Statins demonstrate a broad anti-cytomegalovirus activity in vitro in ganciclovir-susceptible and resistant strains

Ponroy, Nicolas; Taveira, Aline; Mueller, Nicolas J.; Millard, Anne-Laure

doi:10.1002/jmv.23998

Cited by 27 publications

(19 citation statements)

References 65 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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“…Drugs such as lovastatin have been used to lower cell cholesterol levels in virus-infected cells (39)(40)(41) by affecting intermediate steps in the cholesterol-biosynthetic pathway but function only after several hours. The HSV-1 replicative cycle is complete within 18 to 24 h, and the rapid action of M␤CD in reducing cell cholesterol was better suited to this study.…”

Section: Discussionmentioning

confidence: 99%

Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1

Wudiri

Nicola

2017

J Virol

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Cholesterol is an essential component of cell membranes and is required for herpes simplex virus 1 (HSV-1) entry (1-3). Treatment of HSV-1-infected Vero cells with methyl beta-cyclodextrin from 2 to 9 h postentry reduced plaque numbers. Transport of incoming viral capsids to the nuclear periphery was unaffected by the cholesterol reduction, suggesting that cell cholesterol is important for the HSV-1 replicative cycle at a stage(s) beyond entry, after the arrival of capsids at the nucleus. The synthesis and release of infectious HSV-1 and cell-to-cell spread of infection were all impaired in cholesterol-reduced cells. Propagation of HSV-1 on DHCR24 Ϫ/Ϫ fibroblasts, which lack the desmosterol-to-cholesterol conversion enzyme, resulted in the generation of infectious extracellular virions (HSV des ) that lack cholesterol and likely contain desmosterol. The specific infectivities (PFU per viral genome) of HSV chol and HSV des were similar, suggesting cholesterol and desmosterol in the HSV envelope support similar levels of infectivity. However, infected DHCR24 Ϫ/Ϫ fibroblasts released ϳ1 log less infectious HSV des and ϳ1.5 log fewer particles than release of cholesterol-containing particles (HSV chol ) from parental fibroblasts, suggesting that the hydrocarbon tail of cholesterol facilitates viral synthesis. Together, the results suggest multiple roles for cholesterol in the HSV-1 replicative cycle.IMPORTANCE HSV-1 infections are associated with a wide range of clinical manifestations that are of public health importance. Cholesterol is a key player in the complex interaction between viral and cellular factors that allows HSV-1 to enter host cells and establish infection. Previous reports have demonstrated a role for cellular cholesterol in the entry of HSV-1 into target cells. Here, we employed both chemical treatment and cells that were genetically defined to synthesize only desmosterol to demonstrate that cholesterol is important at stages following the initial entry and transport of viral capsids to the nucleus. Viral protein expression, encapsidation of the viral genome, and the release of mature virions were impacted by the reduction of cellular cholesterol. Cholesterol was also critical for cell-to-cell spread of infection. These findings provide new insights into the cholesterol dependence of HSV-1 replication.KEYWORDS cholesterol, herpes simplex virus, herpesviruses, sterols T he entry of several herpesviruses into target cells requires cell membrane cholesterol (1-6). Membrane cholesterol is essential for maintaining membrane order, reducing permeability, and a host of other cellular functions, including cell signaling (7-10). Entry of the alphaherpesviruses herpes simplex virus 1 (HSV-1) and pseudorabies virus requires target membrane cholesterol at the fusion step (1, 3), but not for virus attachment to cells (2, 6). Herpesviruses utilize low-pH endosomal entry pathways and pH-independent routes, both of which require cholesterol (11-13). Membrane cholesterol plays a general role in viral entry...

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“…However, this is unlikely to be the sole cause of the anti‐Hep B effect because other statins, such as lovastatin, failed to produce antiviral effects . Anti‐HCMV activity may result directly from inhibition of HMG‐CoA reductase , which is related to the isoprenoid arm of the mevalonate pathway and linked to the functional nuclear factor‐kappaB‐binding inhibition of the interferon‐ β ‐mediated antiviral innate response .…”

Section: Discussionmentioning

confidence: 99%

Systematic review of the in vitro effects of statins on oral and perioral microorganisms

Ting

Whitaker

Albandar

2015

European J Oral Sciences

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Statins are medications administered orally and are widely used for lowering the blood cholesterol level. The aim of this study was to investigate the effects of orally administered statins on microorganisms infecting oral and perioral tissues. We performed a systematic review of published studies of the in vitro antimicrobial effects of statins on bacteria, viruses, and fungi, and searched PubMed, Web of Science, Cochrane Central, and Google scholar. Studies show that most statins exhibit antimicrobial effects against various oral microorganisms. Simvastatin is most effective against the periodontal pathogens Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, and against most dental plaque bacteria, including Streptococcus mutans. Statins also exhibit antiviral properties against human cytomegalovirus, hepatitis B virus, and hepatitis C virus, and have antifungal properties against Candida albicans, Aspergillus fumigatus, and Zygomycetes spp. There were notable differences in the minimum inhibitory concentrations (MICs) between different studies, which may be attributed to differences in study design. Further studies are warranted to ascertain if statins can be solubilized so that patients, who have been prescribed statins for cardiovascular diseases, can use the medication as a swish and swallow, giving patients the added benefit of the antimicrobial action topically in the mouth against infectious oral diseases.

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Statins demonstrate a broad anti-cytomegalovirus activity in vitro in ganciclovir-susceptible and resistant strains

Cited by 27 publications

References 65 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

Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1

Systematic review of the in vitro effects of statins on oral and perioral microorganisms

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