HIV resistant

Any infectious disease in different people proceeds in different ways. The course of the disease in a particular person is determined by a number of factors: the general state of the body and previous diseases, the type of microorganism that entered the body, the characteristics of the patient's genotype, the presence of concomitant infections, etc. For most diseases, the statistics of typical symptoms and the timing of their course do not include cases when the disease is "mild" or generally asymptomatic. And although such situations usually fall out of the field of view of doctors, they are of particular interest, because they can indicate unknown mechanisms of protection against infections. In this sense, the infamous AIDS, which today is considered an incurable disease, is no exception.

Almost from the very beginning of the HIV epidemic, rare cases were noted when a person was completely resistant to the virus or the carriage of the virus did not pass into the stage of AIDS. Studies have shown that the surface lymphocyte protein CCR5 is to blame for this, or rather, its absence in some people.

The fact is that when the HIV virus enters the body, it seeks to penetrate the lymphocytes - the most important immune blood cells involved in the body's defense against infections. To be able to enter a lymphocyte, the envelope protein on the surface of the virus must bind to two cellular protein receptors on the surface of lymphocytes, one of which is the CCR5 protein (Deng et al., 1996). It turned out that some people are carriers of a mutation that prevents the synthesis of СCR5 and, accordingly, their lymphocytes are resistant to infection with most HIV variants.

There may be other mechanisms of HIV resistance that we simply do not know about. For example, a team of French scientists working with a group of 1,700 HIV-infected people recently published the results of a study of two unusual cases of resistance to infection, which were not associated with a lack of protein CCR5 (Colson et al., 2014). In the first case, the patient was diagnosed as early as 1985, but although he did not take any antiviral drugs, routine tests indicated complete clearance of the virus. Neither in the blood nor in the culture of blood cells of this person were traces of the presence of a "live" virus found.

Of course, the first question arose - was the patient really infected, or did the researchers encounter a rare diagnostic error? However, additional analyzes showed that the fact of infection took place: antibodies to HIV and individual fragments of viral proteins were found in his blood, as well as trace amounts of viral DNA, which could only be determined using highly sensitive methods.

Researchers tried to infect lymphocytes taken from this patient with a "laboratory" variant of HIV. However, this attempt failed, unlike control lymphocytes taken from other patients. This time, the researchers determined that the CCR5 protein was present on the lymphocytes of the unusual patient, and realized that they were dealing with a new mechanism for blocking the replication of the HIV genome.

* A codon is a unit of the genetic code, which is a triplet of nucleotide residues in DNA or RNA encoding one amino acid

A possible clue to explaining this phenomenon was found in those small amounts of viral DNA that were still able to be isolated from the patient's blood. Analysis of their nucleotide sequence showed that this viral genome is simply stuffed with mutations. About a quarter of the codons * encoding the amino acid tryptophan were mutated, which as a result turned into stop codons that stop protein synthesis.

In fact, the immune defense mechanisms that could thus inactivate the virus are already known. HIV belongs to viruses with an RNA genome, and in order to multiply, it must go through the stage of reverse transcription, that is, RNA must turn into DNA. A group of cellular proteins from the APOBEC3G family can “intercept” the viral genome at this stage. They "tear off" the amino group (–NH 2) from cytosine nucleotides, converting them into uracil. As a result, in the genome, instead of complementary nucleotide pairs "cytosine-guanine", pairs "uracil-adenine" appear. And since the tryptophan codon contains two guanines, replacing them with adenine converts the tryptophan codon into a stop codon (Sheehy et al., 2002).

Usually HIV manages to bypass this level of defense: it has a special protein that attacks and destroys APOBEC3G. But for some reason this did not happen this time, and the entire viable virus was mutated to a state of complete loss of functionality.

Assuming that this case may not be an isolated one, the researchers began to look among their one and a half thousand patients with a similar anamnesis. And they found it! This person also failed to detect DNA or RNA viruses by standard methods. The tiny fragments of viral DNA that were found in his blood also contained a large number of mutations, similar to those found in the first case. However, the lymphocytes of the second patient turned out to be unstable to infection with the “laboratory” variant of HIV, so it is possible that his mechanism of resistance to the virus is different.

A promising direction of this work is further investigation of the mechanisms of resistance of the first patient's lymphocytes in experiments on infection with a "laboratory" virus strain. It is assumed that this person has a rare variant of the APOBEC3G gene, which HIV cannot bypass. But although this would be an interesting find, such a discovery, most likely, will not have wide practical application, since only its carriers can benefit from such a mutation. Nevertheless, the hope remains that the research will reveal some previously unknown immune defense mechanisms, which will give an impetus to the development of new drugs or methods to prevent HIV infection.

The authors of this work also put forward a hypothesis that “fragments” of the virus in the form of short proteins, which are formed as a result of early stopping of protein synthesis at new stop codons, can play a role in protecting cells from re-infection with HIV. These proteins can perform a protective function either, for example, by competing with some proteins necessary for the virus, or by stimulating immunity in some special way. It has even been suggested that the observed phenomenon of the formation of viral resistance is a natural process of HIV endogenization, i.e., an evolutionary process as a result of which viral nucleic acid becomes part of the genome of another species (in this case, a human).

This assumption is not so fantastic: our genomes are full of "traces" of ancient infections - infections with retroviruses that can integrate their hereditary material into our DNA. After all, if not a pathogenic, but an inactivated virus is inserted into the carrier's genome, which also gives protection against re-infection, then it has a much greater chance of spreading in the population. And if we start a large-scale search for people who carry a virus with a large number of inactivating mutations, then we will have a chance to observe the endogenization of HIV in real time.

Literature.
Colson P., Ravaux I., Tamalet C., et al. HIV infection enroute to endogenization: two cases. // Clin. Microbiol Infect. 2014. V. 20. N. 12. P. 1280-1288.
Sheehy A. M, Gaddis N. C., Choi J. D., and Malim M. H. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. // Nature. 2002. V. 418. P. 646-650. DOI: 10.1038 / nature00939.
Deng H., Liu R., Ellmeier W., et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996. V. 381. P. 661-666.

Scientists from the Pirogov Russian National Research Medical University together with specialists from the N.I. Kulakova and Moscow State University created human embryos with a genome that determines resistance to infection with the human immunodeficiency virus (HIV).

The results were achieved by editing the genome of embryos at the stage of one cell (zygote) using the CRISPR-Cas9 system. Zygote editing consisted of cutting out 32 nucleotides from the CCR5 gene sequence, which encodes a receptor for which the virus attaches to blood cells.

Do some people on Earth naturally possess exactly this variant of the CCR5 gene? and they have shown increased resistance to HIV infection. Such technology in the future may help protect children from HIV-infected mothers with poor response to antiviral therapy against infection with the immunodeficiency virus.

The "Pravda.Ru" correspondent talked with Denis Rebrikov, Doctor of Biological Sciences, Professor of the Russian Academy of Sciences, Vice-Rector for Research at the Russian National Research Medical University named after V.I. N.I. Pirogova, head of the genome editing laboratory at the N.I. V.I.Kulakov.

- Would you like to know more about the creation of HIV-resistant human embryos?

- In general, work with systems for editing the genome of human embryos began not so long ago. The first attempt was made by Chinese researchers in 2015, three years ago. It was with great difficulty that their work made its way into publication, since scientific journals at that time did not understand well whether it was possible to publish such data and how legislatively it was allowed to do such experiments. Changing the human genome at the embryonic level is a new direction, and it is still poorly developed both from the point of view of the legislative and at the level of perception by society.

Our society is very conservative. Even GMOs, used in agriculture for over 30 years, still cause controversy among people. Already two generations have grown up on GMOs. Numerous studies have proven that GMOs are safer for humans than "classic" agricultural technologies. And society is still wary of genetically engineered plants and animals.

But this is natural: people are always very suspicious of what they do not understand. For them, it is a black box, beautifully presented in cinemas by blockbusters about crazy scientists making mutants in their laboratories. Therefore, the introduction of technologies for changing the genome of human embryos into medical practice will be difficult, primarily due to public perception.

Returning to the history of editing the genome of embryos, it should be clarified that, in fact, DNA changes are carried out not on the embryo as such, but on a single cell - the zygote, which is obtained as a result of fertilization: the fusion of an egg and a sperm cell. The zygote is the first cell from which the human body develops. Accordingly, the most convenient moment when we can change the genetic program so that it is changed throughout the body is the zygote stage.

Interviewed by Lada Korotun

Prepared for publication by Svetlana Shirokova

The inhabitants of Russia are genetically resistant to AIDS - such a paradoxical conclusion was reached by St. Petersburg geneticists, who decided to figure out what prevents the immunodeficiency virus from mowing down careless Russians with its deadly scythe, Novye Izvestia writes today. At the beginning of the 21st century, the Americans were the first to speak about the genetic predisposition of some people to AIDS.

Scientists from the US National Cancer Center were interested in the question: why among drug addicts and other people at high risk of contracting AIDS are people who are constantly bypassed by HIV infection. It turned out that their genes were on the guard of the health of specific people. Rather, a single gene mutation called CKR-5.

According to the publication, the modified gene strengthens lymphocytes and, ultimately, makes the body relatively resistant to HIV infection, although there is still a chance of getting the deadly virus. In extremely rare cases, the same person may have two identical mutations of the mentioned CKR-5 gene, which protects against AIDS by 100%.

Immediately after the sensational discovery of the CKR-5 gene mutation, scientists from other countries became interested. It turned out that the percentage of owners of the altered gene depends on nationality. Poles were the most immune to AIDS. In the course of research, it turned out that 26-27% of Polish residents have a modified gene that protects against AIDS. In England this figure was 22%. But as we moved to the East, the number of lucky ones was rapidly decreasing. Thus, only 2-3% of Turks are resistant to AIDS. In the genotype of the inhabitants of the Land of the Rising Sun, there is no saving mutation at all. Negroid representatives do not have it, regardless of their country of origin.

In Russia, the study of the genotype of citizens was carried out by specialists from the laboratory of prenatal (prenatal) diagnostics of the Ott Research Institute of Obstetrics and Gynecology under the leadership of Corresponding Member of the Russian Academy of Medical Sciences Vladislav Baranov. A total of 700 people were examined, among whom were Russians, Tatars, Uzbeks, Azerbaijanis, Kazakhs, Georgians.

The Russians and Tatars were the most resistant to AIDS infection. Nature has awarded every fourth representative of these peoples with a mutated gene that provides relative resistance to HIV infection. But 1-1.5% of our fellow citizens have as many as two mutations of the CKR-5 gene, which fully protects them from HIV. The Uzbeks were a little less fortunate, only 15% of them have an altered gene. For Azerbaijanis and Kazakhs, the figure is even lower - 10%. And among the Georgians there was not a single lucky person, in this they are sadly similar to the Japanese and Africans. Based on materials from the site: inter.su

Researchers at Stanford Institute have proven that not all people are susceptible to this virus. Let's see what the essence of the virus is and how it works inside the body.

The spread of HIV today is a global biological problem of mankind. Drug addiction, promiscuity, non-sterile medical items, and sometimes an HIV-infected mother are the main routes of transmission from one person to another. People with HIV are considered to be the living dead, since the human immunodeficiency virus goes into acquired immunodeficiency syndrome, and then a person can die from a simple infection or wound, since his body is simply not able to fight anything.

The main task of medical scientists who deal with this particular disease is to find a way to treat HIV. The first step towards finding this very method is the invention of drugs that, no matter how, support the life of patients. They do not cure, but only addictive, but still support the health of patients, which is just as important.
Researchers at Stanford Institute have proven that not all people are susceptible to this virus. Let's see what the essence of the virus is and how it works inside the body. Having penetrated the body, the virus enters the T cells, which are the central regulators of the immune response (in fact, they provide the body's fight against various infections), where the virus binds to the surface of the CCR5 and CXCR4 proteins. It turned out that people who have mutations in CCR5 are resistant to HIV. It turned out as follows. One person had two problems at once: HIV and leukemia. As you know, for the treatment of leukemia, a bone marrow transplant is required, which was done to this person. After the transplant, he got rid of both leukemia and HIV. Scientists, naturally, began to figure out why this happened. It turned out that the donor had mutations in the CCR5 protein, which were passed down to the person who received the bone marrow transplant.

Thus, knowing the ability to remove the virus from the body, it can be treated. The way to make the CCR5 protein "mutated" relies on the technique of Californian scientists. Their work is related precisely to the study of bonds in CCR5, methods of penetration into it and breaking of DNA fragments in a protein. The challenge for the Stanford scientists is to make the correct "folding" of three genes in the DNA in the CCR5 protein, which provide resistance to HIV. Such a triplet provides the strongest protection for a person against HIV infection.
Clinical trials of this treatment method will begin within 3-5 years. For people who are infected with HIV, it is not guaranteed that they will completely get rid of the virus, but they will be able to stop the complete immune inactivity of the body absolutely free of charge. The patients will be injected with mutated T cells.

Is HIV not as bad as it is portrayed?

I have two news for you: good and bad. I'll start with a good one. In September this year, UNAIDS (UNAIDS - the UN organization that deals with HIV / AIDS on a global scale) published new statistics on HIV. Since 2001, the number of reported cases of HIV infection worldwide has decreased by one third. The number of deaths from AIDS has also declined. In 2001, 2.3 million people died from AIDS and related illnesses. In 2012 - 1.6 million people.

This is due to the fact that antiretroviral therapy has become more affordable, the report says. More than half of officially registered HIV-infected are treated.

Back in 2008, epidemiologists gasped and stated: our fears of the HIV pandemic are greatly exaggerated... Extinction of earthlings from AIDS and related diseases is not expected. Perhaps in Africa. And then, if we take the whole world, there are real chances to stop the infection.

Modern medicine claims that HIV can be safely transferred to the category of chronic diseases, with which - with adequate therapy - you can live a full life. With proper therapy and a healthy lifestyle, an HIV-infected person can live longer than an uninfected person. In medical terms, the correct therapy will delay the development of immunodeficiency syndrome indefinitely. Generally, HIV is like diabetes, it cannot be cured, but you can live.

In general, HIV is a slow killer and in most cases is in no hurry to bury its owner. The disease develops within 5-10 years. In this case, the carrier of the virus does not experience any particular inconvenience, except for enlarged lymph nodes, which do not even hurt. The person may be unaware that they are infected... Explicit symptoms appear only in the last two stages. An HIV-infected person can live for 10 years without any treatment. Occasionally more.

The modern method of HIV treatment is complexly called Highly active antiretroviral therapy (HAART or HART). At least 3 drugs are used to suppress and reduce the content of the virus in the body. When the concentration of the virus falls, the number of lymphocytes in the blood is restored. Almost normal immunity returns to the infected. With a minimum content of the virus in the blood, the risk of infecting a partner is greatly reduced and it becomes possible to conceive a healthy child.

There are people who are resistant to HIV infection. These lucky ones have a genetic mutation, which, as scientists assume, appeared about two and a half thousand years ago. What is strange - only in Europe. 1% of the European population is completely immune to HIV, 10-15% of Europeans have partial resistance... Among those already infected, about 10% are nonprogressors, i.e. They do not develop AIDS for a long time.
Elusive and unforgiving killer

Now for the bad news. AIDS is dying. Guaranteed. No matter how well a person is treated, AIDS will sooner or later reap its harvest. For comparison: mortality from the most terrible disease of the past, "God's punishment", bubonic plague - 95%, from pneumonic - 98%. From AIDS - 100%. AIDS makes no exceptions.
Despite the fact that the HIV virus is one of the most studied pathogens of infectious diseases there is no cure for HIV / AIDS... And it may never appear. The difficulty is that the HIV virus has a high mutation capacity. In fact, there is not one HIV virus, but four varieties: HIV-1, HIV-2, HIV-3 and HIV-4. The most common, due to which, in fact, the danger of a pandemic arose, is HIV-1. It was first opened in 1983. HIV-2 is found primarily in West Africa. The other two varieties are rare. There are dozens of recombinant variants of the virus. If you follow the news, you have probably heard or read about a new type of HIV-1 recently identified in Novosibirsk.

That's not all. Each species also knows how to mutate and forms more and more new strains in the host's body. Eventually, a drug resistant strain appears. Doctors do not keep pace with the nimble virus. Developing new vaccines and testing them is long, complex and expensive. therefore any therapy sooner or later becomes ineffective, and the HIV-infected person will die.

HAART only reduces the concentration of the virus in the body and keeps it at a minimum level. Doctors have not learned to completely remove the virus from the body. The virus infects not only lymphocytes, but also other cells with a long lifespan. Such a reservoir for antiviral drugs is invulnerable. In these impregnable fortresses, HIV slumbers for years, waiting in the wings.

In addition, HAART drugs are extremely toxic. The side effects of anti-HIV therapy are as deadly as AIDS itself... Among them are liver necrosis, toxic epidermal necrolysis (Lyell's syndrome), lactic acidosis and other diseases with a high probability of death.
There are known cases of people being infected with two different strains of the HIV virus. This is the so-called superinfection. The causes and methods of its occurrence have not yet been found. The double set of viruses is more resistant to drugs. Superinfected people die much faster.
HIV is not easy to diagnose... There are 3 methods for diagnosing HIV: PCR, ELISA and immunoblot. PCR analysis is the earliest diagnosis of HIV, it can be taken as early as 2-3 weeks after the alleged infection. However, PCR is often deceiving and gives a false negative result. For the ELISA analysis, you will have to wait about a month. Here the situation is the opposite of PCR: ELISA can be positive in people with tuberculosis, multiple blood transfusions, and oncology. The most accurate analysis is immunoblot. For absolute certainty, you need to take the test once a year.

AIDS - a disease of decent people?

HIV entered the former USSR in 1986. As you know, there was no sex in the USSR, drug addiction and homosexuals, too, so they did not pay special attention to the virus. In general, against the background of the rest of the world (AIDS and concomitant diseases in Europe by that time had already become, as doctors cautiously put it, a significant cause of death among the population from 20 to 40 years old), the situation in the USSR was rosy. For the entire Union - less than a thousand identified cases.

And those are mostly students, infected from Africans. The belief that HIV is a disease of drug addicts, homosexuals and prostitutes also played an important role. A decent person has nothing to fear. Some even perceived HIV as the new Stalin, who is carrying out a kind of cleansing of society from the marginals. And then the USSR collapsed, along with the epidemiological service. In 1993-95 HIV declared itself quite aggressively with outbreaks in Nikolaev and Odessa. Since then, it has not been possible to stop him.

Here is the ITAR-TASS infographic for 2012:

A little more statistics, if you're not tired. According to 2013 data, 719,455 HIV-infected were recorded in Russia. Over the past 5 years, their number has doubled. HIV statistics in Russia rival those in Africa. And what is saddest, successfully ... The real number of infected people in Russia may be about a million people. And they are not gay, drug addicts or prostitutes (although they are still considered a high-risk group). Doctors say that HIV in Russia is a respectable person: a person of a socially secured person, often a family man, aged 20 to 40. Up to 45% of infections are not due to infection through syringes or anal sex, but through heterosexual contact. Because of the illusion of safety, people are reluctant to be tested and treated. So it turns out that in the main risk group in modern Russia are those very decent people who believe that they have nothing to fear.

The reason for this, frankly, the catastrophic situation, doctors believe lack of a coherent AIDS program. Academician Pokrovsky is convinced that a systematic preventive campaign is needed among the population. First of all, Russians need to be convinced that HIV can overtake everyone, regardless of the level of decency. Second, explain the need for protection and regular testing. Third, make prevention and testing readily available.

This year 185 million rubles have been allocated from the budget for HIV prevention. True, the competition for the information campaign was announced on October 8. The results of the competition will be announced on November 13. Prevention, therefore, will take a little over a month. And it should be held during the year, to be honest. So, most likely, the story of 2011 will repeat itself. Then the prevention took 37 days. No testing or real help was provided. The money went to TV spots and to promote the Ministry of Health's HIV website. So much for the fight against AIDS in Russian.

What do HIV and Elvis Presley have in common?

No, Elvis was not infected with HIV. But like Presley, HIV has had a profound impact on modern culture. Like Presley, HIV has become the source of a variety of rumors, plausible and not very theories, guesses and versions. This is typical of the modern world, full of people who want to earn money / become famous and have access to the Internet. Or maybe they are just being honest?

There is a whole HIV / AIDS denial movement, the so-called “AIDS dissidents”. Among them, there are many famous scientists and even Nobel laureates. For example, Carey Mullis, who won the Nobel Prize, guess what? For the invention of the PCR method! If you remember, this is one of the methods for diagnosing HIV.

Wikipedia does not provide an intelligible explanation for this striking fact. He only notes that Mullis is not a specialist in virology. Or Heinz Ludwig Sanger, former, as emphasized by Vicki, professor of virology and microbiology. Or Etienne de Harven, again former professor of pathology. Former South African President Thabo Mbeki, successor to Nelson Mandela, also actively denies the viral nature of AIDS. As reported in the press, his anti-AIDS policy led to the death of 330 thousand people.

Dissidents believe that HIV does not cause AIDS. AIDS is a non-communicable disease. Development within 5-10 years is an unusually long time for infection. The causes of AIDS are malnutrition, drugs, stress, anal sex, difficult living conditions, etc. That is why AIDS has chosen Africa, where 70% of the population lives below the poverty line. That is why, despite the allegedly terrible virus, the African population during the official AIDS epidemic, contrary to all forecasts, doubled.

Moreover, dissidents argue that highly toxic HAART drugs may be the cause of AIDS symptoms. It kills what, by design, should save. Some people think HIV / AIDS is like swine flu, a hoax. Pharmacists and government officials invented AIDS to make money selling expensive very expensive drugs. Judge for yourself: the annual cost of therapy ranges from 10 to 15 thousand dollars. But these drugs must be taken for life.

In a word, HIV and the AIDS it causes is the perfect disease to make money... Otherwise, why are the companies that produce HAART drugs so eager to remain monopolists in the market? Why are HAART drugs still imported to Africa and India from developed countries, and not manufactured in Africa and India itself? After all, this would reduce the cost of treatment tenfold. And many more why.

There are opinions that HIV / AIDS is an artificially derived virus. The newest biological weapon, created specifically to save white mankind from the rampant breeding black. As an argument, a story with a study of syphilis in Tuskegee (USA, Alabama) is given. In 1932-1972. Doctors watched the natural development of syphilis in African Americans.

Study participants (read: test subjects) received no treatment. Despite the fact that in 1947 penicillin already appeared, an effective medicine for syphilis. In the case of HIV, the experiment is being carried out on a global scale. It has been proven that blacks are more likely to develop AIDS. In the United States, blacks account for almost half of AIDS patients - 43.1%. It is not typical for a virus to exhibit such racial discrimination. And while Africa's population continues to grow, the AIDS epidemic could have far-reaching demographic implications.

HIV is indeed cleaning up Africa: a 15-year-old African has a 50-50 chance of dying of AIDS before he reaches 30. Real Russian roulette. HIV is systematically killing the working population of Africa of reproductive age: those who can work and make children. Experts believe that the food crisis in southern Africa in 2002 and 2003. was not caused by drought. The real reason is the weakening of agriculture. Workers are dying of AIDS.

Who will win: HIV or us?

Of course, compared to pneumonic plague or the Spanish flu, HIV is just a baby. Compare: in 1918-1919. 50-100 million people died from the Spanish flu. In just a year, the Spaniard killed about 5% of the world's population. Pneumonic plague was the culprit of the first known pandemic. 551-580 the so-called "Justinian's plague" captured the entire civilized world of that time and took with it more than 100 million people. Against the backdrop of these greedy and quick killers, HIV's “achievements” fade: in 32 years after its discovery, HIV has killed “only” 25 million people. According to 2012 data, there are about 32 million HIV-infected people in the world. Even if you add up all the past and potential victims, HIV barely reaches the half record of the Spanish woman.

However, both the Spanish woman and the plague, having reaped the harvest, left the stage. HIV is in no hurry.For 32 years he has been the boss of the planet and is not going to leave. For 32 years, scientists have been struggling with a medicine or vaccine and losing the competition with the virus. HIV constantly mutates, changes masks, but its essence remains the same - an unforgiving killer.

The scariest feature of HIV is that the virus is directly related to the basis of human existence: reproduction (except for the artificially man-made way of spreading the virus through syringes). The only absolutely reliable way to protect yourself from HIV infection is to refuse sex and have children.In other words, to refuse procreation.

It is not known who will win in this terrible game “HIV vs humanity”. Do not forget that besides HIV, there are also a couple of serious candidates for killers of earthlings: nuclear weapons and environmental disaster. Perhaps the question is no longer whether our civilization will die or survive, but what will destroy us first.