The HCV genome is 9.6 kb in size and varies slightly between the 6 genotypes of HCV as well as amongst the subtypes of each genotype. The RNA of HCV encodes both structural and non-structural proteins and depends on both virus and host proteases for cleavage (1). HCV virions are about 100 nm in diameter and circulate as lipo-viral particles in human serum. These particles are made of HCV and very low-density lipoproteins (vLDLs) and their main function is facilitating uptake by hepatocytes and immune evasion (5). HCV entry into host cells proved difficult to study as mouse models did not bind E2, a HCV envelope glycoprotein known to be involved in HCV entry into hepatocytes and due to a lack of cell-culture models for the study of HCV interactions with human cells (6).
However, cDNA expression cloning in the late 1990’s helped to identify tetraspanin CD81 as one of the receptors involved in HCV entry into host cells (5). Up to that point it was speculated that E2 bound to a specific receptor on the surface of hepatocytes, however it was shown that E2 can bind to a multitude of receptors in order to facilitate HCV entry into hepatocytes. CD81 is a cell surface protein expressed on most human cells and is involved in a number of cellular processes, such as adhesion, activation, differentiation of immune cells and infection of hepatocytes by HCV (4). CD81 is characterised by four transmembrane segments linked by intracellular and extracellular stretches, and by its four conserved cysteine residues which form disulphide bonds in the long extracellular loop. In the liver CD81 is expressed on hepatocytes and the sinusoidal epithelium, and has been shown to not only play a role in HCV entry into hepatocytes, but to also play a part in HCV replication and immune response to HCV infection. The E2 binding domain has been shown to be located in the large extracellular loop of CD81 (CD81- LEL) and that antibodies targeting CD81-LEL can counteract HCV infectivity (7).
CD81-LEL is formed of two subdomains which come together to form a mushroom-like domain, stabilised by disulphide bonds which ensures successful interaction with E2. Zhang et al. () REFERENCE proposed that in addition to its known HCV entry functions, CD81 is a key cellular factor for successful HCV RNA replication. This assumption was made after experiments showed that RNA replication is inefficient in HCV infected cells with low levels of CD81. Cells with low levels of CD81 expression showed normal levels of viral protein synthesis, but the replication failed to proceed efficiently in comparison to HCV infected cells with prominent levels of CD81 expression. They concluded their experiments by proposing that CD81 may be controlling viral replication by directing viral RNA template function to RNA replication, as previous experiments showed that CD81 expression is positively correlated with the kinetics of HCV RNA synthesis and negatively correlated with the kinetics of viral protein production.
These findings CD81 involvement in the immune response to HCV starts with the CD81-induced activation of the Ras/ Raf/ MEK/ ERK signalling pathway, which when induced can lead to an immune response to viruses (). Brazolli REFERENCE Induction of B cell aggregation and protein tyrosine phosphorylation post-engagement of HCV envelope proteins to CD81 leads to B cells activation. Additionally, CD81 can form a complex with CD21 and CD19 on B cells which lowers the B cell activation threshold ().
Pileri REFERENCE It has been suggested that HCV targets this complex by binding CD21 and CD81 in order to lower the effects of the immune response triggered by B cell activation.Possible prophylactictreatments targeting the CD81 receptor include the use of anti-CD81 antibodiesto prevent infection with HCV (). Meuleman REFERENCE Use of these antibodies inmice has been shown to protect human liver-uPA-SCID mice from a subsequentchallenge with HCV strains from differing genotypes. This could be used toprevent allograft reinfection in chronically infected HCV patients after livertransplantation.