History of HIV
How it appeared and why there is still no vaccine
Leonid Margolis, Post-Science
Recently, people are most concerned about the problem of the spread of COVID-19. However, this is not the only virus whose methods of combating are not yet fully clear: humanity has long been familiar with HIV, but the disease caused by the immunodeficiency virus still remains incurable, and no vaccine is expected. Doctor of Biological Sciences Leonid Margolis told post-science about how HIV was first discovered, where it came from, how infection occurs and what non-trivial tasks scientists have to solve in order to develop effective drugs for HIV infection.
The defector virus: where did HIV come from
On June 5, 1981, specialists from the US Centers for Disease Control and Prevention (CDC) published in their small newsletter a note about a new strange disease that causes pneumonia unlike others, which first manifested in five young homosexuals from California. So a new epidemic began, which at first few people paid attention to, but which soon covered the entire globe: in a few years tens of millions of people were already ill.
Soon scientists suspected that we were talking about a viral disease. In 1983, the human immunodeficiency virus was discovered independently by two world laboratories at once – specialists from the French Pasteur Institute led by Luc Montagnier and a group of Robert Gallo from the National Cancer Institute in the USA. French researchers managed to see the virus in an electron microscope (later, in 2008, they received the Nobel Prize in physiology or medicine for their discovery), and Robert Gallo and his collaborators proved that it is this virus that causes the disease – acquired immunodeficiency syndrome (AIDS). Earlier, Robert Gallo created a system of permanently activated cells that allows the virus to multiply and investigate its pathogenesis. For the first time, the results of studies of a new retrovirus were published in May 1983 in the journal Science. French scientists named the virus LAV ("virus associated with lymphadenopathy"), and American scientists named it HTLV–III, referring it to HTLV viruses. In 1986, scientists came to the conclusion that in both studies we are talking about genetically identical viruses, and gave them one name – human immunodeficiency virus (HIV).
Today, researchers have long known where HIV came from. And at the very beginning of the epidemic, they talked a lot about its artificial origin, actively spreading conspiracy theories like the one that it was supposedly an artificial virus created to destroy representatives of the black race. In the Soviet Union, they wrote that the virus was created in the CIA, but it does not threaten Soviet youth. In fact, HIV was transmitted to us directly from monkeys (it does not have an intermediate "host", unlike, for example, the coronavirus). The SIV virus (Simian immunodeficiency virus) is still spreading among monkeys, but it does not cause pathologies in most of them. They can artificially, in laboratory conditions, infect only one species of monkeys (rhesus monkeys), and in them SIV causes the same deviations in the immune system as in humans. But the virus does not affect the vital activity of other species of monkeys, such as mangobeys, in any way. At first, scientists thought that these primates have such a good immune system that they simply do not get infected with HIV. In fact – and this was an important discovery in virology – mangobeys simply do not have an immune reaction to this virus.
Paradoxical as it may sound, it is immune activation that is the driving force behind the entire disease caused by HIV. In the human body, this virus, unlike other pathogens, multiplies only in activated lymphocytes (T cells). When we become infected with a virus, our immune system begins to fight it, as with other viruses, and activates other cells, primarily lymphocytes, thereby preparing them for infection. Thus, HIV attacks exactly the cells that are required to suppress it. And in the body of the mangobeys, no reaction to the virus occurs, and it simply has nowhere to reproduce.
When exactly the virus "jumped" from monkeys to humans, you can roughly calculate by its mutations, that is, by looking at how it gradually changed. But this is not an entirely accurate method: it is assumed that this happened either in the 1930s, or in the 1950s. Moreover, it is possible that a similar virus has "jumped" to people more than once. Because of this, there are now two types of it – HIV-1 and HIV-2. More contagious and pathogenic is the first type. But new strains from monkeys are unlikely to be transmitted to humans, because in fact this is a rather rare phenomenon.
The epidemic began in Africa: some people were sick, some even died, but before the era of globalization, HIV could not spread as quickly as it is happening with viruses at the present time. Today, there are already about 38 million HIV-infected people worldwide. Approximately the same number of people have died from AIDS and related diseases since the beginning of the epidemic. In some countries, in terms of the number of cases, this incurable disease is in third place after cancer and vascular diseases. Currently, more than a million people in Russia have the status of HIV-positive.
Methods of virus transmission
HIV is transmitted sexually and through blood. Unlike many other viruses, they cannot be infected either by airborne droplets, or through the skin, or through a handshake, or through dishes, so communication with an HIV-positive person is absolutely safe for others.
Initially, there were more men among those infected with HIV: the epidemic began among homosexuals. The probability of infection with anal intercourse is 10-20 times higher than with vaginal intercourse, since the virus easily penetrates the body through the thin, fragile walls of the rectum. Heterosexual anal contact is just as dangerous as homosexual. During vaginal intercourse, it is more difficult to get infected, because the walls of the vagina are covered with a thick layer of epithelium. Transmission of the virus through oral sex is also possible, but even less likely: there are enzymes in saliva that reduce the ability of HIV to infect CD4 lymphocytes. However, due to the frequency of sexual contacts among people in general, as well as due to various diseases of the female reproductive system, the probability of getting infected in any case remains quite high. Moreover, during sexual contact, the virus more often passes from a man to a woman.
Until recently, the highest rates of HIV infection, especially in In Russia, they were observed among drug users: dirty syringes are almost a 95 percent guarantee of transmission of the virus. But now there are fewer homosexuals and drug users among HIV-infected people as a percentage: the infection has penetrated into the heterosexual population and continues to spread in it. Today, women and adolescents are becoming infected with HIV more and more often around the world, but men are still leading in the total number of infections.
HIV prevention
On the one hand, the refusal of injecting drugs and the use of condoms protect well from infection. On the other hand, the epidemic is still ongoing.
Firstly, some people simply do not know that they are HIV-infected: in the first few days after infection, a slight malaise may be felt, and then there are no symptoms of the disease for a long time, and you can only find out about infection by passing a special analysis. Such people are carriers of infection.
Secondly, people neglect the rules of safe sex. This is how human psychology works. We know that according to statistics, many people die under the wheels of cars, but few people are warned by this knowledge against running across the road at a red light. It seems to us that this will not happen to us. Once upon a time in A study was conducted in St. Petersburg: people were interviewed who knew they could be infected. When asked if they often use condoms, only half of the respondents answered in the affirmative.
HIV diagnosis
The symptoms of HIV infection are similar to colds: during the week there may be general malaise, fever, sore throat. And then the person's well–being normalizes, and he can live for several years without knowing about his status - unless he is specifically tested for HIV.
This is the survival strategy of the immunodeficiency virus: it wants to be overlooked for longer. If at the very beginning there is a lot of virus in the blood of an infected person, then it is impossible to find it there later. For a long time, scientists thought that the virus really disappears, and only then realized that it passes from the blood into the lymphatic tissue, which is difficult to study, but where the virus gradually multiplies, destroying it. And a few years later, when AIDS begins, the virus returns to the blood again.
Drawings by Katya Zolotareva
Acquired immunodeficiency syndrome (AIDS) – a pathological condition that develops as a result of HIV infection. The virus affects the cells of the immune system, its work is suppressed, the body of a sick person ceases to defend itself and becomes susceptible to various oncological and opportunistic diseases: viral, bacterial, parasitic or fungal infections, characteristic of people with immunodeficiency conditions (candidiasis, pneumocystis pneumonia, histoplasmosis, coccidiomycosis, toxoplasmosis, cytomegalovirus infection, etc.).
Blood tests for HIV give an accurate result. One of them is enzyme immunoassay (ELISA) – based on the detection of antibodies to the virus. The immune response cannot cope with HIV infection, but is produced in all infected within 6-12 weeks. The positive result demonstrated by the ELISA is rechecked using another test called "Western blotting" (immunoblot). An accurate diagnosis is made only on the basis of the results of both systems. Another blood test for HIV is polymerase chain reaction (PCR). It can be done much earlier than the ELISA, but only a preliminary diagnosis is made on its basis.
There are also rapid HIV tests that can find antibodies to the virus in blood, saliva or urine. Experts recommend using them three months after the suspected infection.
Minus protein: how the mutation protects against HIV
Some people are immune to HIV. The reason for this is that they lack one of the proteins that are on the surface of the cells.
All viruses have a specific cellular target that they hit. For example, in the case of coronavirus, these are lung and respiratory tract cells. HIV attacks lymphocytes of a certain class. There is a protein on the surface of the virus that has an affinity for a certain protein on the surface of CD4 lymphocytes (T helper cells). Moreover, it turned out that HIV even requires two proteins, and not one, as is usually the case with viruses. When HIV infects CD4 lymphocytes, it must latch onto two receptor molecules at once: the CD4 protein, which we have in all lymphocytes, and the CCR5 or CXCR4 coreceptor. But in less than 1% of representatives of the so-called Caucasian race, the second protein, CCR5, is absent on the surface of T cells. People are immune to HIV if they have this mutation on both chromosomes encoding the protein the virus needs. The exact cause of this mutation is difficult to establish. It most likely occurred in Europe, at least after the division of mankind into races.
Scientists suggest that the mutation occurred due to some unknown infection and the subsequent natural selection of people resistant to it.
Researchers have been trying to develop the idea of artificially suppressing CCR5 to fight HIV. However, in laboratory conditions, after its removal, offspring with defects of the cardiovascular system were born in mice. In addition, people who cannot become infected with HIV have been particularly susceptible to the West Nile virus, which causes serious neurodegenerative consequences.
Studying HIV
Firstly, HIV can be studied – within ethical norms – on sick people.
Secondly, scientists managed to modify the protein in the immunodeficiency virus in such a way that it began to infect monkeys – this strain was called SHIV (Simian/human immunodeficiency virus). This is how an experimental model for studying the virus on monkeys appeared, on which experiments that are unacceptable on humans can be carried out.
Thirdly, HIV is studied at the cellular level: planted human cells are studied or grown separately in Petri dishes, observing their infection with the immunodeficiency virus in stages. In addition, in the laboratory of the National Institute of Health in A system has been developed in Washington that allows us to study reproduction and the main pathological events of infection on pieces of lymphatic tissues.
Record holder for mutations
The immunodeficiency virus has several survival strategies. Firstly, the duration of the course of the disease: the virus needs it in order for a person to have time to transmit the infection to other people. Secondly, the virus benefits from the very way the pathogen enters the body, especially the sexual route of transmission.
With unprotected heterosexual sexual contact with an HIV-infected person, women have a higher risk of contracting the immunodeficiency virus than men, about 3 times. This is due to the fact that large concentrations of viral particles are found in the seminal fluid, and its amount is two to four times greater than the volume of female sexual secretions. In addition, women have a larger surface area through which HIV can enter the body, and hygiene procedures after sexual intercourse are simpler and more effective for men than for women. Another beneficial sexual transmission strategy for the virus is that the immune system is suppressed in the uterus. Otherwise, a fertilized egg containing paternal proteins alien to the maternal organism would have been rejected. Weakened local immunity protects and HIV from an immune attack.
The third strategy for the survival of the immunodeficiency virus is its entry into the human immune system. And finally, another "invention" of HIV in the struggle for survival is mutations, which for him are a guarantee that the infected person's immune response will not be able to hit him. It takes time for an immune response to occur. For example, if a person has the flu, it takes about a week for the immune system to activate and destroy the virus. But HIV mutates so quickly that the immunity that occurs in an infected person, after a week, the virus simply does not recognize.
As a rule, RNA polymerase (an enzyme that synthesizes new copies of viral RNA from copies that have emerged from the cellular cytoplasm) works extremely accurately, and mutations rarely occur. In the case of HIV, a DNA-dependent RNA polymerase or reverse transcriptase synthesizing new viral RNAS intentionally makes many mistakes (for example, it can create about 250 incorrect nucleotides at a time), and the result is a mutated virus. If there are about 300 mutations per viral particle, then an astronomical number of mutant viruses is produced in the entire body of an HIV-infected person in one day – about 10-11.
About 99% of new virions HIV in the human body mutates so quickly and accumulates so many errors that they eventually cease to be infectious. Infection occurs in the 1% of particles in which mutations have occurred successfully and give them the opportunity to continue to effectively cause the disease. It's all about natural selection, thanks to which viruses with the most effective survival strategy flourish: for example, HIV is unprofitable to kill a person right away – on the contrary, it is necessary that he has time to pass the virus on. It is for this reason that all infections in the history of mankind weaken by themselves, even without drugs. However, HIV has come to us too recently to have time to weaken – this can only happen in a few hundred years.
HIV pills
Modern treatment of HIV and AIDS usually consists of highly active antiretroviral therapy (HAART) and symptomatic therapy of opportunistic infections. The earlier a person starts antiretroviral therapy, the more effective it will work.
One of the main problems of HIV suppression is the ability of the immunodeficiency virus to modify its RNA and mutate, adapting to life in different conditions. Previously, antiretroviral therapy consisted of taking only one drug (zidovudine or azidothymidine – AZT), but HIV quickly adapted to this drug. Modern VAART is based on the simultaneous use of several medications at once, preventing various stages of HIV development and suppressing mutant forms of the virus.
In order for cells to become infected with HIV, it must, firstly, contact them, and secondly, merge with their surface: its shell remains outside, and the genome gets inside, which is transported to the nucleus (unlike other viruses that remain in the cellular cytoplasm). There, a copy of DNA is removed from the genome of the virus, consisting of RNA, and implanted into DNA of human cells. Then the reverse process occurs: a copy of the viral RNA is made from the DNA of the cells, which goes into the cytoplasm. There the virus "gathers" again and leaves the cell.
Antiretroviral therapy works in such a way that a separate drug is used against each of the stages of HIV activity: one prevents the virus from merging with the cell, the other prevents it from passing into the nucleus and penetrating into The DNA of the cell, the rest interfere with reading from DNA to RNA and from RNA to protein. Therefore, in HIV therapy, three or four drugs are used at once to resist the virus at each stage - for example, fusion inhibitors, reverse transcriptase inhibitors (translation of RNA into DNA), RNA polymerase inhibitors.
To date, there are more than 30 HIV drugs, and the set of drugs for the treatment of HIV infection is approximately the same in all countries. And the opening of each new facility requires large financial investments and lengthy trials. Researchers are also busy developing new means of protection against HIV during sexual intercourse and methods of post- and pre-contact protection, as well as continuing to search for strategies to create a vaccine against the immunodeficiency virus.
HIV medicines are constantly being improved: gradually they should become less toxic. Ideally, a person should not take them every day – it is better if it is a drug that acts for a long time. Another development option is to combine several medications into one.
One of the directions in the development of a new drug for the virus is to find a way to block proteins on the surface of lymphocytes to which the virus attaches. The task of another direction of scientific research in this area is to make immune cells stop activating. The difficulty is that a person still needs immunity: if it is suppressed, people will become infected with other diseases and die from a banal cold. It is necessary that the body's immune system is not activated by the immunodeficiency virus and at the same time remains able to respond to other infections.
With the support of modern drugs, an HIV-infected person can live a normal life for almost as long as healthy people who are not infected with the virus. Another colossal success of science and medicine in the field of HIV treatment is the reduction of the risks of giving birth to infected children in HIV–positive mothers. Scientists have found out that HIV transmission most often occurs not during pregnancy, but already during childbirth, when an infant, passing through the birth canal, absorbs infected fluids. Without drug therapy, the probability of infecting a child reaches 40%. However, if a woman starts taking medication a few weeks before giving birth (because of its toxicity, it cannot be drunk all her life), then the child will most likely be born healthy. Currently, the probability of infecting a child with HIV from the mother is about 1-2%.
Silent cells and the Berlin patient
Thirty-odd antiviral drugs that exist today can suppress a viral infection, and a person will live a normal life, and the concentration of the virus in his body will be lower than can be determined by the most accurate modern diagnostic methods. However, if you stop taking medications, the so–called silent cells will wake up, whose DNA already has the DNA of the virus, and internal infection will occur - from the resources that have been preserved in the body. Unfortunately, the lifetime of these cells is more than 70 years, and you can't get rid of them in a lifetime.
In addition, even if an infected person takes medications that suppress the virus until the end of his life, and he manages to live a normal life, sometimes for completely incomprehensible reasons, immunoactivation occurs in his body, which contributes to the development of many other diseases, the causes of which are not yet fully understood, for example, cardiovascular diseases. It has long been known that general immunoactivation leads to a heart attack. Even smoking not only causes lung cancer due to the deposition of nicotine in the respiratory tract, but also contributes to diabetes and cardiovascular diseases - just because of immunoactivation. This process leads to the fact that HIV-infected people, even those undergoing antiretroviral therapy, can suddenly develop diseases characteristic of the elderly: cardiovascular diseases, bone fragility, some psychological disorders, diabetes.
The first person cured of AIDS is an American Timothy Ray Brown. He was nicknamed the "Berlin patient" because he was diagnosed with HIV in 1995 while studying in Germany. In 2007, Brown underwent hematopoietic stem cell transplantation to treat leukemia. And although Brown stopped taking antiviral medications, even three years after the operation, doctors did not find the immunodeficiency virus in his blood. This happened because doctors chose a donor for transplantation with just that rare mutation characterized by the absence of a second T-lymphocyte protein to which HIV attaches to infect the cell. However, bone marrow hematopoietic cell transplantation is a dangerous procedure, complications after it can be worse than HIV itself, which excludes its mass implementation.
What about the vaccine?
Despite the fact that HIV began to be studied back in the 1980s, vaccines against it have not yet been invented, and some scientists believe that it is impossible to develop it in principle. This is due to the fact that the virus, once in the body, mutates too quickly for the immune system to develop an effective response.
Other researchers persistently continue to work in this direction. Their idea is that with the help of genetic engineering, it is possible to remove its infectious origin from the virus and insert another necessary gene into it. That is, scientists are trying to create a virus that will not infect, but will cause an immune response, and they want to use it as a vaccine. But so far the work in this area has not been crowned with success. It is likely that a person may become immune to this artificial model of a non-infectious virus. But if he gets infected with real HIV, then he will again mutate quickly and "run away" from the immune response.
Therefore, one of the directions of the development of science in this area is the search for conservative sequences, that is, those parts of the viral protein that do not change during mutations. It is very difficult to detect them, because in HIV, while it floats in the blood or multiplies in the lymphatic tissue, they are hidden. The virus is revealed only at the moment of adhesion and fusion with the cell.
Current HIV research
Today there are two big problems in the fight against HIV. First, you need to understand how to get rid of silent cells that become active if an HIV-infected person stops taking medications. We tried to stimulate them so that they would start producing a virus and antiviral drugs could be used. But it is not possible to activate them 100% – there are still "silent" cells. In 2020, the Nobel Prize in Chemistry was awarded to scientists working on genome editing. Perhaps in the future it will be possible to cope with HIV in this way – by cutting out the part related to the immunodeficiency virus from the DNA of cells.
Secondly, scientists need to understand how to resist the immunoactivation occurring in the body of an HIV-infected person.
In general, the genetic branch of HIV science is well developed today: we know a lot about the virus, its genome and mutations, the process of cell infection, the mechanism of fusion, and so on. However, much less is known about how the mechanism that leads to immunodeficiency is triggered. We still cannot answer the question exactly why, in addition to T-lymphocytes infected by the virus, other cells die. In particular, we don't know why B cells die. In a recent article published in the leading European journal The EMBO Journal, researchers are just wondering why immunodeficiency begins when infected with HIV, namely why, if antibodies are produced by B cells that the virus does not infect, the production of antiviral antibodies is inhibited. It turned out that viruses have proteins, one of which is Nef (Negative Regulatory Factor), which previously seemed insignificant to scientists, and later, as it turned out, contributes to infection; it stops many of the vital processes of B cells. In addition, this small accessory protein continues to be produced in the body even when HIV itself is not produced.
Potentially, it is Nef that can be another target for therapy. Its development is a big task that needs to be solved in order to defeat HIV.
About the author: Leonid Margolis – Doctor of Biological Sciences, Head of the Department of Intercellular Interaction of the National Institutes of Health of the USA, Professor of the Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University.
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