Saturday, January 4, 2014

Hepatitis C Virus – the Core Structure of a Key Viral Protein

Hepatitis C virus (HCV) is a major cause of liver diseases such as hepatitis, cirrhosis of the liver and liver cancer.  This virus was discovered in 1989 and was identified as the causative agent of non-A, non-B hepatitis.  It has now been estimated that 2-3% of the entire world population – an estimated 170 million individuals - is infected with this viral agent.  This reality represents an extraordinary incidence of infection on a global scale.  Therefore, there is much interest in developing an effective vaccine.  This has proved problematic on account of the high variability of the genetic structure of this pathogen analogous to the difficulty in developing an effective vaccine against the human immunodeficiency virus 1 (HIV-1).

A virus, as a class of disease-producing organisms, is essentially dormant until it gains access to its cellular target.  Once it does so, it can subvert the cellular machinery of its host to produce proteins whose structure is dictated by the information found within the virus’ genetic material.  The end result of this process allows the virus to effectively make many copies of itself and eventually kill the host cell and spread the infection. 
Some of the problematic issues that face researchers are the fact that the virus has, as of yet, remained resistant to efforts to grow it in culture and that there is no suitable animal model for the disease.  HCV is a member of the hepacivirus genus.  HV is a so-called retrovirus – analogous to the HIV/AIDS virus.  Its infectious genetic material is RNA.  One of its disturbing features is its ability to produce chronic infection.  An unfortunate side effect of this capability is that of HCV infection can lead to liver cancer – hepatocellular carcinoma.  The development of a reliable vaccine is dependent on a fuller understanding of the particular mode of action of this virus.

In an effort to understand the mechanism of infection of HCV, Dr. Leopold Kong and his associates at the Department of Integrative Structural and Computational Biology at the Scripps Research Institute in La Jolla, California, have examined the molecular mechanism through which HCV gains entry into the target hepatic (liver) cell.  What they have discovered is of particular interest in regards to the eventual production of an effective vaccine.

It seems that at the surface of the virus there is a key glycoprotein (E2) that V H
combines with another glycoprotein, E1, on its surface – a glycoprotein is a kind of protein that is bonded to a sugar.  It is this E1/E2 complex that allows the virus to gain entry into the target cell by preferentially binding to a receptor protein on the cell membrane of liver cells – this receptor is referred to as CD81.  Interestingly, E2 is a target for the body’s natural immune response; however, due to the great variability in the structure of E2, this strategy is essentially ineffective.
These investigators were able to determine the three dimensional structure of E2 with a resolution of 2.65 angstroms using X-ray crystallography – an angstrom  is equivalent to one ten-billionth of a meter.  This level of detail may prove to be invaluable in future drug and vaccine design.

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