Virus resistance
Georgy Bazykin, Post-science
Pathogens attacking humans have several problems. The first problem they encounter is that pathogens must learn to be transmitted in humans as a species. The latest sensational news about new epidemics and infectious diseases that have arisen in humans (for example, SARS or human immunodeficiency virus, swine or bird flu) are associated with the transfer of pre-existing viruses, pathogens from other species. The pathogen does not arise out of nothing, and the first thing it must do is learn to be transmitted in humans.
It should happen that there is an average of more than one infection per infected person. Then a person becomes a reservoir for this virus. Not all viruses, fortunately, have passed this way, many, we hope, will stop at this stage. For example, people sometimes get infected with avian flu, but almost always these are cases of infection from birds, and not further transmission from person to person. Nevertheless, we know that there are mutations that the avian influenza virus can acquire and as a result become capable of being transmitted in the human population too. The second thing that needs to happen is that the virus has to learn how to cope with our immune system somehow. Finally, he must learn to cope with what we are trying to fight against him: either with vaccines or with medications.
We can talk as concrete examples about two very important viruses that lead to a very large number of deaths, including due to infectious diseases in general - this is the human immunodeficiency virus and the influenza virus. The human immunodeficiency virus is a huge problem. He came to the human population around the 20-40s of the XX century. Now it is clear that he intensively adapts to life in a person at various levels. Firstly, it turned out that different human populations a priori had some mechanisms of protection against it. We have a human leukocyte antigen – an important protein necessary to fight pathogens, it is a component of our immune system. Different people have slightly different variants of this protein, and it turns out that in different geographical populations of people they give different protection against different variants of HIV, that is, the virus that leads to AIDS. For several decades after the emergence and transfer of HIV to these populations in populations that have protection, the form of HIV that learns and knows how to bypass this protection has emerged and become more frequent.
The same process occurs not only at the population level, but also at the level of each person. It turns out that inside the patient's body, after he becomes infected, there is a colossal and very rapid evolution of the virus. If it were not for evolution, then a person would probably recover from HIV within a week, just like with viral influenza - once in a lifetime (immunity to influenza is lifelong, and we just get sick with different strains all the time). A person has remedies that have arisen as a response to previous, long-standing infections. We don't know anything about them now, they took place several thousand years ago. For example, the European population has a variant of a gene expressed on the surface of cells of the immune system, which gives partial protection against HIV. These people were lucky, and all thanks to the fact that some of their long-standing ancestors survived a terrible epidemic that raged, maybe 10,000 years ago on the European continent, and we don't know anything about it now.
We have medicines to fight HIV. They are associated with all the same problems as with antibiotics, namely: resistance to them arises. Moreover, stability arises anew at the level of each patient. Here it is very important to use an evolutionary consideration to think about how to deal with this resistance.
How can we deal with sustainability? We have a virus, it is one thousandth likely to get a mutation that will make it resistant to a particular drug. What can be done here? You can use not one drug, but two. If we use two drugs, then resistance to each of them will arise with a probability of one thousandth, to both together – with a probability of one millionth, which is a much less likely event. If there are three drugs, then it will be already one billionth, and, most likely, there will not be so many viral particles in the body to acquire this resistance. Therefore, an important idea of using such cocktails of drugs is simultaneous complex therapy consisting of several drugs. The main therapy that is currently being used or should be used for HIV is a simultaneous attack on several different systems that the virus uses.
Unfortunately, HIV has a system that allows us to partially circumvent this problem. He has such a mechanism for mixing genetic material, which is called recombination. If one viral particle acquires one mutation of resistance to one drug, another – resistance to another drug, and after that they meet in the same cell, then they can mix their genetic material, creating a version that is resistant to both drugs. Then you don't have to wait a million generations, that is, it creates a problem. If we can't use cocktails of drugs, sometimes we can do something else. For example, use more complex time regimes: use the drug for some time, and then stop for a while. Not in the context of HIV specifically, but in the context of pathogen control.
The second important means of protection that we have is vaccines. There is no vaccine for HIV, but we have a very good and effective flu vaccine. Influenza is also a virus whose genetic information is recorded on an RNA molecule. This virus is changing very quickly, evolving on the time scale of human life. The flu virus that is walking now is not the one that walked 30 years ago. This process is carefully monitored all the time. Since the genomes of viruses are quite short, they can be easily and quickly read, it is quite cheap. Now centers around the world, including in Russia, collect information in real time and look at which strains of the flu virus people are sick with. With this information, we can try to predict the evolution of the flu. Why do we need this? This is necessary in order to plan vaccines.
The vaccine production cycle takes approximately 6 months. To start vaccinating people in October, in March of the same year, we need to understand which several strains we need to put in the vaccine. Then it remains to hope that in six months the most common strains will not change so much that the vaccine will be completely ineffective. As a rule, in the vast majority of years it succeeds. For example, in 2016-2017, the vaccine is quite effective, it falls exactly into which strains are walking. Vaccination of those who were vaccinated was quite effective and useful. Most years this is true, but in some years the World Health Organization, which decides on the composition of the vaccine, misses, and it turns out that the vaccine is not quite optimal. A very interesting question: can we use more accurate models in order to predict the further evolution of the virus, to predict which of the currently circulating strains will be the most "fashionable", the most common next year? This is what, in particular, our laboratory, as well as many other laboratories in the world, is doing – compiling mathematical models that predict which of the currently walking strains of the virus will become the most frequent in six months. This is a task with an obvious applied orientation and applied interest.
Another big problem, which, however, we do not know how to solve and do not know how to approach it at all, is to predict which pathogens will jump into a person. Unfortunately, we are very bad at predicting completely new infections. Although here the primacy is not with theoretical evolutionary biology, but with experimental biology. We can take natural viruses that humans have to come into contact with, try to mutate them experimentally and see if they can adapt to life in mammalian cells. In the case of influenza, a ferret is often used as a model object: can viruses be transmitted between ferrets? Avian influenza, for example, needs to gain about five mutations in order to start being transmitted between mammals. But there are so many viruses around and potential organisms from which we can get them that it is very difficult to monitor everything here. Although this would be a very correct direction of work. Predicting new infections, new transfers of infectious agents between species is a big unsolved task.
About the author:
Georgy Bazykin – Candidate of Biological Sciences, PhD, Princeton University, Head. Department of Molecular Evolution of IPPR RAS, Leading researcher at the Faculty of Bioengineering and Bioinformatics of Moscow State University.
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24.03.2017