No vaccine for HIV has been developed for almost 40 years

It has been nearly 40 years since the human immunodeficiency virus (HIV) responsible for the deadly disease known as AIDS was identified. In 1985, during the first international conference on AIDS, it was announced that we would have to wait about two or two and a half years for an effective and safe vaccine. So far, we have allocated huge funds to its development, e.g. in 2017 we spent 845 million dollars. More than 40 potential vaccines have already been tested, but the results have been disappointing. Meanwhile, the number of AIDS patients is currently estimated at over 38 million.

1. No effective vaccine against HIV has been developed for almost 40 years
2. This virus seems to be trying to outsmart medicine – it mutates and changes too quickly for us to find one effective vaccine
3. However, scientists are not giving up and are still looking for a way to fight the AIDS epidemic. However, there are still more successes in the field of treatment than of prevention
4. You can find more such stories on the TvoiLokony home page

HIV integrates its genetic material into human DNA

– In the 80s, this virus was a mystery to us – says Dr. n. med. Maciej Przybylski virologist from the Chair and Department of Medical Microbiology at the Medical University of Warsaw. – Discovering how it works is a matter of the past 20 years. In the 60s, the subject of reverse transcriptase was a fashionable novelty, and in the 80s it was recognized on a scientific level. Selected laboratories and scientists had specialist knowledge. At the moment when the problem of HIV appeared and it turned out that AIDS can be contracted by anyone, reverse transcriptase and its relationship with the biology of the virus suddenly became a very important topic, and only then did detailed research begin in full swing – adds Dr. Przybylski.

The virus attacks the immune system directly; this means that its target cells, i.e. the ones it destroys, are cells of the immune system. Its uniqueness consists of several features. First of all, after penetrating into cells, it can be cleverly hidden.

Current vaccines protect against disease, but are not always able to fully prevent infection, whereas HIV infection is characterized by a long dormancy period before it becomes AIDS. During this period, the virus “hides” in the DNA of an infected person. How does he do it? It is thanks to reverse transcriptase and integration into the human genome.

– If we take SARS-CoV-2 as an example, we can see that it works like most viruses. It enters the cell, produces certain proteins and multiplies its genetic material, and then begins to produce proteins of a different type, packs the genetic material into the protein shell and leaves the cell – describes Dr. Przybylski. It is quite simple and our immune system is quite good at dealing with this type of virus. In the case of HIV, this is not the case.

– If we are talking about RNA viruses, most of them enter the cell, attach their RNA to the ribosome and produce proteins, then the RNA is multiplied, attaches to the ribosome again and produces proteins again, and the cycle closes – explains Dr. Przybylski. – On the other hand, HIV uses an additional enzyme rarely found in viruses, i.e. reverse transcriptase, and transcribes its RNA into DNA.

Reverse transcriptase is an unusual enzyme. Typically, the rewriting is done the other way around – the basic template, something like a hard disk in a cell, is DNA, and the cache is RNA. In the case of HIV, the process works so that the template is viral RNA that is transcribed into DNA, and the enzyme responsible for this is reverse transcriptase. This transcribed from viral RNA is then incorporated into human DNA, cell DNA – another HIV enzyme, integrase, which is responsible for this process. Thus, a person infected with HIV has a genome in his cellular DNA, or in fact many copies of the viral genome.

Virological dogma says that we cannot cope with a latent or dormant virus, one whose genetic material remains for a long time inside our cell. Once infected, a cell will contain a provirus if not destroyed. The provirus is the DNA form of the HIV retrovirus that is integrated into the genome of the cell. Such a provirus is the information base for the production of further viral particles.

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The HIV virus mutates rapidly

A specific vaccine always targets a specific variant of the virus. If the virus changes, the vaccine may no longer work. Here’s another problem.

The HIV provirus can be called a specific form of the DNA virus. However, HIV is by nature an RNA virus and mutates fairly quickly. The high genetic variability of HIV leads to the virus changing too quickly for us to find one effective vaccine.

– HIV also has the advantage that for it immune cells that are constantly present in the peripheral blood are target cells – emphasizes Dr. Przybylski. – When it multiplies in the human body, it is present in the blood for a long time. While in the classic model of viral infection, viruses can also be found in the blood for some time, but then disappear – adds Dr. Przybylski. – This is due to an effective immune system. The problem with HIV is that it attacks the cells that recognize and fight pathogens. So we are dealing with a virus that, firstly, we cannot remove from infected cells, and secondly, it stays there for a long time, constantly replicating and infecting new cells. In addition, it attacks our immune system and undergoes constant mutations.

It can be said that HIV evolves in the course of an infection in an individual.

– If someone becomes infected with a strain of HIV, but does not die of infection because he is taking antiviral drugs, and after a few years we take a blood sample from him, find infected lymphocytes, isolate the virus sequence and compare it with the original virus, it turns out that We are dealing with many completely different strains of HIV – emphasizes Dr. Przybylski. – Such an evolution in the body of an individual person takes place continuously, therefore in this one person we are still dealing with other varieties of the virus. And if we multiply that by the number of all infected, then suddenly we see such variability that it is difficult to think about developing a vaccine.

What can AIDS drugs do?

In the 80s, the detection of HIV infection resulted in a death sentence. Now the situation has changed. We are able to keep the infected alive with the help of the available drugs. It should be emphasized that modern antiretroviral therapy is effective. A person who takes medication not only does not die, but also does not suffer from opportunistic diseases. Scientists came up with the idea of ​​using combination therapy, i.e. the simultaneous administration of several preparations, each of which hits different parts of the virus replication cycle.

– We have a number of classes of antiretroviral drugs that work at different stages of HIV replication – says Dr. Przybylski. – Within each classroom, we usually have several drugs to choose from. We can use them in various combinations and treat people who are newly infected, people who have recurrences or those who have been treated for a long time, and we are concerned that resistance may have developed. Because a virus that is exposed long enough to a particular drug begins to become resistant to it.

There are drugs that can be used in pregnant women or in other specific situations, such as co-infection with HIV-HBV or HIV-HCV or HIV-tuberculosis. Doctors have a lot to choose from and can use a therapy that, provided that the drugs are taken continuously, the infected people live and do not get sick.

HIV Vaccine Development – A Stumble Checklist

Vaccines usually mimic the immune response of those who have had an infection, but with HIV almost no recovery. As a result, it is difficult to talk about a model immune response that would become a model for a vaccine.

Most vaccines contain inactivated (“killed”) or weakened viruses or their purified proteins. However, inactivated HIV does not elicit an effective immune response, and any live form of HIV is too dangerous to use.

Most vaccines are tested on animals. These types of studies allow scientists to make sure that they are likely to be safe and effective before being tried in humans. However, in the case of HIV, this method does not work. No animal tests have shown how humans would respond to the vaccine.

One of the most successful clinical trials is a US military study conducted in Thailand in 2009. The study, known as the RV144 trial, used a combination of vaccines: a basic (ALVAC) and a booster (AIDSVAX B / E) vaccine. The combination vaccine has been found to be safe and fairly effective. The combination lowered the transmission speed by 31 percent. compared to placebo. However, a 31% reduction is not enough to move to a wider use of this combination.

A complementary study called HVTN 100 tested a modified version of the RV144 regimen in South Africa. Another substance was used to fortify the vaccine. The study participants also received one more dose compared to those with RV144.

The study showed that in a group of around 200 participants, the vaccine improved the immune response associated with the risk of HIV infection. Based on these results, a larger follow-up study, called HVTN 5404, was launched in 702 volunteers. This was to see if the vaccine actually prevented transmission of HIV. Unfortunately, the results just published turned out to be disappointing. The study was stopped because the vaccine did not prevent the infection. A total of 2704 adults received the vaccine and the remaining 2700 received a placebo. The researchers found nearly identical infection rates, regardless of what was given to the volunteers. HIV infection occurred in 138 vaccinated subjects and 133 subjects who received placebo.

Should we believe in developing an HIV vaccine?

Scientists are still counting on the fact that they will be able to find such a component of the virus, a protein whose blocking will lead to the body gaining immunity, and at the same time, this protein will be an important element of the virus and will be so immunogenic, i.e. it will effectively provoke a response immune system that they can be used as a vaccine.

Research also goes in other directions, because we ourselves may have mutations that make us insensitive to HIV infection. There are those fortunate enough to have mutations in the proteins responsible for the attachment and entry of the virus into the cell, which prevent the virus from harming them.

Scientists have called this phenomenon the Nigerian Prostitute Paradox. It is known that Africa is the main reservoir and, at the same time, the continent most affected by HIV infection. The study found that among the prostitutes in Nigeria there is a group that should have died of AIDS a long time ago, and that it is doing very well.

– It turns out that their resistance to HIV infection is related to a specific mutation of the protein with which the virus binds when it enters the cell – explains Dr. Przybylski. – Then another protein protecting against the development of HIV infection was discovered, this time related to the activity of the immune system, effectively limiting the development of the infection. However, specific mutations in proteins that protect against HIV infection are relatively rare. Using this mechanism is a potential way to fight the virus, however, we are no longer talking about genetic engineering of the virus, but about human genetic engineering. And this is associated with great concerns and legal restrictions, because we do not want to deal with eugenics or modifying human genes.

There is another method of experimental treatment associated with this mechanism of defense against the virus. It is a blood cell transplant that is targeted for HIV but from a donor who has a mutation that protects against infection.

– It concerned an HIV-infected person who was later diagnosed with acute myeloid leukemia – says Dr. Przybylski. – At that time, this person was transplanted with bone marrow from a donor with a mutation that protects against HIV infection, and there are many indications that this procedure is very effective in the fight against the virus. However, hematopoietic cell transplantation is used to treat people suffering from blood cancers – leukemias and lymphomas. Therefore, we need a donor with a mutation that protects against HIV infection, and besides, such a transplant is a very complicated procedure and requires the use of immunosuppression.

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