in the cellular presence of viral genomic RNA and proteins that fail to take the normal assembly pathway.

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Defective rotavirus particle assembly in lovastatin-treated MA104 cells

Cited by 23 publications

References 31 publications

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Inhibitory Effects of Bile Acids and Synthetic Farnesoid X Receptor Agonists on Rotavirus Replication

Statins Reduce Dengue Virus Production via Decreased Virion Assembly

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