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Sci Tech
Understanding Hepatitis-C virus: a silent killer
OF ALL the organs of the human body, the most unsung is the liver. May be this has to do with appearances, since the liver is not as pretty in shape as the heart, the lips or the eyes. It looks like a cut piece of raw meat, the kind we see in the butcher shop, and is huge (weighs about a kilo and a half). But in complexity it shames most other organs that usually grab the headlines. And it does more than 500 jobs for the body, participating in just about everything that the body does. It is the liver that produces over 1000 enzymes that the body needs in order to function well. It makes the clotting factor that helps stop bleeding. It detoxifies most of the poisons and drugs that enter the body, including the alcohol that we down as cocktails. When you drink a bit more than you can handle, your liver works all night to get rid of the excess. When muscles tire and pain with accumulated lactic acid, it is the liver that converts it to glycogen, a usable form of energy. It is the liver again which extracts usable material out of dying blood cells to help recycle them and to produce the digestive juice called the bile fluid that is sent to the gall bladder.
And it does many more functions that eagle-eyed readers will rap me for not writing about. On top of it all, the liver can function even when a large part of it is diseased or inactivated, and can regenerate itself to full size even if part of it is removed. Truly, the liver is a wonder organ that needs a greater press. Is it not sad that more songs are written about a broken heart? The only famous song I can recall about the liver is by Sehgal "Lag Gayee Chhot Kalejwa pe Hai Ram", but even there, he uses Kaleja to mean not the liver but the heart of the mind.
Disease of the liver is referred to as hepatitis. The hepa comes from Latin through Greek for liver, and the itis is a learned borrowing from Greek for inflammation and disorder of any organ. Hepatitis comes about due to a variety of reasons, largely infection. (Diseases due to other factors, such as excess alcohol or other drugs, lead to cirrhosis or stringy fibre formation, scarring and loss of function. If left untreated, liver degeneration and cancerous growth (hepatoma) result, threatening life.
The most common disease of the liver is surely infective hepatitis, caused by viral infection. Five types of hepatitis viruses are known, named as A, B, C, D and E. [More are being discovered, such as G and H]. The hepatitis A and E viruses are transmitted mostly through contaminated water. While A is seen world wide, E is mostly in developing countries. With A, in most cases, there is no illness or at best a mild jaundice- like condition that is quickly taken care of. Vaccines against hepatitis A are available and effective. Hepatitis E, on the other hand, is a tougher one and to date there is no vaccine against it. Being one more prevalent in the Third World, attention on it has been focused by scientists in this region. Drs Subrata Kumar Panda of AIIMS and Shahid Jameel of ICGEB, both in New Delhi; are actively researching into the basic aspects of this viral infection, and we hope there will shortly be a vaccine against E as well, from India. Such a vaccine is vital since treatment with drugs is expensive and non-specific.
Vaccines against hepatitis B are, fortunately effective and available. Not a bit too soon either, since B affects as many as 40 million Indians yearly. At least 2 Indian companies are manufacturing hepatitis B vaccine, competing effectively against foreign pharma companies, and thus bringing the price down. In each of these cases, it has been a joint effort between a basic research laboratory and an industry using genetic engineering methods to make the vaccine.
The new entrant is hepatitis C virus or HCV. It was only in the 1970s that people found out that a new forum of hepatitis was attacking the livers of some blood-transfusion patients. The culprit was identified at the Chiron Corporation as a new virus that stores its genetic information not as DNA, but RNA (a retrovirus, as the AIDS virus is]. Unlike A, B or E, which evoke jaundice like illness or even cancer, C is a silent killer. Infection by HCV leads to persistent and chronic infection that may show up as late as 20-30 years after infection in the body, as cirrhosis or even liver cancer.
Already there are as many as 175 million people across the world infected by HCV, and every 15th carrier is an Indian. That amounts to about 12.5 million of them. HCV is deadlier since recovery rate after its infection is only 50 per cent compared to 99 per cent with HAV or 95 per cent No vaccine is yet available against HCV, and the only treatment to date is a combination of interferon and ribivarin, which is effective only upto 30 per cent expensive on top of it. But, prevention of HCV is possible just as of HBV since they are both blood-borne. Taking care not to share any material that may be blood-stained (injection needles, toothbrush, razor), practising safe sex, ensuring that blood for transfusion is uncontaminated and getting vaccinated against HAV and HBV are some essential precautions to be taken. It is also imperative that blood banks ensure that the blood they store and supply are tested and kept free of such viruses and microbes.
HCV has posed a sustained challenge to researchers the world over during these dozen years. Two months ago, over a 1000 scientists met at Paris to take stock and propose new strategies to win over HCV. This virus has stubbornly refused to grow in the lab, and the animal models in which it could be studied have also been disappointing. Drs Ralf Bartenschlager of Mainz, Germany, and Charles Rice of the Rockefeller University, New York have built slightly clipped versions of the HCV genome, called replicons, and attempted to grow it in tissue culture. It grows but does not build itself into the virus (does it need something from the infected "host" liver to do so?) Dr Norman Kneteman and colleagues at the University of Alberta in Canada have made a hybrid set of mice which can "take" human liver cells, and infected them with HCV. This new animal model is exciting with possibilities.
The other exciting news from Paris is that the human immune system does remember an earlier encounter by HCV and is primed to mount a quick counter-attack. This basic need of immunology, and basis for a vaccine, was not established until now! But now that it is, there is hope building fast for a HCV vaccine.
The third important point to note is that the entire RNA genome of HCV has been sequenced. It is small, has only 10 genes coding for 10 proteins. Of these 4 are structural proteins while the remainder are regulatory. The genomes of various strains of HCV, isolated from different regions, have been compared and their commonality identified. Such a comparison is vital since a vaccine or a drug targeted against HCV that is found, say, in Angola may not work as well against the virus found in Andhra, because the two may differ subtly in their gene sequences and thus in their proteins. Such a problem has been faced with the AIDS virus isolated in different parts of the world.
It is therefore important that we isolate HCV found in India [nd its various regions] study its genome and properties in comparison with others. Such "local" fingerprinting will help in detecting it, understanding it and combating it. Happily enough, such studies have been going on in India over the last 10 years or so. Scientists such as Drs Panda, Jamil, and Dr Acharya of AIIMS, and Drs M R Das and C M Habibullah of Hyderabad have been studying Indian isolates of HCV.
Dr. M R Das (then at CCMB now at Rajiv Gandhi Centre for Biotechnology, Trivandrum) has been devising both a gene-based and peptide-based detection but against strains of HCV isolated in Hyderabad (by Dr. C. M. Habibullah's group at Deccan Medical College) and in Kerala. Such a detection kit is a crying need to diagnose the disease in the first place. Commercial kits now available in India detect HCV in general, but not specific to Indian isolates.
Habibullah has, in the meanwhile, also joined hands with Professor Ramareddy V Guntaka of the University of Tennessee at Memphis and together they have sequenced the genome of the HCV isolated from a patient in Hyderabad. The results, as Drs Guntaka, Habibullah and Dr. Mohammed N. Khaja, scientist tell me, are very interesting. The genome of the Indian virus is substantially different in coding for the so called hypervariable region of the envelope protein E2. Likewise, they see some changes in the areas of the genome that are implicated in efficient viral replication. They are looking at these closely, and would like to introduce them into a replicon and study in greater detail. Such a study could lead to the development of antiviral drugs. They are also studying the steps that lead to the assembly of the virus, so that they can interfere and thus disable the path open.
Just as HBV research and development has been vibrant in India, we need to push activities in the HCV front it too is our disease. We need Industry, Universities and Research Labs to get together to wage the war against this pathogen. The trio Guntaka Habibullah-Sudarshan Biotech has done just that, and we wish them success in their endeavor. More groups should address the issue, and develop not only detection kits, but also vaccines and drugs. The present drug combination is too expensive and also somewhat non-specific; thus there is a great need for developing new drugs as well.
D. Balasubramanian
L. V. Prasad Eye Institute
Hyderabad 500 034
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