Targeting Lipid Metabolism in the Treatment of Hepatitis C Virus Infection

Amemiya, Fumitake; Maekawa, Shinya; Itakura, Yoshie; Kanayama, Asuka; Matsui, Akira; Takano, Shinichi; Yamaguchi, Tatsuya; Itakura, Jun; Kitamura, Takatoshi; Inoue, Taisuke; Sakamoto, Minoru; Yamauchi, Kozue; Okada, Shunichi; Yamashita, Atsuya; Sakamoto, Naoya; Itoh, Masahiko; Enomoto, Nobuyuki

doi:10.1086/525287

Cited by 55 publications

(54 citation statements)

References 30 publications

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“…Because sphingolipid metabolism is currently considered as a suitable target for antiviral development (55)(56)(57), our data support the potential of modulating SM levels as an antiviral strategy to combat WNV.…”

Section: Discussionsupporting

confidence: 65%

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Host sphingomyelin increases West Nile virus infection in vivo

Martín-Acebes

Gabandé‐Rodríguez

García-Cabrero

et al. 2016

Journal of Lipid Research

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The fl avivirus, West Nile virus (WNV), is a neurotropic enveloped plus-strand RNA virus transmitted through the bite of mosquitoes. This virus is responsible for recurrent outbreaks of febrile illness and meningoencephalitis worldwide, accounting for hundreds of human deaths every year ( 2 ). The WNV lifecycle is intimately associated to cellular lipids, and RNA replication and virion biogenesis are coupled into highly remodeled intracellular membranes ( 3, 4 ). In a parallel manner to that described for other fl aviviruses, both RNA replication and acquisition of lipid envelope are associated to specialized membranous structures derived from the endoplasmic reticulum (ER) ( 3-6 ). To generate this adequate environment for viral multiplication, WNV promotes the synthesis and accumulation of specifi c lipids (fatty acids, cholesterol, glycerophospholipids, and sphingolipids) within infected cells ( 5,(7)(8)(9). This selective manipulation of host cell lipid metabolism is not a unique feature of WNV infection, as it is also observed in cells infected with other fl aviviruses ( 10-12 ).Among the cellular lipids co-opted by WNV, sphingolipids merit special attention because they are particularly enriched in the nervous system, a major target tissue during WNV infection ( 13,14 ). Sphingolipids derive from sphingosine, a long-chain amino alcohol that is acylated with a long-chain fatty acid to give ceramide, which

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Section: Discussionsupporting

confidence: 65%

“…GM16195 is homozygous for a T to C transition at nucleotide 905 of the SPMD1 gene, resulting in a Leu to Pro substitution at codon 302. Cells were cultured (37°C, 5% CO 2 ) in DMEM supplemented with 2 mM glutamine, by guest, on March 28, 2019 www.jlr.org…”

Section: Cells and Virusesmentioning

confidence: 99%

Host sphingomyelin increases West Nile virus infection in vivo

Martín-Acebes

Gabandé‐Rodríguez

García-Cabrero

et al. 2016

Journal of Lipid Research

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“…30 HCV RNA replication in vitro has been found to be dependent on intracellular lipid metabolism; however, influence of serum cholesterol levels on virological response to antiviral treatment in vivo has not yet been understood. 31,32 In conclusion, in this large placebo-controlled, doubleblinded multicenter study in patients with chronic hepatitis C, amantadine even at a dose of 400 mg/day was not able to improve virological response rates of PEG IFN-␣-2a and ribavirin. Therefore, amantadine has no relevance in the antiviral treatment of chronic hepatitis C. Currently, direct antiviral agents such as inhibitors of the HCV serine protease and the RNA-dependent RNA polymerase are under clinical investigations, and initial phase I/II trials have shown that the combination of PEG IFN-␣ and ribavirin together with a direct antiviral compound can increase sustained virological response rates in genotype HCV-1-infected patients.…”

Section: Discussionmentioning

confidence: 78%

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Wagner¹,

Hofmann²,

Teuber³

et al. 2008

Hepatology

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The impact of amantadine on virologic response rates of interferon-based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)-1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa-2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV-1-infected patients (mean age, 46 ؎ 12 years) were randomized to (A) amantadine-sulphate (400 mg/day) (n ‫؍‬ 352) or (B) placebo (n ‫؍‬ 352), both in combination with 180 g peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24-week follow-up period were assessed by qualitative reverse transcription polymerase chain reaction (RT-PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On-treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P ‫؍‬ 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per-protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). Conclusion: In this large placebo-controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa-2a and ribavirin in patients with chronic genotype HCV-1 infection. (HEPATOLOGY 2008;

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“…However, cell culture models of HCV infection have demonstrated that anti-HCV activity is not the same for all statins: fluvastatin, atorvastatin, simvastatin, and lovastatin inhibit viral replication to variable extents, whereas pravastatin and rosuvastatin have little to no anti-HCV activity. [18][19][20][21] The underlying mechanism remains unclear; however, data suggest that HCV enters hepatocytes via several lipoprotein receptors (LDL and scavenger receptor class B type 1). At first glance, this appears to be counterintuitive because the statins increase LDL receptors on hepatocytes and in theory increase HCV infectivity.…”

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confidence: 99%

Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

et al. 2010

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Elevated low-density lipoprotein (LDL) levels and statin use have been associated with higher sustained virological response (SVR) rates in patients receiving chronic hepatitis C therapy. However, these relationships have not been well characterized in randomized controlled trials. Furthermore, little is known about the relationship between high-density lipoprotein (HDL) and virological response. To determine whether baseline LDL or HDL levels and statin use affect SVR rates, we retrospectively evaluated the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial, in which 3070 treatment-naive, hepatitis C virus (HCV) genotype 1-infected patients were treated for up to 48 weeks in one of the following arms: (1) peginterferon (PEG-IFN) alfa-2b at 1.5 lg/kg/week with ribavirin (RBV) at 800 to 1400 mg/day, (2) PEG-IFN alfa2b at 1.0 lg/kg/week with RBV at 800 to 1400 mg/day, or (3) PEG-IFN alfa-2a at 180 lg/week with RBV at 1000 to 1200 mg/day. Virological responses were assessed by pretreatment statin use and baseline elevated LDL levels (!130 mg/dL) or low HDL levels (<40 mg/dL for men and <50 mg/dL for women). In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001). In 66 patients receiving a statin pretreatment, the SVR rate was higher than the rate of those not receiving it (53.0% versus 39.3%, P 5 0.02). In a multivariate logistic regression analysis using the stepwise selection method with baseline characteristics, a high LDL level [odds ratio (OR) 5 1.6, 95% confidence interval (CI) 5 1.4-1.8, P < 0.001], a low HDL level (OR 5 0.5, 95% CI 5 0.3-0.8, P 5 0.004), and statin use (OR 5 2.0, 95% CI 5 1.1-3.7, P 5 0.02) were independently associated with SVR. Conclusion: Baseline elevated LDL levels or low HDL levels and preemptive statin usage were associated with higher SVR rates. Prospective studies may be considered to explore the biological impact of these factors on HCV RNA replication and treatment response. (HEPATOLOGY 2010;52:864-874)

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Targeting Lipid Metabolism in the Treatment of Hepatitis C Virus Infection

Cited by 55 publications

References 30 publications

Host sphingomyelin increases West Nile virus infection in vivo

Host sphingomyelin increases West Nile virus infection in vivo

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

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