by Alexander RYLOV, journalist

There were episodes in the history of disease control when headlong accumulation of knowledge on some of them suddenly resulted in a mighty breakthrough - a discovery, making the solution of the problem quite close. We should like to believe that such a breakthrough with viral hepatitis С was recently made by a team of scientists headed by Pyotr Deryabin, Dr. Sc. (Med.), Deputy Director of Ivanovsky Institute of Virology, Russian Academy of Medical Sciences (Moscow).

TWO BROTHERS, NOT RESEMBLING EACH OTHER

Of the inflammatory viral diseases of the liver, whose causative agents are transmitted through blood, the most prevalent and best studied are hepatites В and C. Their epidemiology is similar; under certain conditions they can cause cirrhosis or hepatocellular carcinoma (one of the most malignant tumors).

It must be pointed out that the former is less danger-ous than the latter. It usually develops as an acute infec-tion, more often ending in complete recovery (only 10-20 percent patients develop the chronic form, ending in the above-mentioned dangerous complications). In addition, intensive research, unfolded in many labora-tories of the world, including Russia, due to the progress in molecular genetics of the last decades of the 20th century, led to excellent results in its prevention and therapy. A gene engineering vaccine was created for pre-vention of hepatitis В in the 1980s; today it is manufac-tured by many pharmaceutical companies. The inci-dence of this disease was limited significantly in coun-tries with the best developed economy due to its use. The American specialists created an antiviral drug lamivudin for control of hepatitis: this drug is also used for the treatment of patients infected by HIV.

As for hepatitis C, the mankind is still unprotected from this infection, while it is intensively spreading all over the planet.

OMNIVOROUS AGGRESSOR

About 3 percent of residents of our planet (about 300 mln people) are infected by hepatitis С virus. However, in many countries only its most obvious (icteric) forms are recorded, and in some countries there is no statistics of this kind. According to the World Health Organi-zation, in the nearest one or two decades the chronic form of this disease will become an enormous problem for many countries, though the infection rate varies from 0.6-1.4 percent in the USA to 4-5 percent in Africa. In Russia this figure varies from 0.7 percent in the Central region to 3.8 percent in the Central Cherno-zem region, as was shown by recent studies headed by Academician Dmitry Lvov, RAMS, Director of Ivanovsky Institute of Virology.

The liver affected with hepatitis С.

More than 6,500 cases of primary cancer of the liver are annually recorded in our country, as a rule, caused by hepatitis C. It is noteworthy that 60-80 percent of infected people suffer from the chronic form (it is not accidental that the incidence of cirrhosis and cancer of the liver in this case is much higher than in case of hepatitis B). Moreover, the microorganism causing this disease is "omnivorous" with regard to many tissues and can cause a pathology in many organs, for example, glomerulonephritis (renal disease characterized by inflammation of the renal glomeruli), diabetes, affec-tion of lymphatic nodes, nervous system, myocardium, skin diseases, arthritis, and sexual dysfunctions.

ESCAPING QUASISPECIES

The causative agent of hepatitis С was identified (and received an appropriate name) 20 years ago. The base of its structure-RNA molecules-were identified at the same time. The analysis of RNA sequences has shown that this microorganism belongs to the Flaviviridae fam-ily, including its "relatives" such as viruses causing yel-low fever, Japanese and tick-borne encephalitis, etc.

Besides humans, only the Chimpanzee monkeys are sensitive to this virus. But these primates are very expen-sive and difficult to look after, and hence, they are rarely used as a model for studies of the infection, which, no doubt, makes its control particularly difficult. In addi-tion, the microorganism has under consideration a dan-gerous feature, genetic heterogeneity: its genome has many unstable zones, where mutations constantly "flare up". As a result, by the present time six different vari-ants-genotypes of the causative agent-have been revealed, each consisting of about 10 subtypes. In a word, the "family" is constantly growing, which ham-pers the work of pharmacologists, who create vaccines and drugs to protect from hepatitis C.

And now the most unpleasant thing. Starting repro-duction, the "supershippery" virus gives the progeny, continuing to modify its characteristics as a result of new mutations! As a result, the so-called quasispecies of the virus emerge. They are not new subtypes, though have sufficiently "bright individual characteristics"; they are capable of escaping neutralizing effects of anti-bodies, produced by the patient's immune system with regard to their "predecessors". So far nobody in the world knows how to control these quasispecies.

THE MEDICAL PROBLEM BECOMES A SOCIAL ONE

The stimulant of hepatitis С (and of HIV infection) is transmitted through blood. Hence, intravenous drug users are a priority risk group. In fact, according to the national statistics of recent years, every second case of this disease is connected with an intravenous drug injec-tion (the remaining 50 percent are patients with hemo-philia and those getting treatment at hemodialysis departments, i.e. blood purification by means of the "artificial kidney" apparatus, and people contacting with infected blood-medical workers, barbers, etc.). Hence, the problem under consideration is a social one.

The incubation period of hepatitis С is on average 40-50 days. The infection cannot be always identified soon enough, and this is one of its perfidious characteristics: its latent course results in the above-mentioned severe after-effects. According to a great number of specialists, the disease is slowly progressing, and the virus (accord-ing to Dmitry Lvov) is like a tender killer.

Due to the capacity of the quasispecies of the agent under consideration to "escape" the immune "con-trol", the course of the disease is rather intricate and difficult to predict. Generally, it can be divided into three stages: acute, chronic, and reactivation (new out-break). The first stage is traditionally limited by a 6-month period; it can show some external symptoms, but, unfortunately, more often it has a latent form. In such cases the disease can be diagnosed only by means of an overall screening of the people belonging to groups of a high risk of infection. Patients with evident symp-toms of the acute phase of hepatitis С (no more than 20 percent of their total number) complain of bad general state, flabbiness, weakness, of decreasing physical activ-ity, fits of fatigue, and poor appetite. Yellow sclera (anterior parts of the eyeball) and skin can help diag-nose the disease. However, symptoms of jaundice are revealed only in 8 percent of cases.

In the overwhelming majority of patients the acute phase of hepatitis С is followed by the latent phase with the virus persistence (long asymptomatic co-existence with body cells), which can last for 10-20 years. The majority of infected people consider themselves healthy during this period, though they are potential sources of infection. Their only complaint may be slight heaviness in the right hypochondrium in case of an incorrect diet and physical work. Besides, the following symptoms are established in patients: enlargement and hardening of the liver and spleen, a slight increase of the alanine

aminotransferase enzyme level*; hepatitis С virus genome is revealed periodically.

The third phase is reactivation, which, as a rule, emerges 14 years later, on average. Then it can trans-form into cirrhosis of the liver and hepatocellular carci-noma. This period of the disease is characterized by fits of fatigue, flabbiness, reduction of working capacity, insomnia plus daytime sleepiness, heaviness in the right hypochondrium, poor appetite, loss of body weight, slight rise of the body temperature without symptoms of jaundice. Examinations show enlargement and harden-ing of the liver, and then enlargement of the spleen. However, this is not all. Despite tremendous efforts of specialists all over the world, including Russia, there is still no vaccine to prevent it. That is why the preventive measures, similar to those used for AIDS control, are extremely important: drug control, analysis of blood and its products, individual precautionary measures, sanitary-educational work.

The therapy for hepatitis С is also in need of improve-ment. The existing drugs (interferon, virasole, etc.) are not sufficiently effective. However, according to the records of many clinics of the world, 40-45 percent of patients respond to the therapy. But is even this modest result trustworthy? For example, studies carried out at Ivanovsky Institute of Virology have shown that the "slippery" virus, disappearing from blood, is revealed in the liver of patients seemingly cured by these drugs. In addition, interferon is expensive, and it can cause side effects.

SUCKLING MICE WILL HELP OVERCOME HEPATITIS С

Numerous attempts to create a model of this infection in human liver and blood cell cultures have failed, as the agent did not multiply in them for a long time, while the artificial virus, created by recombinant DNA** tech-nologies-the so-called replicon-differs significantly from the natural virus, as many scientists think. Thus, the model was created at Ivanovsky Institute of Virology, using an unusual approach. The favorite "food" for the Flaviviridae family viruses (tick-borne and Japanese encephalitis, yellow fever, and other mosquito-borne viruses), to which hepatitis С virus belongs, is animal and human nervous cells. Hence, the brain of newborn suckling mice became a model for isolation of these microorganisms from infected mosquitoes, humans, and animals. It was logical to assume that hepatitis С virus would multiply in its cells as well.

In order to answer this question, the scientists derived a culture from the brain of newborn (2-3 days of age) mice, infected it with human serum containing RNA of hepatitis С virus, and 4-5 days later the cells in experi-mental samples started to die. The thorough testing has shown that the death could be caused only by the "destructive" activity of rapidly multiplying agents of hepatitis C. It must also be pointed out that these processes went on even after infection. Thus, the virus multiplied, accumulating in this medium in high con-centrations.

Moreover, it was found that all hepatitis С genotypes and subtypes, which had been tested, behaved similarly. Hence, this model can be used in laboratories all over the world, as its varieties are widely used on the planet. Proceeding with the studies, the scientists of the Institute isolated viruses capable of forming acute and chronic infections in cultures of cells of different origin (including blood and liver cells), created a "collection" of highly productive variants of causative agents, fit for development of preventive, therapeutic, and diagnostic means on their basis. In other words, it has become pos-sible to carry out preclinical tests of drugs, vaccines, and immunoglobulins.

Thus, the experimental model of viral hepatitis in cul-tures of brain cells has been created for the first time in the world. So, the victory over this infection has become more realizable.

* Alanine aminotransferase enzyme is synthesized in cells, and normal-ly just a small portion of it is released into the blood. In hepatic diseases (hepatitis, cirrhosis), the destruction of liver cells results in an increase of the content of this enzyme in blood above normal, which is revealed by laboratory methods.-Ed.

** Recombinant DNA are obtained by in vitro (not in the body) con-nection of alien (never existing together in nature) fragments of DNA by the gene engineering methods.-Ed.