Transmission of low‐density hepatitis C viral particles during sexually transmitted acute resolving infection

Diaz, Olivier; Cubero, Meritxell; Trabaud, Mary‐Anne; Quer, Josep; Icard, Vinca; Esteban, Juan Ignacio; Lotteau, Vincent; André, Patrice

doi:10.1002/jmv.21037

Cited by 12 publications

(9 citation statements)

References 19 publications

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“…In addition, not only could low-density fractions transmit HCV to experimental animal models,13 but the infectious titre of HCV-positive inocula was inversely correlated with the buoyant density of HCV RNA-carrying particles,14 hinting at a critical role for the association with lipoproteins in conferring infectivity. Low-density HCV particles were subsequently also shown to be infectious in vitro15 and in natural human infections 16. Furthermore, cell culture grown HCV successfully transmitted to the chimpanzee is associated with low-density fractions 15…”

Section: Hcv and Lipoproteinsmentioning

confidence: 99%

Abnormalities of lipid metabolism in hepatitis C virus infection

Negro¹

2010

Gut

146

131

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Hepatitis C virus (HCV) is a human pathogen responsible for acute and chronic liver disease, infecting an estimated 130-170 million persons worldwide. An intriguing feature of HCV infection is its peculiar relationship with lipids: (1) HCV virions circulate in serum bound to lipoproteins; (2) lipids have been shown to modulate (and, indeed, are essential to) the HCV life cycle; and (3) an occasionally severe accumulation of triglycerides is found in a distinct subgroup of patients in the form of hepatic steatosis. As a result, lipid metabolism is overall altered, conferring an idiosyncratic profile to HCV infection. The scope of this review is to discuss these aspects, focusing on both their molecular mechanisms and their clinical consequences.

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Section: Hcv and Lipoproteinsmentioning

confidence: 99%

Abnormalities of lipid metabolism in hepatitis C virus infection

Negro¹

2010

Gut

146

131

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“…Indeed, HCV interference with lipid metabolism has been extensively studied since the virus associates with lipoproteins and forms infectious hybrid particles, the lipo-viral particles (LVP) that are secreted from hepatocytes (5,(7)(8)(9). Association of the virus with lipids confers low density to LVP and is correlated to higher infectivity (10)(11)(12). Secreted LVP are particularly rich in neutral lipids, such as triglycerides, which require fatty acids to be synthesized.…”

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confidence: 99%

Activity of Hexokinase Is Increased by Its Interaction with Hepatitis C Virus Protein NS5A

Ramière

Rodriguez

Enache

et al. 2014

J Virol

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The study of cellular central carbon metabolism modulations induced by viruses is an emerging field. Human cytomegalovirus (HCMV), herpes simplex virus (HSV), Kaposi's sarcoma-associated herpesvirus (KSHV), and hepatitis C virus (HCV) have been shown recently to reprogram cell metabolism to support their replication. During HCV infection the global glucidolipidic metabolism of hepatocytes is highly impacted. It was suggested that HCV might modify glucose uptake and glycolysis to increase fatty acids synthesis, but underlying mechanisms have not been completely elucidated. We thus investigated how HCV may modulate glycolysis. We observed that in infected Huh7.5 cells and in subgenomic replicon-positive Huh9.13 cells, glucose consumption as well as lactate secretion was increased. Using protein complementation assays and coimmunoprecipitation, we identified a direct interaction between the HCV NS5A protein and cellular hexokinase 2 (HK2), the first rate-limiting enzyme of glycolysis. NS5A expression was sufficient to enhance glucose consumption and lactate secretion in Huh7.5 cells. Moreover, determination of HK activity in cell homogenates revealed that addition of exogenous NS5A protein, either the full-length protein or its D2 or D3, but not D1, domain, was sufficient to increase enzyme activity. Finally, determination of recombinant HK2 catalytic parameters (V max and K m ) in the presence of NS5A identified this viral protein as an activator of the enzyme. In summary, this study describes a direct interaction between HCV NS5A protein and cellular HK2 which is accompanied by an increase in HK2 activity that might contribute to an increased glycolysis rate during HCV infection. IMPORTANCESubstantial evidence indicates that viruses reprogram the central carbon metabolism of the cell to support their replication. Nevertheless, precise underlying mechanisms are poorly described. Metabolic pathways are structured as connected enzymatic cascades providing elemental biomolecular blocks necessary for cell life and viral replication. In this study, we observed an increase in glucose consumption and lactate secretion in HCV-infected cells, revealing higher glycolytic activity. We also identified an interaction between the HCV NS5A nonstructural protein and cellular hexokinase 2, the first rate-limiting enzyme of glycolysis. This interaction results in an enhancement of catalytic parameters of the enzyme, which might explain, at least in part, the aerobic glycolysis shift observed in HCV-infected cells. C hronic infection with hepatitis C virus (HCV) is associated with abnormalities in glucidolipidic metabolism that have been shown to play important roles in various aspects of the virus life cycle, such as genome replication, viral assembly, and secretion (1, 2). In vitro, HCV replication is efficiently inhibited by cholesterol and fatty acid biosynthetic pathway inhibitors (3), and release of viral particles from infected cells can be inhibited by modulation of the very-low-density lipoprotein (VLDL) assembly pr...

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“…It has been postulated that HCV is sexually transmitted via low-density viral particles and the prolonged exposure in the absence of other risk factors is not an independent risk factor. 9,21,22 The risk of acquiring HCV through casual or ongoing sexual contact without other risk factors is extremely low but not zero and without genital abrasion or bleeding. 2,23 In Australia, about 211 700 persons were HCV chronic carriers by the end of 2008.…”

Section: Discussionmentioning

confidence: 99%