Self-Enhancement of Hepatitis C Virus Replication by Promotion of Specific Sphingolipid Biosynthesis

Abstract

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes (SGMS1 and 2) encoding human SM synthases 1 and 2. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane (DRM) fraction in which HCV replicates. SGMS1 expression had a correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase (SPT) inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle.

Host sphingomyelin increases West Nile virus infection in vivo

“…In fact, the results shown in the present report indicate that a higher content of cellular SM (ASMko mice, NPA fi broblasts, or addition of exogenous SM) promoted WNV infection. This effect of SM on WNV infection is also consistent with the recently reported positive effect of SM on hepatitis C virus replication ( 19,54 ).…”

“…Lipidomic analyses have shown an increase in the content of both ceramide and SM in fl avivirusinfected cells ( 8,12 ), and ceramide has specifi cally been associated with WNV replication and viral particle biogenesis ( 8,9 ). Regarding SM, it is enriched in membranes from the replication complex of viruses phylogenetically related to WNV, such as dengue virus and hepatitis C virus ( 12,19 ). For WNV, an enrichment of SM in the viral envelope relative to total cellular membranes has been described ( 8 ).…”

“…Among the lipids co-opted by viruses for this process, sphingolipids are of growing interest ( 17,18 ). In fact, an upregulation of sphingolipid synthesis occurs in cells infected with WNV ( 8 ) and other related viruses ( 12,19 ). However, to our knowledge, the relevance of sphingolipids in fl avivirus pathogenesis in vivo remains unexplored.…”

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

“…HCV RNA replication is thought to occur in modified ER membranes condensed in the form of a membranous web (16). It has been shown that HCV replication occurs at specific ER locations within detergent-resistant membrane subdomains rich in cholesterol and specific subsets of sphingolipids (17)(18)(19)(20). While all the viral components of the replicase complex are directly or indirectly bound to the ER membrane, only NS4B (21) and NS5A (22) have been shown to be capable of modifying the architecture of the membranes where they are inserted, and this property is essential for efficient HCV RNA replication (21,22).…”

“…While all the viral components of the replicase complex are directly or indirectly bound to the ER membrane, only NS4B (21) and NS5A (22) have been shown to be capable of modifying the architecture of the membranes where they are inserted, and this property is essential for efficient HCV RNA replication (21,22). Other viral proteins promote membrane remodeling by recruiting specific lipids (20) or cellular enzymes capable of producing a specific lipid environment (23,24). These modifications and others derived from the direct interac-tion of viral proteins with multiple cellular factors (25,26) lead to the construction of specialized structures that bear the viral replicase (22).…”