Biology Reference
In-Depth Information
revealed that the binding site is of a conformational nature involving
amino acids 480-493 and 544-551 within the E2 protein.
30,31
Recently,
the LEL domain of hCD81 has been crystallized in a hexagonal form
at 1.6 Å resolution.
49
hCD81-LEL displays a mushroom-shaped struc-
ture (stalk and head subdomains) composed of five a-helices and forms
a dimmer in the crystallographic asymmetric unit. This head subdomain
exposed to surface region of solvent has the amino acid residues which
are essential for the binding of E2 protein. Although the crystal struc-
ture of the E2 protein has not been determined yet, crystallography
studies might become clearer the interaction of E2 protein and hCD81.
Genotype specificity of affinity of E2 to hCD81 has been reported
that E2 protein of H strain exhibited high affinity to hCD81with
10
−9
M,
79
whereas those cloned from other genotypes showed lower
affinity to hCD81.
84,94
The most important question to be addressed is whether expression
of hCD81 alone is sufficient for HCV infection. Replacement of mouse
CD81 with hCD81 did not confer mouse susceptible to HCV infec-
tion.
65
Although hCD81 can bind to HCV E2 with a
Kd
value of
1.8 nM, it may simply serve as an attachment molecule because hCD81
does not efficiently internalize ligands.
79
HCV E2 protein, HCV-LPs
and pseudotype VSVs also bound or entered to the hepatoblastoma cell
line HepG2 that does not express detectable levels of hCD81.
66,79,112
In contrast, pseudotype retroviruses exhibited high susceptibility
to the hepatocarcinoma cell line Huh7 which expresses hCD81. The
infection of the pseudotype virus was blocked by soluble recombinant
hCD81 or by knockdown of hCD81 expression by small interfering
RNAs (siRNAs).
119
Although pseudotype retroviruses failed to infect
HepG2 cells, the same cells became susceptible by transduction of
hCD81.
10,24,67
However, non-hepatic cells engineered to express
hCD81 were not permissive and the binding of pseudotype viruses
were not correlated to the expression of hCD81, suggesting that
hCD81 is one of the important factors involved in the pseudotype
retrovirus infection, but other factors present in human hepatocytes
are still required for the virus entry. Thus, hCD81 together with addi-
tional unknown hepatocyte specific molecule(s), may contribute to the
virus-cell binding and/or entry process.
