Characterization of the inhibition of hepatitis C virus entry byIn vitro-generated and patient-derived oxidized low-density lipoprotein

Abstract

Oxidized low-density lipoprotein (oxLDL) has been reported as an inhibitor of hepatitis C virus (HCV) cell entry, making it the only known component of human lipid metabolism with an antiviral effect on HCV. However, several questions remain open, including its effect on full-length cell-culture-grown HCV (HCVcc) of different genotypes or on other steps of the viral replication cycle, its mechanism of action, and whether endogenous oxLDL shares the anti-HCV properties of in vitro-generated oxLDL. We combined molecular virology tools with oxLDL serum measurements in different patient cohorts to address these questions. We found that oxLDL inhibits HCVcc at least as potently as HCV pseudoparticles. There was moderate variation between genotypes, with genotype 4 appearing the most oxLDL sensitive. Intracellular RNA replication and assembly and release of new particles were unaffected. HCV particles entering target cells lost oxLDL sensitivity with time kinetics parallel to anti-SR-BI (scavenger receptor class B type I), but significantly earlier than anti-CD81, suggesting that oxLDL acts by perturbing interaction between HCV and SR-BI. Finally, in chronically HCV-infected individuals, endogenous serum oxLDL levels did not correlate with viral load, but in HCV-negative sera, high endogenous oxLDL had a negative effect on HCV infectivity in vitro. Conclusion: oxLDL is a potent pangenotype HCV entry inhibitor that maintains its activity in the context of human serum and targets an early step of HCV entry. (HEPATOLOGY 2013;57:1716-1724 C hronic hepatitis C virus (HCV) infection affects an estimated 160 million people worldwide. 1 Chronic HCV is a frequent cause of end-stageliver diseases (ESLDs) and hepatocellular carcinoma as well as a common indication for liver transplantation (LT). Treatment remains problematic because of side effects and high cost. A particular problem is graft reinfection that occurs immediately after LT for HCVassociated ESLD and often leads to transplant hepatitis and graft loss. 2 The HCV replication cycle is intricately linked to host lipid metabolism. 3 The production of infectious viral particles is dependent on the cellular very-lowdensity lipoprotein (VLDL) assembly machinery, and

Oxidized Low-Density Lipoprotein Is a Novel Predictor of Interferon Responsiveness in Chronic Hepatitis C Infection

“…Again, this is not proof but a finding that is consistent with a reduced rate of new cell infection. Finally, our observations that oxLDL inhibits cell-to-cell spread together with previously published data suggesting that oxLDL inhibits HCV cell entry by perturbing the interaction between the virus and SR-BI 21 seem to suggest that HCV uses SR-BI for cell-to-cell spread as well as for infection through the cell-free route. 37 , 38 …”

“…We have previously identified and characterized oxidized low-density lipoprotein (oxLDL)—a naturally occurring derivative of native LDL that has undergone oxidative modifications—as a potent endogenous inhibitor of HCV cell entry. 20 , 21 In vivo oxLDL is detectable at low levels in human serum. Oxidized LDL binds to SR-BI, and our earlier work suggested that it perturbs the interaction between HCV and SR-BI in a noncompetitive manner.…”

Apolipoprotein(a) inhibits hepatitis C virus entry through interaction with infectious particles

“…In addition, we previously showed that highly infectious sera displayed a specific profile with low levels of several cytokines/growth factors that could impact hepatocyte biology and infection efficiency . Finally, in addition to innate and adaptive humoral immunity components, several factors in human serum, such as serum amyloid A, lipoprotein lipase, VLDLs, and oxidized LDLs, have been shown to inhibit HCV infection. In this study, we identified apo(a) as an additional inhibitory factor present in human serum.…”

DrugPattern: a web-based tool for drug set enrichment analysis

“…Moreover, another systematic review had revealed that low serum LDL level is associated with depression (33). Beyond our prediction, oxLDL also inhibits hepatitis C virus (HCV) infection (40,41). OxLDL also upregulates miR-146a to inhibit macrophage activation in cultured human THP-1 macrophages (42).…”