Do not release HIV from hibernation
Scientists from the USA have discovered two molecules that suppress "sleeping" HIV
American molecular biologists have found out how special "traitor proteins" work, helping HIV to quickly "resurrect itself" after stopping taking medications, and discovered substances that block their action. The results of the first experiments are described in the journal Antimicrobial Agents and Chemotherapy (Vargas et al., Inhibitors of Signaling Pathways that Block Reversal of HIV-1 Latency).
"We still have a poor understanding of what cellular systems HIV uses in order to fall into "hibernation" and come out of it. The simplest and most effective way to find an answer to this question is to block the work of some or all of the genes responsible for the transmission of intracellular signals," says Benni Vargas from the University of Pittsburgh (USA).
Trench warfare
Today, HIV patients can live for decades thanks to the use of antiretroviral drugs – substances that suppress various stages of virus replication in the cells of the body. Since they often have strong side effects, patients are forced to stop taking them for several weeks.
When they stop taking them, HIV "gets out of the trenches" and begins to intensively copy itself, often returning to the initial scale of infection in three or two weeks. In recent years, scientists have been actively trying to find drugs or antibodies that would help avoid such a "counterattack" of the virus, or would allow the virus to be "kicked out" of cells.
Relatively recently, biologists have found out that the virus "digs in" not only in the T-cells that it usually infects, but also in the so–called macrophages - amoeboid cells that destroy bacteria, toxic particles and various "garbage". This discovery forced scientists to embark on a large-scale search for other HIV "bunkers" and methods of smoking the virus out of them.
These searches, as Vargas explains, are complicated by the fact that human cells contain several hundred genes that HIV can use to monitor the level of immune activity and the presence of antiretroviral drugs in the blood of its victim.
These sections of DNA are responsible for the assembly of special signaling molecules and enzymes, so-called kinases, many of which play a critical role in the work of the body. For this reason, the removal of the most important of them can result in the death of a person, which did not allow scientists to find a "simple" solution to this problem.
Vargas and his colleagues propose a radically different method of conducting "trench warfare". To win over HIV does not necessarily completely destroy the virus or deprive it of the help of "traitor proteins". You can simply change the work of these kinases in such a way that he will never "wake up" again.
Massive attack on HIV
Guided by this idea, molecular biologists have tested how four hundred already discovered molecules that destroy or suppress these proteins will act on immune cells, inside which a special version of HIV is hiding.
The genome of this virus was modified in such a way that the immune cells infected with them began to produce and release into the nutrient medium glowing molecules not found in ordinary human cells. Accordingly, the "awakening" of HIV and the infection of new cells led to an increase in the concentration of this substance, and the suppression of infection led to a drop in its proportion.
Such a technique, as Vargas notes, allowed his team to quickly sort through all 416 potential drugs and find that four of them at once prevented HIV from coming out of hibernation with any combination of signals that usually cause reactivation of the virus.
Two of them, PF-3758309 and danuserib, did not interfere with the work of other components of the cell and were extremely efficient. As further experiments showed, even small doses of these substances repeatedly "put to sleep" the virus in the cells of several volunteers infected with "normal" HIV.
These drugs, as scientists note, act on different types of kinases. PF-3758309 suppresses the PAK4 protein associated with the work of the "skeleton" of cells, and danuserib is the Aurora B enzyme that controls the process of their division. Both substances have already been approved by regulatory authorities as medicines for bone marrow cancer and tumors of various internal glands.
Further study of the proteins suppressed by them, respectively, will help to understand exactly how HIV uses them, and the drugs themselves will soon begin to undergo clinical trials. Scientists place special hopes on PF-3758309, which has a record high effect on infected cells.
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