In hepatitis C virus
infection, replication of the viral genome and virion assembly are linked to cellular metabolic processes. In particular, lipid droplets, which store principally triacylglycerides (TAGs) and
cholesterol esters (CEs), have been implicated in production of infectious virus. Here, we examine the effect on productive
infection of
triacsin C and
YIC-C8-434, which inhibit synthesis of TAGs and CEs by targeting
long-chain acyl-CoA synthetase and
acyl-CoA:cholesterol acyltransferase, respectively. Our results present high resolution data on the
acylglycerol and
cholesterol ester species that were affected by the compounds. Moreover,
triacsin C, which blocks both
triglyceride and
cholesterol ester synthesis, cleared most of the lipid droplets in cells. By contrast,
YIC-C8-434, which only abrogates production of
cholesterol esters, induced an increase in size of droplets. Although both compounds slightly reduced
viral RNA synthesis, they significantly impaired assembly of infectious virions in infected cells. In the case of
triacsin C, reduced stability of the viral core
protein, which forms the virion nucleocapsid and is targeted to the surface of lipid droplets, correlated with lower virion assembly. In addition, the virus particles that were released from cells had reduced specific infectivity.
YIC-C8-434 did not alter the association of core with lipid droplets but appeared to decrease production of infectious virus particles, suggesting a block in virion assembly. Thus, the compounds have
antiviral properties, indicating that targeting synthesis of
lipids stored in lipid droplets might be an option for therapeutic intervention in treating
chronic hepatitis C virus infection.