30 November 2016

The plague of the XX century: a look from the XXI

Vaccines, gene therapy and other new HIV treatments

Mikhail Petrov, "The Attic"

HIV is the most studied virus by humans. We already know almost everything about its structure, life cycle and relationship with other viruses, but this does not always help with treatment, and even more so with the prevention of the disease. Therefore, scientists continue to look for new ways to fight HIV.

AIDS, or acquired immune deficiency syndrome, is the last stage of the development of HIV infection (human immunodeficiency virus). In rare cases, AIDS can be caused by other causes, but still HIV and AIDS are most often used as synonyms.

HIV infections are transmitted through blood, during sexual contact, or from mother to child while breastfeeding. The virus infects cells of the human immune system, namely one of the varieties of T-helper cells – CD4 cells. The death of these cells leads to a complete imbalance of immunity, and in a sense that is why it is so difficult to fight HIV.

Already in the first weeks after infection, HIV destroys up to half of all CD4 lymphocytes. At this time, patients suffer from acute fever, pharyngitis, diarrhea, headache and other symptoms. After that, the picture is smoothed out, the condition is normalized and the latent stage of the disease occurs, during which there are more and more viral particles in the body, and fewer and fewer lymphocytes. In the end, the weakened immune system can no longer make up for the loss of lymphocytes and the last stage of the disease – AIDS, during which various secondary diseases develop (tuberculosis, malignant tumors and many others). In the absence of treatment, it lasts on average one to two years.

The HIV particle itself is two single-stranded RNA molecules surrounded by a protein shell. It searches for CD4 cells and, recognizing them, binds to them to deliver its genetic material inside a healthy cell. There, DNA is already synthesized by RNA, which is embedded in the original DNA of the immune cell and forces it to synthesize new viral RNAs and viral proteins, from which new viral particles are assembled.

HIV is very flexible genetically and constantly changes its outer protein shell, which allows it to escape from the immune system, which is trying to recognize and destroy the invader parasitizing on itself. Therefore, HIV is now being treated with highly active antiretroviral therapy: the patient is given three or four drugs at once that turn off various stages of the virus' life cycle. With careful use of these drugs (each omission in taking medication can significantly worsen the course of treatment) and simultaneous treatment of concomitant diseases, the life expectancy of infected people increases to 70 years.

However, this therapy is not suitable for everyone and can lead to side effects. In addition, highly active antiretroviral therapy does not completely remove HIV from the body: in trace amounts, it still remains inside the patient. Therefore, scientists are looking for new methods to combat HIV.

Antibody injections

In addition to T-lymphocytes, humans also have NK-lymphocytes, which monitor the condition of the body's own cells, and B-lymphocytes, which recognize foreign pathogens and produce antibodies in response to them. B-lymphocytes mark pathogens and trigger a further immune response, and sometimes they themselves bind to bacteria and viruses and block some of their functions.

Normally, the immune system, when a new stimulus enters it, sorts out all the already synthesized antibodies and selects the optimal one to combat the new danger, but with HIV this process is disrupted due to the incredible variability of its viral particles. As a result, HIV antibodies are suitable only for individual viral molecules, and even those can rapidly mutate and develop immunity.

However, in some patients, two to three years after infection, antibodies appear that are suitable for many variants of HIV at once and do not lose their strength over time. Now there are already several dozen such universal antibodies, and they all point to the "weak points" of HIV – those areas in its shell that almost do not rebuild even during the most severe mutations. For example, these antibodies are often sharpened to recognize the ENV protein of the virus envelope responsible for binding to the CD4 cell.

It would seem that for the treatment of HIV, you can simply inject these universal antibodies to infected people so that they trigger a cascade of the necessary immune reactions, but in reality this approach does not work yet. Firstly, often these antibodies, for reasons not fully understood, can only work in the bodies of those patients in whom they first appeared, and secondly, their injections themselves can cause a side immune response.

Nevertheless, scientists continue to experiment in this area. For example, researchers from the United States recently showed that even a one-time injection of a mixture of universal antibodies from three different patients prevented macaques from contracting HIV even after 23 weekly injections of the virus. No such effect has yet been observed in humans.

HIV vaccines

Another promising way to combat HIV is vaccination, the introduction of not ready–made immune solutions (antibodies), but training material for the immune system (weakened and modified pathogens or their fragments, for example, viral proteins), on which the immune system can train for future work.

Back in 2009, Thailand presented a vaccine that reduced the likelihood of contracting AIDS by about 31% and was administered to people in two stages. At first, patients were injected with a modified virus that was not capable of further reproduction, but contained several original HIV genes. On this material, the immune system developed the necessary T-cells, and a week later its success was consolidated by a second injection, which already contained HIV envelope proteins, to which suitable antibodies were selected.

Those trials ended optimistically, but the vaccine has not yet been released to the clinic – perhaps because its effect is not zero, but still a modest effect is not enough for commercial use. But over the past seven years, the vaccine has had many competitors with very original ideas.

For example, researchers from France and China decided not to train the immune system to fight viruses faster and more effectively, but, on the contrary, to develop its tolerance to the virus. The fact is that HIV can multiply only in activated CD4 cells, and therefore, with its inept and sloppy responses in the first days after infection, our immune system helps the virus spread in the body.

Therefore, scientists took Lactobacillus plantarum bacteria, which are well known to our body (they live in the intestine and do not cause any immune response) and mixed them with trace amounts of VIO (monkey immunodeficiency virus, very similar to HIV), and then gave this mixture to macaques. Such a kind of vaccination did not cause any increase in the content of antibodies to VIO in the body – the immune system of monkeys did not seem to notice the danger. As a result, when macaques began to be rectally infected with already serious doses of VIO, the virus in their bodies multiplied much slower than usual, and the immune system managed to take it under control on its own without any additional antiviral drugs.

Another unusual vaccine was proposed by Louis Wicker's group. They did not rely on masking bacteria, but on the herpes virus HHV-5, the latent form of which infected up to 100% of adults in some countries. Trace amounts of herpes viruses in them are localized in the tissues of the mucous membranes (which are primarily affected by HIV), are completely controlled by T cells and cause virtually no health problems.

The researchers made a weakened version of the hepatitis virus, inserted a part of the VIO genome into it and injected this vaccine into 12 macaques, hoping that an organism trained on such material would then be able to successfully fight VIO. After the monkeys were rectally infected with VIO, and six of them had positive results: the immune system very quickly suppressed the virus, which eventually ceased to manifest itself even in trace amounts.

Genetic therapy

One of the main obstacles to a complete cure from HIV is the sections of viral DNA sewn into the genomes of infected immune cells. Even when there are no more viral particles left in the human body, they can be synthesized on these DNA again, and that is why HIV-positive patients now need to take antiviral throughout their lives.

Scientists propose to correct this situation with the help of CRISP/Cas9 – the famous genome editing system, with which you can pointwise break DNA chains in those places where areas with viral hereditary information are embedded in them. Such a gap stimulates the repair of the original DNA of the cell, during which all extraneous viral genes will be cut out.

Researchers have already successfully conducted verification experiments on human cultures from T-lymphocytes and more recently conducted a similar experiment in living organisms – mice and rats. The study showed that gene therapy reduced the activity of viral genes in rodent cells by 80-90%.

Finally, another important story about AIDS and genes appeared in 2014, but so far it has nothing to do with practice. Then scientists found one person in a group of 1,700 infected people whose body was completely cured of HIV: he had no traces of viral genes in lymphocytes, much less free viral particles, despite the fact that he did not even take any antiviral drugs.

At the same time, the patient was clearly infected with HIV in the past: characteristic antibodies remained in the blood, as well as fragments of viral DNA, according to which it was possible to reconstruct the picture of events. It turns out that some proteins of the APOBEC family in the cells of this person intercepted viral RNA at the stage of its transformation into DNA and provoked abundant mutations that completely disabled DNA. Usually HIV manages to bypass this protective organism present in all cells, but, apparently, the rare genes of this patient gave him immunity from HIV or, more precisely, from AIDS (the patient still got sick, but then recovered before the onset of the AIDS stage). After that, similar cases were observed with other people.

The mechanisms of such a cure are not yet fully understood, and the practical benefits are vague, but one thing is clear: the current state of science allows not only to stop HIV and turn it into a chronic form, but also to prevent infection. Another thing is that the most important role in the spread of HIV is still played by social rather than medical factors: for example, the most effective prevention of the virus during its sexual transmission is still the simple use of condoms.

Portal "Eternal youth" http://vechnayamolodost.ru  30.11.2016

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