Mutant killers take orders
Immune mutants overtake AIDSPyotr Smirnov, "Newspaper.
Now scientists have developed mutant immune cells that are tens and hundreds of times better at this task. They have time to multiply faster than the virus, and can help the body defeat AIDS.
Despite the relatively young age of HIV compared to long-lived infections such as malaria or tuberculosis, this virus infects about 30 million people worldwide every year. 2.5–3 million people per year die from acquired immunodeficiency syndrome – about the same as from malaria, and twice as many as from tuberculosis.
The invention and rapid introduction of dozens of highly active antiviral drugs already allows patients to lead a normal lifestyle for a long time, but reports of complete elimination of HIV so far look more like fiction. All these drugs at one stage or another slow down the division of the virus, preventing the formation of new copies of genetic material or the assembly of an entire viral particle.
James Riley and co-authors of the publication in Nature Medicine decided to go a fundamentally different way and help the immune system itself cope with the virus. Scientists have "armed" killer cells of the immune system with a new variant of the receptor, which allows recognizing and destroying cells affected by the virus.
Of course, this is not the first attempt to force the immune system to cope with HIV on its own, but the high variability of the virus and its exploitation of immune cells, undermining their work, greatly complicate the development of vaccines. Riley and colleagues decided to focus on agents designed directly to destroy virus–infected cells of the body - the so-called T-killers. A similar approach in the form of cell therapy has already shown its effectiveness in the treatment of malignant tumors.
On the surface of each cell of our body there are so-called molecules of the histocompatibility complex type I, MHC I (from the English Major Histocompatibility Complex). This structure is a kind of "display", which displays the processes of protein synthesis occurring inside the cell. Every time a new protein is formed in the cell, a small portion of ten to fifteen amino acids is sent to the surface, where it is "displayed" as part of MHC I.
T-killers continuously "scan" all the cells of the body, and if on one of them the mentioned amino acid chain turns out to be alien – the one for which the T-killer is trained, then they are immediately taken for destruction. The problem with viruses and tumors is that they either manage to "hide" their own proteins from representation in the composition of MHC I, or they have such high variability that the immune system simply does not keep up with continuously changing enemies.
The immunodeficiency virus is famous for its exceptional variability, but it also has proteins that you can't really play with. One of them is called p17.
Virologists have chosen as a target for HIV identification a small, 9 amino acid–long section of this protein, codenamed SL9, from the 77th to the 85th amino acids. In three out of four cases of HIV infection, this chain necessarily gets to the surface of the cells.
The absolute majority of Caucasians have a gene encoding the T-cell receptor TCR 868, which triggers a program to kill infected cells when binding to SL9. The problem is that even when meeting with this chain, the receptor does not always bind to it and for a very short time. Commands to multiply SL9-specific cells and kill cells infected with HIV are rarely issued. As a result, the virus multiplies faster than T-killers capable of destroying it.
Riley and colleagues isolated the DNA encoding TCR 868 and made several slightly different copies of it. The proteins taken from this matrix differed slightly from TCR 868 and also bound to SL9. To find out which one is better, scientists even arranged for these cells a kind of evolutionary competition of these artificially obtained mutant proteins, forcing the strongest to survive.
According to some indicators, the winning mutant surpassed its progenitor by more than 100 times. For example, the binding time of a T-killer, on the surface of which there was a mutant receptor, with an infected HIV cell increased from 1 minute to 2.5 hours. Under in vitro culture conditions, this allowed the T-killers to suppress the reproduction of HIV and even produce a sufficient amount of cytokines, which in the body should only enhance the destruction reaction.
But, most importantly, embedding the mutant receptor gene into the T-killer genome produced the same effect, even if altered SL9 chains were the target.
Riley and his colleagues expect to begin the first trials of a new method of treating AIDS patients next year – if the tests on mice that are already underway are successful. The approximate treatment plan will resemble the existing methods of cell therapy of tumors, with the exception that doctors will not choose the most suitable cells from the patient's T-killers, but will create them using gene therapy.
An approximate treatment regimen will look like this: a little blood is taken from a vein from the patient, all T-killers are isolated from this blood, then a gene encoding "mutant 868" is inserted into their DNA in an active form, after which cells are multiplied in vitro culture and injected back into the patient. As a result, T-killers capable of effectively recognizing HIV-infected cells end up in the body, are distributed through the bloodstream, and each encounter with a target leads to the formation of new T-killers, only intensifying the destruction reaction.
How effective these attempts will be, "The newspaper.Ru" will definitely tell you, and the scientists themselves are already planning to use the method they developed when creating new T-receptors to fight tumors.
Portal "Eternal youth" www.vechnayamolodost.ru10.11.2008