*2.1. Sphingolipids and HCV Entry*

There is strong evidence in the literature implying that sphingolipids and glycosphingolipids play an intimate role in HCV replication in liver cells. First, Merz et al. utilized lipid mass spectrometry to demonstrate that affinity-purified HCV particles are enriched in sphingomyelin [39], suggesting that sphingolipids are integral components of HCV envelope. This study did not address the role of sphingomyelin in HCV propagation, but another study by Aizaki et al. [40] demonstrated that sphingomyelin facilitates HCV internalization, perhaps via fusion of the virus envelope with endocytic membrane to release HCV genome into the cytoplasm.

#### *2.2. Sphingolipids, Glycosphingolipids, and HCV Genome Replication*

Sphingolipids are also known to facilitate HCV genome replication. In one study led by Hirata et al. [14], the authors showed that HCV infection stimulates sphingomyelin production, leading to sphingomyelin enrichment in the HCV replication complex and sphingomyelin-induced stimulation of HCV RNA-dependent RNA polymerase to synthesize more viral RNA. During infection, HCV induces the formation of a distinct membrane structure in the cell. This platform called the membranous web [4,41,42] recruits viral and host factors to foster HCV genome amplification. In another study from our laboratory, we found that HCV redirects the glycosphingolipid carrier protein, FAPP2 (Figure 1), to the membranous web to facilitate HCV genome replication [20]. It is likely that FAPP2 transports glycosphingolipids to the virus replication platform, as FAPP2 knockdown impedes HCV replication, whereas providing glycosphingolipids to the FAPP2 knockdown cells rescues HCV genome replication [20]. Finally, FAPP2 knockdown was found to disrupt the membranous web and alter the colocalization of HCV replicase proteins, implying that FAPP2 and/or glycosphingolipids contribute to the formation or maintenance of the HCV replication platform.
