Abstract
The hepatitis C virus (HCV) is a major cause of chronic liver disease, affecting around 71 million people worldwide. Viral RNA replication occurs in a membranous compartment composed of double-membrane vesicles (DMVs), whereas virus particles are thought to form by budding into the endoplasmic reticulum (ER). It is unknown how these steps are orchestrated in space and time. Here, we established an imaging system to visualize HCV structural and replicase proteins in live cells and with high resolution. We determined the conditions for the recruitment of viral proteins to putative assembly sites and studied the dynamics of this event and the underlying ultrastructure. Most notable was the selective recruitment of ER membranes around lipid droplets where structural proteins and the viral replicase colocalize. Moreover, ER membranes wrapping lipid droplets were decorated with double membrane vesicles, providing a topological map of how HCV might coordinate the steps of viral replication and virion assembly.
Highlights
The hepatitis C virus (HCV) is a major cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma
Viral RNA replication occurs in a membranous compartment composed of doublemembrane vesicles (DMVs), whereas virus particles are thought to form by budding into the endoplasmic reticulum (ER)
Most notable was the selective recruitment of ER membranes around lipid droplets where structural proteins and the viral replicase colocalize
Summary
The hepatitis C virus (HCV) is a major cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma. The RNA is translated at the rough endoplasmic reticulum (ER), giving rise to a polyprotein that is cleaved co- and posttranslationally into 10 proteins These are as follows (from N to C terminus): Core; envelope proteins 1 (E1) and 2 (E2), which are the structural proteins constituting the virion; and 7 nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which are involved in viral RNA replication as well as the assembly and release of HCV particles (Bartenschlager et al, 2011). RNA replication occurs in a distinct compartment that is composed of double-membrane vesicles (DMVs) derived from the ER (Romero-Brey et al, 2012) These membranes have a distinct lipid composition and harbor the viral replication machinery (Paul and Bartenschlager, 2015)
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