Protective effect of fluvastatin on influenza virus infection

Peng, Jing; Zhang, Dingmei; Ma, Yu; Wang, Guoling; Z, Guo; Lu, Jiahai

doi:10.3892/mmr.2014.2076

Cited by 28 publications

(24 citation statements)

References 30 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: 79%

“…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: 79%

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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“…The addition of geranylgeraniol, which is involved in protein trafficking to membrane compartments, restored viral replication thus suggesting a non-direct antiviral activity of statins. Antiviral effects of statins have also been described for HBV, HIV, influenza virus, DENV, HCMV and norovirus [161][162][163][164][165][166][167][168][169] . However the antiviral efficacy of statins in vivo was only marginal and drug-drug interactions with DAAs have been reported 170,171 .…”

Section: Bsas Derived From Fungi: Cyclosporine Statins and Mycophenomentioning

confidence: 96%

Antiviral drug discovery: broad-spectrum drugs from nature

et al. 2015

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, but cannot be converted to PDF. You must view these files (e.g. movies) online.Scheme 1_(structures 1-5)_named.cdx Scheme 2_(structures 6-8)_named.cdx Scheme 3_(structure 9)_named.cdx Scheme 4_(structure 10)_named.cdx Scheme 5_ (structures 11-12) The development of drugs with broad-spectrum antiviral activities is a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of many viruses, yet the development of such host-targeting drugs has been met with skepticism mainly due to toxicity issues and poor translation to in vivo models. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can efficiently treat a wide range of viral infections by blocking specific host functions has rebloomed. Here we critically review the state-of-the-art in broad-spectrum antiviral drug discovery. We discuss putative targets and treatment strategies, taking particular focus on natural products as promising starting points for antiviral lead development.

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“…The RNAi mediated knockdown of HMGCR protein levels and pharmaceutical inhibition of HMGCR activity down-regulates viral activity ( Figure 1) and have the potential to protect hosts from viral infection [1, [22][23][24][25]. Moreover, the inhibition of HMGCR increases the expression of interferon-responsive genes [26].…”

Section: Is the Degradation Of Hmgcr Induced By Iav Infection Dependementioning

confidence: 99%

Down regulation ofHmgcrin response to Influenza A infection is independent of the IFN response in human cells

Talbot

2019

Preprint

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Previous studies have demonstrated that the product of the Interferon stimulated gene Ch25h, 25-Hydroxycholestrol, provides an immediate and rapid mechanism for down-regulating sterol biosynthesis, through the inhibition of Hmgcr gene expression and proteolytic degradation of HMGCR protein. Further studies provide evidence that inhibition of the sterol biosynthesis pathway by 25-HC has broad antiviral effects. In this study, Influenza A virus (IAV) replication was inhibited in cells treated with Fluvastatin or where Hmgcr expression was inhibited with an siRNA. Treatment of A549 cells with 25-HC however, resulted in a 2-fold enhancement of IAV replication despite the fact that 25-HC promotes the proteolytic degradation of HMGCR. A549 cells infected with IAV revealed a rapid loss of HMGCR protein, a reduction in Hmgcr gene expression as well as an increase in the expression of Ch25h, that were all independent of the IFN pathway.Infection of both wild-type and Ch25h -/murine BMDMs with IAV also revealed a rapid loss of HMGCR abundance indicating that 25-HC independent mechanisms exist for promoting proteolytic degradation of HMGCR. These data for the human A549 cell line contrast with the induction of Ch25h and subsequent loss of HMGCR in murine cells that has been shown to be dependent on IFN signalling.

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Protective effect of fluvastatin on influenza virus infection

Cited by 28 publications

References 30 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

Antiviral drug discovery: broad-spectrum drugs from nature

Down regulation ofHmgcrin response to Influenza A infection is independent of the IFN response in human cells

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