Biology Reference
In-Depth Information
are synthesized at the ER relocalize to lipid raft membranes when they
are actively engaged in RNA replication. It has been shown by the
membrane separation analysis that HCV nonstructural proteins
existed both in the ER and the Golgi, but the activity of viral RNA
replication was detected mainly in the Golgi fraction.
76,100
Further
studies to elucidate where and how the HCV genome replicates in the
infected cells are needed.
Following is a model for the HCV RC formation proposed by
Aizaki
et al
.
76
HCV nonstructural proteins are processed from pre-
cursor polyprotein by the viral proteases and localized at the ER.
A part of the nonstructural proteins and host factors interacted are
transported to the Golgi, where they associate directly or indirectly,
via protein-protein interactions, with lipid rafts (Fig. 1). NS4B may
bind to lipid rafts first and then recruit other viral proteins consecu-
tively to form RCs, since it appears that NS4B, but not other HCV
proteins, associate with lipid rafts when expressed alone. A vesicle-
associated protein hVAP-33, which possibly binds to NS5A and
NS5B,
98
may also contribute to the formation of HCV RCs. Rafts
harboring putative RCs may then be stabilized and combined to create
DRM structures, presumably involved in the nature that NS4B can be
oligomerized.
101
During the process of RC polymerization, HCV
RNA is enclosed within the membrane complex. This process, which
permits high local concentration of NS5B and the viral RNA, may be
advantageous in order to confer template specificity and ensure RNA
synthesis with necessary fidelity during the viral replication.
Host Factors Possibly Involved in HCV
RNA Replication
Studies with the RNA replicons have demonstrated that the viral
RNA level is highest in the growth phase of the cells and drops sig-
nificantly when cells reach a confluent state, suggesting that HCV
replication and/or translation are tightly linked to host cell metabo-
lism.
99
Huh-7 cells in which adapted replicons are cured by treatment
with IFN are able to yield cell populations that are more permissive
for the replicon tested. Thus, it is likely that some interplay between
