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HIV infections are treated with antiviral drugs that are effective in preventing the disease from developing. Although pharmacological therapy for HIV has advanced considerably, the virus cannot be completely eliminated from the body with currently available drugs.
However, in about a fifth of patients infected with HIV, the immune system does not recover as expected: the amount of CD4 T cells, reflecting the state of the immune system, remains low even when the amount of HI virus in the blood. is reduced to very low levels or below the measurement threshold. In these patients, indications of chronic immune activation, which erodes the immune system, can be detected.
In cooperation with the University of Erlangen-Nuremberg in Germany, researchers at the University of Helsinki have already shown that the Nef protein, a central factor associated with the HI virus, can continue low-level production in the tissues of the patient for a long time even after viral multiplication is successfully suppressed. The extracellular vesicles generated by Nef circulating in the blood and promoting chronic immune activation are important for this immune eroding activity.
In a new study, Professor Kalle Saksela’s research group has discovered an intracellular mechanism by which the chain of events associated with immune activation is initiated.
The study was published in the Journal of Virology.
“The new findings demonstrate that the Nef protein triggers this chain of harmful events via cell signaling: it activates the Src family protein kinases, which leads to the activation of Raf and MAPK protein kinases. As these two protein kinases are activated, the production of extracellular vesicles mediated by them begins, ”explains Saksela.
Protein kinase inhibitors as a new treatment option?
Pharmaceutical agents that inhibit Src, Raf and MAPK protein kinases are already in clinical use, and researchers at the University of Helsinki have also investigated their usefulness.
By studying the drugs in tissue cultures, they observed that it was possible to completely prevent the production of inflammatory extracellular vesicles caused by the Nef protein using the same drug levels as in current clinical use of the inhibitors. protein kinase.
“Our findings allow the rapid exploration of new therapies in patients whose immunodeficiency is not sufficiently reversed with current antiretroviral therapies. The reorientation of kinase inhibitors to treat HIV infection appears to be a very promising way to solve this important medical challenge, ”says Professor Saksela.
In recent years, around 150 new HIV infections have been diagnosed each year in Finland. Throughout the 2000s, the number of new infections per year remained below 200. In 2018, an estimated 38 million people were estimated to be HIV-positive, most of them in Africa.
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The study is part of the doctoral thesis of doctoral student Zhe Zhao, who works in the research group of Professor Kalle Saksela, the latest article in the soon-to-be-published book.
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