When scientists defeat HIV April. Editing human genes is the way to fight AIDS

By 2017, despite significant progress in the field of medicine and biomedical technologies, humanity has not yet invented a cure for HIV . What are the difficulties? There are several difficult problems that scientists face:

Virus reservoirs in dormant cells of the immune system. Research in recent years has shown that HIV can affect and remain for a long time not only in CD4-lymphocytes, but also in other cells: macrophages, dendritic cells, astrocytes, as well as blood stem cells. The problem is that not all of these cells are susceptible to the antiretroviral drugs used, which means that it is very difficult to achieve their complete destruction.

High mutation rate. Thus, the virus quickly adapts to drugs, developing resistance to them. Read more about the features of the human immunodeficiency virus in the special article “HIV is a virus that is important to know about.”

Mechanisms that help hide from the immune system. The immune system works on the principle of friend-foe recognition. Therefore, to avoid destruction, the virus has adapted to imitate the proteins of human cells, becoming invisible to the human immune system. Besides, HIV disrupts the normal communication between cells of the immune system, which leads to malfunctions in its functioning.

Official treatment of HIV infection today

Currently the only treatment option is HIV-infection is antiretroviral therapy. Its operating principle is blocking various enzymes or receptors of the virus, with the help of HIV carries out its life activities. Officially, 28 drugs are approved and used in Russia. Depending on the subtle mechanism of action, they are divided into several groups:

• Reverse transcriptase inhibitors;
• Protease inhibitors;
• Integrase inhibitors;
• Fusion inhibitors;
• CCR5 receptor antagonists.

Tablets are used alone or in various combinations every day throughout your life. It would seem that, HIV defeated, however, the problem of virus resistance to drugs is becoming increasingly urgent and science is faced with the question of developing a fundamentally new approach to combat HIV.

Antiretroviral therapy allows you to block enzymes or receptors of the virus, with the help of which it carries out vital functions

New in HIV treatment

When will there be a cure for HIV? Will a remedy be found to help avoid the stage AIDS A? These questions concern more than one hundred people. So far, the scientific community is only taking small steps closer to an answer. The activities of scientists in the fight against HIV covers several areas:

Development of new drugs against HIV.

Search for new forms of administration of antiretroviral drugs.

Use of auxiliary drugs.

Cell therapy.

New drugs against HIV

The first medicine in the world, registered to combat HIV , zidovudine, appeared in 1987. Since then, almost every year has been marked by the discovery of a new drug. For 2017 in the world for treatment HIV 42 drugs and their combinations are officially approved. Since 2010, 4 new molecules and 10 combinations of already created drugs have appeared. Among them are rilpivirine, dolutegravir, elvitegravir, cobicistat, and combinations - Triumeq (abacavir, dolutegravir, lamivudine), Evotaz (atazanavir, cobicistat), Prezcobix (darunavir, cobicistat), Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alaferamide fumarate), Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate), odefsey (emtricitabine, rilpivirine, tenofovir alafenamide fumarate), complera (emtricitabine, rilpivirine, tenofovir disoproxil fumarate), Descovay (emtricitabine, tenofovir alafenamide fumarate), ress, viramune.

However, all of these drugs are variations of old molecules, the last time a new class of drugs was discovered was a decade ago.

The situation was changed by the news that clinical trials of two groups of antiretroviral drugs with fundamentally different mechanisms of action were continuing in 2017:

Capsid inhibitors. A drug - CA1, currently at the animal research stage, disrupts the formation of the outer shell of the virus, thereby preventing its reproduction. In 2018, it is planned to launch the first phase of human trials of the drug.

Monoclonal antibodies. Currently, two drugs are in late-stage human trials, so if successful, we can expect them to hit the market in the next couple of years. Ibalizumab molecule binds to protein CD4 on the surface of human lymphocytes, thereby preventing the virus from entering the cell. This medicine has shown its effectiveness for patients with multidrug resistance HIV. Another molecule called PRO 140 also causes persistent suppression of the virus over a long period of time.

As of 2017, 42 drugs and their combinations are officially approved for the treatment of HIV worldwide.

In addition to developing molecules with new mechanisms of action, Research into antiretroviral drug molecules continues previously known classes:

New forms of administration of antiretroviral drugs

Intramuscular injections of extended action. A long period of drug disintegration in the body is achieved by using nanoparticles. New forms of administration of the drugs rilpivirine, cabotegravir, as well as their combination, dolutegravir, and raltegravir are in development.

Enemas. The advantage of rectal enemas is the delivery of a large dose of the drug directly to the rectum. Therefore, this form of administration is considered as prophylaxis HIV-infections.

Transdermal, or percutaneous administration in the form of gels and patches. The use of this form of delivery has been studied on the drugs zidovudine, zalcitabine, didanosine, lamivudine, as well as IQP-0410. The last molecule is considered the most promising. All drugs are tested so far only in test tubes; no tests have been carried out on animals or humans.

Ancillary drugs

CRISPR /Cas9 , ZFN , TALENS, meganucleases.

The essence of all of these methods is that certain proteins find a given area in the thread DNA and cut out a strictly defined number of nucleotides, then stitching the resulting ends together. The methods have already been tested on people and showed good results. The simplified version of the procedure is as follows: part of the patient’s own CD4 cells, processed using the enzymes listed, and then reintroduced to the patient.

HIV vaccine

Vaccines against HIV are divided into the usual preventive ones, which prevent diseases in healthy individuals, and therapeutic ones, which help those already infected to fight the virus and prevent AIDS A. Attempts to create a vaccine have been made since the 80s of the 20th century. Since then no vaccines have been registered. However, the last five years have been rich in clinical trials of new vaccines:

In 2016, a large-scale trial of a vaccine against HIV in public. This is the first clinical trial in 7 years, called HVTN 702, which has reached its final stages. The vaccine is based on a molecule that showed modest effectiveness in 2009 tests in Thailand. Vaccine trial results are expected by 2020.

At the same time, the vaccine entered the first phase of clinical trials on humans. VRC01, which are antibodies similar to those naturally produced in the body. The results are planned to be obtained in 2022.

Vaccine Ad26 In 2017, it underwent its first successful human trials. This year it is planned to move to a larger next phase of research, which will take at least three years.

HIV cure cases: what is known so far

To date 4 known cases of cure for human immunodeficiency virus:

Berlin patient. For 2017 this is the world's only confirmed case of complete recovery from HIV . Timothy Ray Brown is sick HIV-infection in 1995. He took antiretroviral drugs for 11 years, and the disease progressed non-aggressively until he was diagnosed with leukemia in 2006. Her treatment required a bone marrow transplant. Then the hematologist who was observing Timothy had the idea to select a stem cell donor with a mutation in the protein CCR5, protecting cells from the immunodeficiency virus. The transplantation was successful, and after some time scientists confirmed the absence of the virus in the patient’s body.

Group VISCONTI. This group includes 20 people who stopped taking therapy, but have had low levels of the blood virus for at least eight years and have not shown any symptoms of the disease. All patients started antiretroviral therapy several weeks after infection. That is why early initiation of medication is considered the main principle of treatment HIV-infections.

A kid from Mississippi. Until 2014, this girl was considered the second person to defeat HIV. The child was born in 2010 from HIV- a positive mother. 30 hours after birth, the baby was given a course of intensive antiretroviral therapy, after which the virus concentration was undetectable for three years. However, in 2014, the virus was again found in the girl’s blood.

Boston patients. These two men, like the Berlin patient, received bone marrow transplants for lymphoma. However, some time after stopping antiretroviral therapy, the virus returned.

By 2017, scientists had not found a cure for HIV. However, promising developments are underway around the world of new means of combating it. In the meantime, there is no need to wait until they invent a cure for HIV. Modern antiretroviral therapy makes it possible to control the disease for many years.

The Lancet journal published the results of preliminary clinical trials of a new HIV vaccine. The study involved 393 people from five countries and 72 macaques. The researchers found a robust immune response in each of the subjects. The results were so impressive that representatives of the Johnson & Johnson company had reason to talk about a complete and unconditional victory over HIV in the near future. “360” understood the features of the “holy grail” of pharmacology.

HIV-uninfected volunteers were collected from 12 clinics in the United States, Rwanda, Uganda, South Africa and Thailand. They were divided into eight groups. Seven groups received various combinations of drugs according to the “prime-boost” regimen, and the eighth, control, took a placebo - a weak salt solution. “Prime boost” means multiple vaccinations using two or more drugs.

All vaccination regimens were found to be safe, with only five subjects reporting side effects such as general malaise, dizziness, or abdominal or back pain. Researchers observed the formation of HIV-specific antibodies in 100 percent of participants who received the vaccine.

There are approximately 37 million people around the world living with HIV or AIDS. There are about 1.8 million new cases every year

International AIDS Vaccine Initiative.

In parallel with the human trials, tests were carried out on a group of 72 monkeys, who also underwent different vaccination regimens with the same drugs. According to the results of the experiment, two thirds of the monkeys developed immunity to the animal analogue of HIV.

The laboratory name of the vaccine is Ad26.Mos.HIV. The abbreviation Ad stands for adenoviruses. The newest vaccination technique using adenoviruses is based on delivering into cells only the genes that create antibodies. In this case, scientists can encode several genes in one vaccine, which will accordingly produce different antibodies. This technology makes it possible to completely exclude viruses or bacteria from the vaccine, which, albeit in a weakened form, are used in traditional preparations. There are currently at least 15 different HIV vaccines based on different types of adenovirus in earlier stages of clinical trials.

Scientists have been working on creating a vaccine for more than thirty years. HIV has several biological characteristics that make its development significantly more difficult. The virus changes incredibly quickly and in a variety of ways under the influence of unfavorable factors. It is believed that no two HIV infections are identical. The virus is able to hide in certain types of cells.

It is impossible to create a traditional vaccine based on a weakened or dead virus: dead HIV does not provoke an immune response, and even a small amount of live virus is extremely dangerous. HIV does not infect animals, there are analogs that infect non-human primates, but they are not found in humans, so it is impossible to fully transfer the results of animal experiments to humans. This is why the development of vaccines based on adenoviruses seems so promising: they do not use the virus itself, and the drug material makes it possible to create “matrices” for several types of antibodies.

“The results are encouraging, but it is too early to draw concrete conclusions. At week 52 of the study, we observed a robust and comparable immune response to the vaccine in both humans and primates,” Dan Baruk, a professor at Harvard Medical School and lead author of the study, said in the final part of the published work.

“The genetic diversity of the immunodeficiency virus greatly complicates our work, but we are committed to creating a 'global vaccine' that is effective against the full range of strains of the virus. Our goal is to develop a vaccine that will end HIV once and for all,” said Johnson & Johnson Vice Chairman and Chief Scientific Officer Paul Stoffels.

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Official optimism

Speakers at the forum did not skimp on optimistic statements. Thus, the head of Rospotrebnadzor Anna Popova said that the outgoing year 2017 demonstrated a tendency to “reduce” the growth rate of AIDS incidence “by half.” She also drew attention to a significant decrease in the proportion of young people aged 15 to 20 among those infected. If in 2001, among the total number of identified infected people, the age group from 15 to 20 years accounted for 25%, then in 2016 - only 1%, she explained, adding that 20% of the identified cases were in the next age group - from 20 to 30 years.

In turn, the head of the Ministry of Health, Veronika Skvortsova, said that of the 36 and a half million people infected with AIDS on the planet, 900 thousand live in Russia. This represents almost 0.6% of the country's population. At the same time, the state is making increasingly significant efforts to diagnose the disease: for example, according to Skvortsova, last year “more than 32 million people passed HIV tests.” Nevertheless, concluded Svetlana Medvedeva, president of the Foundation for Social and Cultural Initiatives, “young people are still at high risk,” so today “it is especially important to pay attention to informing them about the existing problem, as well as spiritual and moral education and educational work with the younger generation." In order to prevent the development of the “epidemic,” in October 2016, the Russian government approved the State Strategy to Combat the Spread of HIV Infection for the Period until 2020 and Beyond.

Ministry of Education and Science: “the prognosis is unfavorable”

Meanwhile, the reality of the AIDS situation in Russia in recent years is somewhat at odds with the optimism of official statements. The head of the Ministry of Health was forced to admit the existence of the “epidemic,” speaking at the forum that “the UN and WHO set us the task of putting an end to it by 2020.” According to recommendations prepared by the Ministry of Education and sent to the regions, 64% of new HIV diagnoses in Europe occur specifically in our country. Russia ranks third in terms of incidence growth, second only to South Africa and Nigeria. From 2011 to 2016, the annual increase in new AIDS cases averaged 10%.

HIV-infected people are registered in all 85 regions of the Russian Federation. According to the Federal Service for Surveillance on Consumer Rights Protection and Human Welfare (Rospotrebnadzor), a high level of infection with the immunodeficiency virus is observed in 30 large constituent entities of the Russian Federation, where 45.3% of the country’s population live. The most unfavorable regions, where the number of people living with HIV exceeds one thousand people per 100 thousand population, are:

Sverdlovsk (1647.9 people per 100 thousand population), Irkutsk (1636), Kemerovo (1582.5), Samara (1476.9), Orenburg (1217) regions, Khanty-Mansiysk Autonomous Okrug (1201.7), and also Leningrad (1147.3), Tyumen (1085.4), Chelyabinsk (1079.6) and Novosibirsk (1021.9) regions.

The “specificity” of Russia, so to speak, is that since 2016 the role of sexual transmission of HIV infection has increased. In 2017, this trend only strengthened. Moreover, the sexual route has overtaken the drug route: thus, in the first half of 2017, the share of the sexual route of HIV infection was 52.2%, through the use of injection drugs - 46.6%," the Ministry of Education and Science clarifies. Cases of infection of children through breastfeeding continue to be identified. : in 2014, 41 children were infected, in 2015 - 47 children, in 2016 - 59.

"AIDS is a myth created by pharmaceutical companies"

But that's not all. In a situation where every hour in Russia 10 people become infected with AIDS and 80 die every day from causes related to HIV infection, only 77.5% of Russians living with this diagnosis are registered in specialized medical institutions. Of these, according to Rospotrebnadzor in 2016, only 42.3% received antiretroviral therapy.

00:56 — REGNUM Scientists call the situation with the human immunodeficiency virus (HIV) a pandemic: worldwide it affected 78 million people, killing 40 million. In Russia, HIV infection was diagnosed in 1.1 million people, of whom 240 thousand died in working age.

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“HIV infection became the leading cause of death among Russians from infectious diseases in 2015”, - said at a meeting of the Presidium of the Russian Academy of Sciences on Tuesday (December 27, 2016), the head of the Federal Scientific and Methodological Center for the Prevention and Control of AIDS, Academician of the Russian Academy of Sciences Vadim Pokrovsky. The scientist gave an exclusive interview IAREGNUM on the problem of HIV/AIDS.

— Is the situation with AIDS really so terrible that we can talk about an epidemic?

— Of course, 100 thousand new cases this year and about the same number last year. This can be called an epidemic - there are more than 250 cases per day. Why isn't this called an epidemic? Because this is a hidden process, unlike a flu epidemic, when everyone suddenly starts sneezing and coughing. This happens hidden, and with regard to such infections it is generally accepted that the epidemic begins from the moment HIV transmission begins in the territory of a given country. In our country it started 30 years ago, and has now reached its maximum compared to previous years. It is no longer possible to delay and not take any serious action.

— Humanity has managed to cope with such serious infectious diseases as plague and smallpox. The world has been fighting AIDS for a long time, why can’t we defeat it?

— This is a very specific infection: immunity is not developed to this virus. Once you've had smallpox, you won't get it again, so it was relatively easy to create a vaccine there. That is, some weakened virus is introduced, and immunity is developed. With HIV infection, immunity is not developed. Therefore, creating a vaccine is very difficult. We need some extra-unusual approaches. So far, what we have received are very weak vaccines, their effectiveness is questionable to be used. There are currently about 30 vaccines in various stages of development. A large trial of one of them has now begun in South Africa, perhaps there will be a positive result. But this will still be a partial effect, so we cannot talk about a vaccine yet.

— What to do? Is it possible to fight AIDS?

“We need to influence the population, which actually turned out to be very difficult. Not everyone wants to use the same condom. It is necessary to create motivation for safe behavior, which is quite difficult.

— In your opinion, the main thing in the control strategy is prevention and educational work?

- Undoubtedly. But this is not educational work, but much more serious. It is necessary for a person not only to know that a condom protects, but also for him to use it. It turned out to be very difficult. Another trend is to use chemotherapy drugs that suppress HIV. If infected people take them regularly, their sexual partners are less likely to become infected. You need to take these drugs for life; if you stop taking them, the virus will appear again. There are risks here too, because if someone takes the drugs incorrectly, treatment-resistant strains of HIV will appear and begin to spread.

— Will AIDS ever be defeated?

— You can win, but you need a comprehensive approach. And education of the population, and drug therapy, and all approaches that are considered scientifically proven today. The WHO collects this data and we need to apply it. What we are currently developing is an attempt to solve the problem using the same methods and resources that we did before. We talked a little about HIV infection on the information channel and said something. Some patients were provided with treatment.

Now only a quarter are receiving treatment of those identified and registered .

This is clearly not enough; there must be total drug coverage. We cannot cope without additional programs and, most importantly, additional resources. Maybe one day it will be possible to obtain drugs that completely cure. Nowadays there are many not purely chemical approaches to development, but biotechnological ones.

— What kind of approaches are these?

“This is, for example, an attempt to change the structure of a person’s genes so that his cells become immune to HIV. Such tests are already underway.

— Do we have such developments?

— We made such a drug, but there is no money for clinical trials. It was tested on animals. It is effective, but human studies are very expensive. But we are not the only ones doing this; there are other groups that are developing completely different drugs. This is where basic science can play a big role. If we get a drug that cures the disease, then HIV will become less dangerous. This is a completely different approach. Now we are simply suppressing this virus with chemicals, but here it will be possible to “cut out” this virus when it has become integrated into human DNA. There are special enzymes that cut out this virus. Another thing is possible - molecular immunization of human cells that becomes immune to HIV, that is, molecular vaccination. These are completely new approaches, they exist and are quite promising. Fundamentally new approaches are needed to find a cure. I see them among molecular biological technological methods.

Regarding the so-called AIDS deniers or HIV dissidents, the academician noted that this does not belong to the field of scientific debate, but rather a belief, because it rests mainly on people infected with HIV.

“Their denial of the disease has the character of a psychological defense. This is the main group that everyone else is focused on, say, scammers who offer some other way to improve immunity with the help of cosmic waves, or conspiracy theorists who see in everything some kind of hidden interest of the world government or something else. They cause damage because people go untreated and die. Many HIV dissidents have already died from AIDS.”, noted the academician Vadim Pokrovsky. Around the world, about a million people die from the disease every year. During the entire period of observation, about 70 million patients with HIV/AIDS were registered, 35 million of them died.
By the end of 2018, there were 1,007,369 HIV-infected people in Russia (1.2% of the country’s adult population). The number of sick Russians is constantly growing.
Prevention is considered the most effective strategy to combat the spread of HIV. Drugs that completely cure HIV have not yet been invented. Reports regularly appearing in the media about the discovery of a panacea for HIV-AIDS have not yet been confirmed.
According to some experts, in order to control the spread of the disease in Russia, it will be necessary to spend about 100 billion rubles annually.

AIDS patients still have only one hope - antiretroviral therapy, which is based on drugs that prevent the replication of HIV. The genome of this virus is written in RNA, so after entering the cell, it uses the enzyme reverse transcriptase to make a copy of the DNA on the template of its own RNA. Then, from this DNA, the cell’s own proteins begin to stamp viral RNA. If, say, the reverse transcriptase of a virus is suppressed, then it will not be able to reproduce.

However, even cocktails of antiretroviral drugs only help to transfer the disease from the acute phase to the chronic phase. Such therapy cannot do anything with a virus that floats in the blood or is dormant in a cell. Therefore, researchers are looking for a way to get rid of the virus itself, and not just suppress its ability to reproduce. (By the way, conventional anti-HIV therapy theoretically allows you to get rid of the virus, but only under special conditions, and such cases, alas, are rare.)

But when it comes to completely eliminating HIV, everyone agrees that there is no better tool than antibodies. On the one hand, everything is simple here, it is enough to find immunoglobulins that would recognize the protein of the viral envelope, bind to it and signal to the killer immune cells that this complex needs to be destroyed. The problem, however, is that HIV has enormous variability, and antibodies usually catch only a certain fraction of viral particles, because the same protein is endowed with a number of differences due to which antibodies do not see it.

But our immunity is still able to cope with such a diversity of the virus, creating broad-spectrum antibodies. Scientists discovered in 2010 that the immune system can produce immunoglobulins that recognize more than 90% of HIV varieties, and this discovery, of course, gave everyone hope that AIDS was about to fall. But over time, it turned out that such antibodies arise rarely and after a huge period of time, moreover, exclusively in response to a real infection - that is, it will not be possible to provoke their synthesis using a vaccine from a killed pathogen.

Meanwhile, scientists continued to work with similar antibodies. And not so long ago, it was possible to discover universal antibodies, which appear much earlier and look simpler than those observed before - however, their universality turned out to be lower. But is it necessary to force the immune system itself to produce such antibodies? As experiments by two research groups - from the Beth Israel Deaconess Medical Center and the National Institute of Allergy and Infectious Diseases (both in the USA) have shown - broad-spectrum immunoglobulins, simply injected into the blood, effectively lower the level of HIV.

The groups of Dan Baruch and Malcolm Martin experimented with monkeys: rhesus monkeys were infected with hybrid monkey-human HIV, which multiplied in macaques, but looked similar to the human virus. The weapon against it was broad-spectrum antibodies obtained from AIDS patients.

Baruch and his colleagues used a cocktail of three types of antibodies, and within a week the level of the virus dropped so much that it was undetectable. A similar result was observed when only one type of immunoglobulin was used instead of a mixture of immunoglobulins. After the level of such antibodies in the blood began to decline, the concentration of the virus rose again, but in some monkeys it still remained indistinguishably low even without additional doses of antibodies.

The work of Martin and his colleagues deals with approximately the same thing, only here the researchers used other types of antibodies against HIV. Again, the concentration of the virus dropped within seven days in the macaques to an undetectable (once again: undetectable!) level and remained there for 56 days, until the antibodies themselves began to disappear. Then everything depended on how much virus the monkeys had initially: if there was little, then after the antibodies disappeared, the virus remained under the control of the animals’ own immunity, but if there was initially a lot of it, then the level began to increase.

As the researchers emphasize, the virus disappeared both from the blood and from other tissues, and it did not develop any resistance to the administered antibodies. (There was, however, one exception: when only one antibody was administered in the second study, and the test subject was a macaque with 3 years of experience cohabiting with the virus, it developed a resistant viral strain.)

In two cases, scientists did not treat the virus with human antibodies for very long because they were afraid that the monkeys' immune systems would begin to rebel against foreign immune proteins, and perhaps this was the reason that in most cases the virus was restored. That is, it is not yet clear whether this effect can be made “long-lasting.” All this will become clear only after clinical trials; As for the results described above, the enthusiasm of the researchers can be understood - for the first time in a living organism it was possible to reduce the level of viremia so much.