Abstract
The high prevalence of hepatitis C virus (HCV) infection in the human population has triggered intensive research efforts that have led to the development of curative antiviral therapy. Moreover, HCV has become a role model to study fundamental principles that govern the replication cycle of a positive strand RNA virus. In fact, for most HCV proteins high-resolution X-ray and NMR (Nuclear Magnetic Resonance)-based structures have been established and profound insights into their biochemical and biological properties have been gained. One example is p7, a small hydrophobic protein that is dispensable for RNA replication, but crucial for the production and release of infectious HCV particles from infected cells. Owing to its ability to insert into membranes and assemble into homo-oligomeric complexes that function as minimalistic ion channels, HCV p7 is a member of the viroporin family. This review compiles the most recent findings related to the structure and dual pore/ion channel activity of p7 of different HCV genotypes. The alternative conformations and topologies proposed for HCV p7 in its monomeric and oligomeric state are described and discussed in detail. We also summarize the different roles p7 might play in the HCV replication cycle and highlight both the ion channel/pore-like function and the additional roles of p7 unrelated to its channel activity. Finally, we discuss possibilities to utilize viroporin inhibitors for antagonizing p7 ion channel/pore-like activity.
Highlights
The hepatitis C virus (HCV) forms the genus Hepacivirus within the Flaviviridae family
JFH-1) from a Japanese patient suffering from fulminant hepatitis [18,19]. This isolate that efficiently replicates in human hepatoma cell lines and produces infectious virus particles was used to demonstrate that p7 is essential for particle assembly and release [20,21], a finding that is consistent with an earlier study demonstrating that p7 is essential for productive HCV propagation in vivo [22]
Gt-specific interactions between p7, NS2 and the structural proteins [86]. Overall these findings suggest that p7 is involved in consecutive steps during assembly of HCV
Summary
The hepatitis C virus (HCV) forms the genus Hepacivirus within the Flaviviridae family. The initial development of a self-replicating subgenomic replicon, based on the HCV replicase factors (i.e., NS3, NS4A, NS4B, NS5A, NS5B and the NTRs), demonstrated that the structural proteins and p7 were dispensable for viral RNA replication [8] Since these replicons only recapitulate the intracellular steps of the HCV replication cycle, the possible role of p7 for virus production could not be addressed. JFH-1) from a Japanese patient suffering from fulminant hepatitis [18,19] This isolate that efficiently replicates in human hepatoma cell lines and produces infectious virus particles was used to demonstrate that p7 is essential for particle assembly and release [20,21], a finding that is consistent with an earlier study demonstrating that p7 is essential for productive HCV propagation in vivo [22].
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