Biology Reference
In-Depth Information
bovine viral diarrhea virus
46
are attached and entered to the cells with
involvement of GAGs. An early interaction between HCV and cell
surface GAGs has also been demonstrated by several experiments
using envelope proteins, HCV-LPs or pseudotype viruses. Several
groups showed that heparin or heparan sulfate but not other GAGs
such as keratan sulfate, chondroitin sulfate, or dermatan sulfate inhib-
ited the cellular binding of recombinant E2 protein and the entry of
HCV-LPs
6
or the entry of pseudotype viruses
70,101
in a dose-depend-
ent manner. Moreover, GAG lyases (i.e. heparinase or heparitinase)
also inhibited not only E2 binding and HCV-LPs entry
6
but also cell
fusion activity
98
and pseudotype virus entry.
66,101
Another experiments
revealed that interactions of GAGs with E2 proteins are involved in
positively charged E2 hypervariable region 1,
6,12,78
suggesting that E2
protein may easily bind to negatively charged components such as
heparin and heparan sulfate. HCV may be concentrated by heparin
and heparan sulfate on the cell surface at first, and then transferred to
the other binding receptor or entry receptor at the next step.
2)
hCD81
hCD81, a 25-kD membrane-associated protein which is widely
expressed in hematopoietic and epithermal cells, was first reported as
a receptor candidate for HCV by Pireli and colleagues.
80
This protein
belongs to the tetraspanin superfamily, characterized by forming four
transmembrane domains, a short intracellular region, and two extra-
cellular loops.
57
The soluble extracellular domain of HCV E2 protein
could bind to the second extracellular loop (EC2) or the large extra-
cellular loop (LEL) of hCD81. EC2/LEL is highly conserved in
humans and chimpanzees, which are the only known species permis-
sive to HCV infection. In particular, amino acid 186 of hCD81 is crit-
ical for E2 binding and is one of three amino acids that differ from
African green monkey CD81, which does not support E2 binding.
42
E2 protein could also bind to tamarin CD81 (the same amino acid at
position 186 with hCD81) with higher affinity than hCD81, sug-
gesting that species permissiveness to infection of HCV is not due to
CD81. Analyses of the E2 region involved in the CD81 interaction
