Viruses are among us
Together with the publishing house "Peter" we publish an excerpt from Frank Ryan's book "The Mysterious Human Genome", dedicated to describing the work of the genome of various organisms and trying to understand what life is.
When people ask me if poliovirus is a living or inanimate being, I always answer "yes".
Eckard Wimmer
In 2002, Eckard Wimmer, a famous virologist of German origin who has worked in America all his life, and his colleagues amazed the whole world when they managed to restore the polio virus from disparate components in their laboratory. 20 years earlier, Wimmer was the first to sequence the genome of this virus. Even today it is very difficult to say exactly what we mean by the term "virus", and over time the situation only becomes more complicated. For example, giant viruses with 1,000 or more genes have recently been discovered, making them much more complex organisms (from a genetic point of view) than some bacteria. Perhaps, instead of defining viruses, it would be wiser to study some of their basic properties.
All viruses are encoded by genomes, as well as all living things on our planet, from bacteria to mammals. Most viral genomes are based on DNA, but some are based on RNA. In fact, viruses are the only organisms that use the RNA code. This leads some biologists to think that viruses could have appeared at a hypothetical stage of evolution known as the RNA world, which, according to proponents of this theory, preceded our DNA-based world. RNA, unlike DNA, can replicate without the help of protein enzymes. Accordingly, the transition from the primary broth of chemicals to self-replication based on RNA would require a very tiny step. Viruses are obligate parasites, that is, they are always born in the cells of their carriers. They die, like bacteria, under the influence of heat or toxic chemicals. They also go through life cycles that include the reproductive phase, which is another basic characteristic of a living organism. The next and probably most important question is: do viruses develop according to established evolutionary mechanisms? Yes, that's exactly what they do.
Ebola virus contains one RNA chain // DCD Global / flickr.com
The genomes of viruses mutate faster than the genomes of any other organisms known to us. This partly explains why it is so difficult for the human body to fight the HIV-1 virus. A year or two after infection, millions of different modifications of the virus develop in one patient. Viruses themselves do not possess epigenetic inheritance systems, but sometimes, penetrating into the nuclei of the host cells, they capture its system. Are they capable of hybridization? And again, there are many vivid examples – remember at least the new pandemic influenza viruses that regularly sow panic all over the world. Is symbiotic evolution available to viruses, or, in scientific terms, genetic symbiogenesis? Below I will explain why they are an ideal example of this phenomenon.
So, why do some scientists insist that viruses cannot be attributed to the living world? As far as I understand, this idea has developed historically on the basis of an incorrect premise about the emergence of viruses.
When scientists tried to define life in the middle of the twentieth century, we still knew very little about viruses, and biologists came to an agreement that the minimum requirement for recognizing an organism as alive should be the presence of a cell membrane containing enzyme and biochemical agents for metabolism. It seems to me that the creators of this definition have made special efforts to exclude viruses from the concept of living. Why is a creature with a cell membrane considered alive, but a creature with a viral envelope is not? As for the requirement of the presence of internal metabolism, only a small number of so-called autotrophic bacteria are capable of this. The survival of all other life forms, including ourselves, depends on the essential amino acids, fatty acids and vitamins that they get from other organisms. Some scientists believe that viruses should be excluded from the living world because of their parasitic nature, but many types of bacteria are also obligate parasites.
Another incorrect idea that arose during the creation of the "cellular" definition of life was the idea that some viruses, such as bacteriophages and retroviruses, developed from fragments of the host genome that acquired new characteristics. It seems to me that, given the current understanding of the evolution of viruses, this theory does not stand up to criticism. There is evidence indicating that bacteriophages and retroviruses are descendants of ancient lines of viruses that have developed (of course, in close symbiotic union with their carriers, which virologists call coevolution) for many centuries. At the time of creating the definition of life, biologists had no idea about the structure of the genome. Now that we have this information, we can forget about the theory of the development of viruses from the carrier genome once and for all. If phages and retroviruses are really fragments of the host genome, most of the genes in it and in the genome of viruses should match. Instead, we see something completely opposite – most viral genes are found exclusively in the evolutionary lines of viruses. Viruses are incredibly creative evolutionary creatures capable of creating new genes on their own. If there is a genetic similarity between the virus and its host, the exchange of genes is likely to be much more intensive in the direction from the virus to the carrier.
AIDS is called the plague of our time. Infection with the HIV-1 retrovirus leads to this disease. Even in a family of viruses with many strange members, retroviruses seem unusual. The prefix "retro" in their name indicates that they act in violation of the outdated dogma about the rigid order of transition from genes to protein through informational RNA. Retroviruses not only have genomes based on RNA rather than DNA, but also possess their own enzymes capable of converting viral RNA into a complementary DNA sequence before introducing the genome into the host cell nucleus. This process is also key to understanding how retroviruses change the evolutionary history of the carriers they infect. From an evolutionary point of view, a retrovirus is able to "capture" the germ cell lines of its host and thus enter into genetic symbiosis with it, creating a new holobiontic genome consisting of a retrovirus and a human genome.
HIV-1, the main causative agent of the disease, is often spread through unprotected sexual contact (vaginal, anal or oral). The virus enters the human body through the tissues of the mucous membranes. It can also get directly into the bloodstream if an infected and healthy person use the same injection equipment, and be transmitted from the mother to the child during pregnancy, childbirth and breastfeeding. Even at this epidemic stage, when the virus acts as a selfish genetic parasite, we can already talk about the beginning of symbiotic evolution. International studies have shown that the rate of disease progression in infected people depends on the subtype of the human gene known as HLA-B. This is one of the genes that determine the nature of the immune response during organ transplantation. The distribution of HLA-B subtypes in the human population affects the evolution of the virus, and the virus itself, due to the lethality of some subspecies of the same subtypes of genes, changes the gene pool of humanity.
Just like hummingbirds and flowers, humans and viruses influence each other's evolution. This is exactly the pattern that can be expected from symbiotic evolutionary development.
This does not mean that the virus does not develop independently at the same time or the same thing does not happen to humanity. At the same time, natural selection begins to influence not only humans and viruses individually, but also symbiosis as a whole. Virologists call this pattern of parasitic interaction coevolution. From a symbiological point of view, we observe how a union that began with parasitism can eventually turn into mutually beneficial cooperation.
The HIV-1 virus selectively affects immune cells – lymphocytes, called CD+T-helpers. The membranes of these cells contain the important immunoglobulin CD4, which promotes the fusion of the cell and the viral envelope. Thus, the viral genome penetrates into the nucleus, where the virus' own enzyme, called reverse transcriptase, converts the RNA genome of the virus into its DNA equivalent, and then with the help of the integrase enzyme integrates it into the genome of the nucleus. This amazing influence of the virus and host genomes is an important step. After it, the virus can give the host genome the command to produce daughter viruses that will spread to other cells and repeat the same process. Thus, the virus will gradually move through the blood and tissues of an infected person.
Pay attention to what a big role the virus shell plays in attacking the host's immune system, how the virus finds its target and how it merges with the membrane of the selected cell to capture it. As the virus spreads, it will use its shell again and again to avoid the immune system's counteraction, while capturing and killing more and more CD4 cells. As the disease progresses, the virus will reach a stage at which billions of its daughter copies will be produced in the body every day. At the same time, they will mutate at a tremendous rate. It is because of this rapid spread and rapid mutational evolution of the virus in the body of an infected person that it is so difficult to cope with it without medical intervention. During the growth phase, the virus penetrates into the genitals, testes and ovaries, as well as into the glands of the human body, making the seminal fluid, vaginal secretions and human saliva contagious for maximum spread between carriers.
Just as a retrovirus injects its genome into CD4 cells, many retroviruses come with the germ cells of their carriers, that is, with sperm and eggs. This can be seen in the example of a retrovirus epidemic that struck koalas in the eastern part of Australia about 100 years ago. This acute infection shows us what terrible power a sexually transmitted virus can have. Virologists confirm that all animals in the north of the country have already been infected, and the epidemic is moving south. Over time, all koalas, except island populations, will be infected with this virus. Because of the virus, animals develop leukemia and lymphosarcoma, and the mortality rate is very high. Initially, biologists were worried that because of the epidemic, Australian koalas could face extinction, but, apparently, this will not happen. The retrovirus already affects the germ cells of koalas, so there are already 40 to 50 viral loci in the chromosomes of these animals, which they will pass on to their descendants. Since the holobiontic genomic union takes place within the nuclear, not mitochondrial genome, retrovirus inserts into the koala genome will be inherited in accordance with the classical Mendel laws.
To date, the HIV-1 virus has not yet penetrated into human germ cells. Some virologists believe that this is impossible because HIV belongs to a subgroup of retroviruses called lentiviruses that do not undergo the process of endogenesis. However, lentiviruses have recently been found in the germ cells of European rabbits and Madagascar lemurs, which, like us, are primates. Whether HIV will ever become a part of our body is unknown. We know that a lot of retroviruses got into the germ lines of humans and their ancestors and influenced the evolution of our genome, so about 9% of it today consists of retroviral DNA. Retroviruses capable of capturing the genome of their mammalian host are called endogenous retroviruses, or ERV, while a variety of infecting retroviruses are called exogenous. Endogenous human retroviruses are designated by the abbreviation ERWCH (HER-V). It unites from 30 to 50 virus families, which in turn are divided into more than 200 groups and subgroups. The last of these evolutionary lines that got into the genome of human ancestors are called HERV-K, ten of their subtypes are exclusively human.
Each family and subfamily of HPV was acquired by us during a separate process of genomic colonization, an invasion that occurred during the retroviral epidemic that struck our ancestors. Considering what we see today with the example of AIDS and the koala epidemic, we can imagine a rather gloomy picture of the survival of early humanity between the waves of diseases. When two groups of scientists restored the original genome of the last retrovirus that settled in the human body, they found that it was an extremely contagious exogenous retrovirus with pathogenic potential in tissue cultures. It's nice to understand that we are the heirs of the winners. But today we should consider the consequences of exposure to retroviruses, which still continue to penetrate the developing human genome.
When a retrovirus captures a germ cell, it acts as a parasite, and the host genome begins to fight against its attack. This struggle continues even if defenders have to change weapons every now and then, when the viral genome has already colonized the germ line and created viral loci in chromosomes. Antibodies will no longer be effective against such a genome, so other methods of deactivating viral loci will come into play, for example, epigenetic silencing, which I will discuss in more detail in the next chapter. But epigenetic measures such as methylation of viral loci are not the final solution for suppressing a pathogenic virus. Permanent silencing will require mutations – either harming viral genes and regulatory regions, or introducing unwanted genetic sequences into the viral genome. At the same time, the constant presence of the viral genome in the germ line of the carrier, often in the form of multiple copies distributed across chromosomes, introduces new opportunities for symbiotic genetic interaction between two different genomes. Over time, the number of such opportunities increases.
Please note: despite the fact that the virus and its carrier are independent subjects of evolution, they are familiar with each other. Moreover, they share a common parasitic history, during which the virus has managed to create many strategies for manipulating the host's immune system and the physiology of its cells. In all these strategies, the viral envelope encoded by the viral env gene plays an important role. At the same time, the human genome, and in particular its defense systems (some of them are immutable, and some are extremely variable and adaptive), has also developed many ways to track and neutralize viruses, their foreign proteins and genes.
Within the ERWCH loci, which are whole virus genomes embedded in human chromosomes, mutations have been "silencing" various viral genes for many millions of years. Because of this, early generations of geneticists ignored all viral components as "junk DNA". However, today we know that many viral loci remain active in various ways. Retroviruses have their own regulatory sequences called long terminal sequences (LTR). In viral loci embedded in the human chromosome, LTR sequences represent the border regions of the locus – regulatory mechanisms capable of seizing control over nearby genes. In addition, they are able to interact with other genetic sequences, including epigenetic and regulatory ones. We also know that large sections of the genome called LINE and SINE are structurally linked to the ERWCH and, as Professor Villarreal has shown, coordinate their work with it. ERWCH, LINE and SINE make up approximately 45% of human DNA. This leads to a number of important questions. What role does retroviral heritage play in the holobiontic evolution of the human genome, in our embryology and everyday physiology, including our susceptibility to diseases?
About the author:
Dr Frank Ryan – Medical Adviser to Sheffield PCT; Honorary Research Fellow in Evolutionary Biology, Department of Animal and Plant Sciences, Sheffield University.
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12.07.2017