14 November 2019

Immunotherapy of HIV infection

Scientists have modeled the therapy of HIV patients based on the suppression of regulatory receptors of immune cells

RNF Press Service

Suppression of the immune system is a typical sign of chronic viral infection and cancerous tumors. The resulting insufficient protection of the body leads to complications and aggravation of the patient's condition. An international team of scientists has investigated a way to activate immune cells in the treatment of HIV patients. The article is available in the journal PLOS Computational Biology (Zheltkova et al., Prediction of PD-L1 inhibition effects for HIV-infected individuals). The research is supported by the Russian Scientific Foundation.

T-cells are the basis of our immunity. They play a central role in protecting the body from viral infections and cancers. There is a distribution of responsibilities among T-lymphocytes. Some of them – T-helpers – recognize foreign agents on the surface of specialized cells of the immune system, and T-killers, attracted by their signals, eliminate the threat. Like all cells of our body, ready-to-work T-lymphocytes arise in the process of multiple division and differentiation of progenitor cells that do not have a clear specialization. In the regulation of this complex mechanism, it is possible to distinguish stages that serve as checkpoints, or checkpoints. Their presence makes it possible to detect and neutralize a cell with violations in the life cycle in time. In such checkpoints, the operability and "aptitude" of cells are checked, and if everything is not in order, the process of their suppression is started up to death. One of these checkpoints is the recognition of signaling molecules by special PD-L1 receptors on the surface of T cells.

HIV-infected and cancer patients experience a strong load on the immune system. In the first case, T-helpers die because of the virus that multiplies in them, and in the second - after a course of chemotherapy. In addition, when the cells of the immune system receive an excessive amount of signals, this leads them to a so-called state of exhaustion. T-cells start to work inefficiently, and sometimes their pool stops updating altogether. Today, the treatment of HIV patients is based on the use of highly active antiviral therapy, which helps to restrain the reproduction of viruses and thus reduces the level of infection, but does not restore the immune system.


Scheme of the model of the life cycle and functioning of T-lymphocytes in HIV infection. Source: Gennady Bocharov.

An international team of scientists has found out that when treating tumors with antibodies blocking checkpoint receptors, the process of T-cell division increases. They hypothesized that the use of such "suppressants" of immune response control points can also help in the treatment of HIV-infected patients. The lack of clarity of this result is due to the fact that restoring the role of T cells has a twofold effect: on the one hand, it strengthens infection control with the help of T-killers, and on the other hand, it increases the number of T-helpers in which HIV multiplies.

To test the hypothesis, the scientists isolated T cells from five patients and observed their division in the presence of a "suppressor" of PD-L1 receptors and without it. It turned out that checkpoint blockade has a positive effect on the growth of the T-lymphocyte population. The maximum number of divisions was estimated by labeling cells with fluorescent ("luminous") dye. The results obtained were subsequently described using a mathematical model. Thanks to her, scientists predicted the effect of the blockade on the overall level of viral load and the restoration of the number of healthy T-helpers.

"We have developed a mathematical model that allows us to study the effect of immunotherapy with antibodies blocking the activity of the PD-L1 receptor. With its help, we will be able to predict the clinical results of such therapy for patients with various variants of the course of HIV infection, taking into account individual immune response indicators. The results obtained indicate that PD-L1 immunotherapy should have a beneficial effect for the majority of HIV-infected patients," concludes Gennady Bocharov, Doctor of Physical and Mathematical Sciences, leading researcher Institute of Computational Mathematics named after G. I. Marchuk of the Russian Academy of Sciences and Professor of the I. M. Sechenov First Moscow State Medical University.

The work was also attended by employees of the Faculty of Computational Mathematics and Cybernetics of Lomonosov Moscow State University, the Marchuk Institute of Computational Mathematics of the Russian Academy of Sciences, as well as the Laboratory of Infectious Biology of Pompeu Fabra University (Barcelona, Spain) and the Catalan Institute of Research and Advanced Training (Barcelona, Spain).

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