HIV resistance: one lucky person out of 100
IMPENETRABLE
A certain number of Russians are carriers of a genetic mutation that makes them immune to the immunodeficiency virusAlla Astakhova, "Results"
...The analysis is not terrible at all. Ilya Kofiadi, a researcher at the Laboratory of Human Histocompatibility Genetics at the Institute of Immunology of the Federal Medical and Biological Agency of Russia, hands me a carefully sealed sterile probe. Now I'm going to open the package and scratch my cheek with a stick - with my own hand, so that someone else's DNA doesn't get on the probe. Then the scientist will lower the probe into a test tube with a special reagent. We'll have to wait a bit. In just two hours, I'll find out if I'm one of the lucky ones. On the eve of December 1 - World AIDS Day - it would be useful. Scientists have found that about one percent of the inhabitants of the Old World are immune to the immunodeficiency virus due to a genetic mutation. There are other useful mutations that allow even with HIV infection to postpone the development of the disease for many years.
Virus Login The fact that people react differently to HIV became known shortly after the appearance of AIDS.
"Scientists have found out that there is an immune pattern that makes people more or less sensitive to the immunodeficiency virus," says Eduard Karamov, head of the Laboratory of Molecular Biology at the Institute of Immunology, head of the Laboratory of Immunochemistry at the D. I. Ivanovsky Research Institute of Virology, member of the Coordinating Council of the Global Vaccine Project. - Approximately 7-10 percent of HIV carriers belong to the "long-lived" group - they get AIDS 15-18 years after infection, despite the fact that this period is usually 7-8 years. There are so-called rapid progressors, of which 15-20 percent - such AIDS symptoms appear in a year or two." The object of special interest of scientists were people from another group - repeatedly exposed to the risk of HIV infection, but never received an infection. Trying to answer the question of why they didn't get sick, the researchers decided to "dig" into their DNA.
Candidate genes encoding proteins that are located on the surface of lymphocytes attacked by the virus have come under suspicion. Scientists reasoned this way: in order to infiltrate a cell, the virus must cling to a protein receptor on the cell membrane. Problems with these receptors, arising from mutations in genes, can lead to the fact that entry into the cell for the virus will be difficult. In 1996, examining people who turned out to be incapable of HIV infection, American scientists found "breakdowns" in the gene of the CCR5 receptor protein in the vast majority. This receptor is located mainly on the surface of immune cells and is tuned to chemokine, a low-molecular-weight protein that activates lymphocytes and helps recruit them to the site of infection or inflammation. However, HIV uses this receptor for another purpose - in order to penetrate the cells of the body. Of course, a mutation in the gene encoding the protein is most often associated with some kind of defect. But it turned out that sometimes a new variant of the gene can be useful. In the case of CCR5, the loss of 32 nucleotides from the genetic chain leads to the fact that the receptor protein formed as a result is greatly shortened and does not appear on the cell surface, which means that the immunodeficiency virus cannot effectively use it to attack.
"Every human chromosome has its own pair," says Ilya Kofiadi. - Mutation can occur simultaneously in both paired chromosomes or only in one. If the loss of 32 nucleotide bases from the CCR5 gene occurs in both chromosomes at once, then carriers of such a mutation are practically immune to HIV. At least, not a single case of infection has been recorded among them so far. After all, there is simply no CCR5 receptor on the cell surface in this case." In the second case, when the corresponding mutation occurs only in one chromosome from a pair, the possibility of HIV spreading in the body also decreases. CCR5 receptor proteins are absent in exactly half of the cells, which means that it is more difficult for the immunodeficiency virus to penetrate them.
Pomors under protection Having discovered a useful mutation, scientists immediately wanted to determine which peoples and how often it occurs.
Comparing the results of genetic analysis of people belonging to different ethnic groups, they realized that the origins of the CCR5delta32 mutation should be looked for somewhere in northern Europe, in Scandinavia. The further away from these places, the less it appeared, and in many countries as far away from the named point as possible, such as Japan or Venezuela, it was not at all. The Europeans were more fortunate. Carriers of the CCR5delta32 mutation in both paired chromosomes are about one percent of the inhabitants of the Old World - in principle, not so little. After all, this means that every hundredth of them is immune to HIV. Another 18 percent of Europeans have a mutation in only one of the paired chromosomes. Nature protects them, too, although not so effectively. Infection with the immunodeficiency virus may occur, but the onset of a serious illness, AIDS, will be postponed for at least two years.
Where did the inhabitants of Europe get a useful mutation? The opinions of scientists are divided. Someone believes that it was given to the inhabitants of the Old World about seven hundred years ago by the then raging plague epidemic. After all, the causative agent of this disease, Yersinia pestis, essentially uses the same receptor proteins as HIV to attack the human body. Perhaps in Europe, which was most affected by the plague, there was a selective selection of people with this CCR5 mutation. During the plague epidemic, they had a better chance of surviving. Other researchers argue with this point of view: in their opinion, the frequency of CCR5delta32 mutation in the Bronze Age did not differ at all from what is observed now.
Anyway, the successful mutation gradually diverged in circles from the place of its original origin, but it did not go very far from there. Until recently, it was unclear how this mutation is spread on the territory of Russia and neighboring countries, but the staff of the Institute of Immunology painted over a white spot on the map.
"Our research shows that the CCR5delta32 mutation almost does not occur in Kazakhs, Kyrgyzs, Chechens, Tuvinians," says Kofiadi. - But in Russia there is one ethnic group in which it comes across much more often than the average in Europe." We are talking about the Pomors, a small ethnic group consisting of several thousand people and living today in the Arkhangelsk region. Surprisingly, nature has probably protected these people from HIV the best on the planet. According to researchers at the Institute of Immunology, as many as three percent of them are carriers of the "saving" CCR5delta32 mutation in two paired chromosomes at once, which makes them immune to the immunodeficiency virus. Another 30 percent have a mutation of this gene in one of the chromosomes and, therefore, are much less susceptible to the disease.
Russian scientists have also investigated two other "good" mutations that help to resist the formidable disease. Previously, they were found in the so-called long-lived: people infected with the immunodeficiency virus, but for decades did not show signs of developing AIDS. "About a dozen such genetic mutations have already been studied in the world," says Eduard Karamov. "However, until now it was unclear how common they are in Russia." The staff of the Institute of Immunology drew attention to two of them. The first one is located in the region of the SDF1 gene encoding the amount of production of a ligand molecule that binds to immune cell receptors during the immune response of the body. The "work" of SDF1 is noticeable at the advanced stages of infection, when a large amount of the immunodeficiency virus is already circulating in the human blood. The "breakdown" of the gene, which is expressed in the increased production of a ligand molecule, in this case is able to put a natural barrier on the path of the disease. "After all, if there are too many SDF1 molecules, they bind to receptors on the surface of lymphocytes, leaving no way for HIV to enter the cells," says Ilya Kofiadi. "Deprived of a loophole, the virus remains out of business." The second CCR2-641 mutation associated with the "breakdown" of another gene encoding a receptor protein on the surface of lymphocytes remains mysterious. Scientists were able to detect it in the "long-lived". However, no one knows yet how it is able to slow down the onset of AIDS.
According to most researchers, both mutations are significantly older than CCR5delta32, so there are probably several starting points for them. "It is not known for certain how human migrations can be related to their spread," says Ilya Kofiadi. - But certain waves of these genes in the human population can still be traced. For example, we found that Kazakhs and Kyrgyz have one of the highest rates of the CCR2-641 mutation for the Central Asian region. Then its wave, gradually falling down, goes to Southeast Asia. At the same time, there is also an oncoming movement - the SDF1 mutation, on the contrary, spreads from the southeast to Central Asia." It turns out that the hordes of nomads, rushing across the expanses of Eurasia long before HIV appeared in the human population, simultaneously spread genes capable of fighting it...
Lucky ticket Calculating the frequency of "useful" mutations on the territory of Russia, biologists experienced considerable difficulties with answering the question of who the indigenous Rusaks are.
Residents of the Vologda region were conditionally decided to be considered as such. It turned out that the CCR5delta32 mutation is in one or two paired chromosomes in about ten percent of them. Interestingly, following the famous phrase "scratch the Russian, you will find a Tatar", these people were exactly in the middle between the Pomors and Tatars in terms of the number of mutations. "Three percent of Pomors, thanks to the homozygous CCR5delta32 mutation, are completely protected from HIV, Tatars have one percent of them," says Ilya Kofiadi. "So, on average, Russians may have from one to three percent of people immune to HIV."
Why do we need such information? Firstly, it can be invaluable for a particular person if he passes an individual analysis. Nevertheless, experts do not recommend going all out, even for those who pull out a lucky ticket - they find out that they are the carrier of a successful homozygous mutation CCR5delta32. "Until now, people with such a mutation have never been isolated HIV in any country," says Eduard Karamov. - However, in laboratory conditions, by selecting a special strain of the immunodeficiency virus, it can infect any cells. We conducted such experiments."
Without taking into account human genetics, any serious scientific research related to HIV is unlikely to be possible in the near future. For example, some experts explain last year's failure of Merck's AIDS vaccine trials, in particular, by the fact that cohorts of participants were not examined for genetic mutations. However, in the near future, scientists will no longer have the opportunity to make such an annoying blunder. A grandiose scientific project is currently unfolding in the United States to study 300 human genes that affect the reproduction of HIV in the body. Even the genes responsible for the proteins with which muscles contract unexpectedly got into this list. So very soon we will all really find out about our relationship with AIDS.
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01.12.2008