Biology Reference
In-Depth Information
chronic hepatitis, cirrhosis and hepatocellular carcinoma, while acute
cases are extremely rare. Although the principal site of HCV replication
is thought to be the liver, recent studies revealed that B cell lymphocyte
seems to be another site of HCV replication because of the abnormali-
ties of B cells including cryoglobulinemia and an increased risk of non-
Hodgkins B-cell lymphoma in hepatitis C patients.
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A comprehensive
blood-screening system was established soon after the identification of
HCV as a causative agent of non-A, non-B hepatitis. The incidence of
post-transfusion hepatitis C has significantly decreased after the intro-
duction of this blood-screening system, however, more than two mil-
lion people have already been infected with HCV in Japan.
HCV belongs to the family of
Flaviviridae
which includes fla-
viviruses such as yellow fever virus, dengue virus and West Nile virus
and pestiviruses such as bovine viral diarrhea virus and classical swine
fever virus. The genome of HCV is comprised of a 9.4 kb single-
stranded positive sense RNA that encodes a precursor polyprotein
composed of 3010-3030 amino acids. This viral polyprotein is cleaved
by a host signal peptidase and viral encoded proteases, resulting in at
least 10 viral proteins including capsid (core) protein, two envelope
glycoproteins (E1 and E2), p7, nonstructural (NS) protein NS2, NS3,
NS4A, NS4B, NS5A and NS5B. The open reading frame of the
polyprotein is flanked at both ends by highly conserved untranslated
regions (UTR), which are required for viral RNA replication.
32,116
The
5
-UTR harbors an internal ribosome entry site that is essential for Cap
independent translation of viral RNA. HCV is grouped into six major
genotypes and more than 50 subtypes.
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Although variability has been
documented across the entire genome, the most variable proteins are
the envelope glycoproteins. Distinct envelope protein variants are most
likely determined at the level of virus-receptor interaction(s).
The lack of an
in vitro
cell culture system has hampered the study
of HCV. Based on studies of the assembly and budding of Kunjin
virus,
63
it is inferred that HCV particles budded from the endo-
plasmic reticulum (ER) are released via the secretory pathway. In fact,
all of the HCV proteins are associated with the ER or ER-derived
membranes, suggesting that genome replication and assembly occur
in association with an ER-derived compartment.
27
HCV is thought to
interact with a specific cell surface receptor (or receptor complex) for
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