**2. Hepatitis C Virus Propagation and Sphingolipids**

Hepatitis C virus (HCV) is responsible for chronic liver disease in 60–90 million people worldwide [31] and is a member of the Flaviviridae family of viruses that encompass dengue virus, West Nile virus, and Zika virus. HCV is an enveloped virus with a positive-stranded RNA genome encoding structural proteins (Core, E1, and E2) (Figure 2) required for infectious HCV particles formation. The nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) are involved in the replication of HCV genome and the packaging of the newly generated genome [32,33]. Major insights in the molecular and structural biology of HCV have led to the development of direct acting antivirals (DAAs) targeting HCV NS34/A protease (e.g., Simeprivir and Voxilaprevir), NS5A (e.g., Ledipasvir and Pibrentasvir), and NS5B RNA-dependent RNA polymerase or RDRp (e.g., Sofosbuvir and Dasabuvir) [34,35]. However, the high error rate (2.5 <sup>×</sup> <sup>10</sup>-5 per nucleotide per genome replication) [36] of the HCV RdRp has resulted in the presence of resistance-associated variants [37,38]. Thus, novel antivirals targeting other HCV proteins, or host factors, are needed.

**Figure 2.** Diagram of hepatitis C virus genome. The HCV genome consists of a single open reading frame (ORF) flanked by the 5' and 3' untranslated regions (UTRs). The ORF is translated into a single polyprotein, which is further processed into individual proteins. The 5' and 3' UTRs are critical for internal ribosome binding, translation, and HCV genome replication.
