Hepatitis C (HCV) is an enveloped single-stranded RNA virus of the family Flaviviridae, genus Hepacivirus which can cause chronic hepatitis in the human liver (1). Chronic infection with this positive-sense virus leads to chronic liver disease with hepatic fibrosis and cirrhosis which may lead to hepatocellular carcinoma. As there are numerous interactions between HCV and human hepatocytes, the CD81 receptor and the low-density lipoproteins receptor (LDL-R) interactions with HCV will be focused on in this work.
HCV transmission is generally through contaminated blood products, with 50-80% of infections in developed countries present among people who inject drugs (PWID) as transmission in these groups commonly occurs by sharing infected needles and other drug paraphernalia. Clinical symptoms of HCV infection are non-specific and are generally experienced by only about 25% of those infected (2). Common clinical symptoms manifest as fever, loss of appetite, fatigue and jaundice. Whilst some people can clear the infection, an estimated 80% of cases will become chronically infected with HCV and develop liver disease which has profound consequences on the quality of life of those affected.
Currently, HCV infections in the UK are diagnosed by commercially available ELISA, immunoblot tests and by the highly sensitive quantitative RT PCR test (3). Treatment of hepatitis C is carried out by advising on lifestyle measures and depending on the strain of HCV, combined antiviral treatment commonly comprised of pegylated interferon and ribavirin will be prescribed. Newer treatments such as protease inhibitors have fewer side effects when compared to traditional treatments and can overcome drug resistance to previous treatments (4).
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 immune evasion and facilitating uptake by hepatocytes (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. 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).
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 I 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 (6). 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.
Possible prophylactic treatments targeting the CD81 receptor include the use of anti-CD81 antibodies to prevent infection with HCV (). REFERENCE Use of these antibodies in mice has been shown to protected human liver-uPA-SCID mice from a subsequent challenge with HCV strains from differing genotypes. This could be used to prevent allograft reinfection in chronically infected HCV patients after orthotopic liver transplantation.
LDL-R is an attachment factor found on the cell surface of hepatocytes which is involved in the attachment of HCV viral particles to hepatocytes (). REFERENCE Preliminary attachment of LDL-R and other attachment factors allows contact between the HCV particle and specific cell entry factors, such as CD81 leading to internalisation of the particle by clathrin-mediated endocytosis and fusion to the membrane of an early endosome (). REFERENCE
In experiments conducted in mice, HCVpp entry into cells was barely affected by the knockdown of LDL-R, suggesting that whilst this receptor plays a role in the HCV life cycle, it is not an essential factor of HCV entry into cells (). REFERENCE These experiments then led to further investigations into the role of LDL-R in hepatocyte interactions with HCV.
LDL-R was shown to play a role in HCV replication, as the presence of mAb C7 (binds the ?rst repeat of the LDLR ligand-binding domain and partially blocks lipoprotein binding) induced a decrease in HCV replication in mouse experiments (). REFERENCE
CD81 and LDL-R are two receptors that play a vital role in the selective association of HCV with human hepatocytes in order to initiate a hepatitis C infection in the human liver. These interactions have been explored and summarised within this work in order to give a small insight into the virus-host interaction of HCV and the human liver.
CD81 plays a role in HCV entry into hepatocytes by direct interaction with E2 and LDL-R has been shown to interact directly with the HCV particle and play a function in HCV replication. Some research has been done into targeting these two receptors in order to prevent HCV infectivity with varying degrees of success, but further research into their interactions is necessary in order to fully understand them and develop cost effective treatment for HCV. Successful determination of host-targeting entry inhibitors will also help to overcome the resistance to traditional antiviral treatments that is on the rise.
Current understanding of these interactions has contributed to the development of currently used antiviral treatments, but further research into these interactions will help us to develop new cost-effective treatments, a functioning preventative vaccine as well as helping us refine our current treatments in order to make them easier to manufacture and deliver them to their targeted organ and receptor.
As a preventative vaccine is currently proving to be difficult to develop and new direct acting agents are very expensive, the most economically sustainable way of controlling the hepatitis C epidemic is by preventative measures. These measures include screening of blood donors and blood products and control of transmission between intravenous drug users. These measures should be maintained whilst research into new cost-effective treatments is on-going.