A new study shows that protein kinases, enzymes that initiate the process that erodes the body’s immunity, are partly responsible for immunodeficiency in HIV patients. The findings will help explore new treatment options for the condition.
Human immunodeficiency virus (HIV) attacks the body’s immune system and is currently treated with antiviral drugs that prevent the virus from developing. While HIV therapies have improved significantly over the years, existing drugs are still unable to eradicate the virus from the body completely.
The immune system of one in five HIV patients does not recover properly, as the quantity of CD4+ T cells, which play an important role in the immune system, remains low even when the quantity of HI viruses in the blood has been suppressed to very low levels. In these patients, indications of chronic immune activation, which erodes the immune system and leads to immunodeficiency, can be found.
Chronic immune activation
Collaborative research between the University of Helsinki and the University of Erlangen-Nuremberg has found that the Negative Regulatory Factor (Nef) protein, which is primarily associated with HIV, continues low-level production in the tissues of patients whose immune system does not recover, even after viral multiplication is successfully suppressed. Nef produces extracellular vesicles that circulate in the blood and stimulate chronic immune activation.
In this new study, published in the Journal of Virology, the research group led by Professor Kalle Saksela has discovered an intracellular mechanism that initiates the chain of events leading to chronic immune activation which causes immunodeficiency.
“The new findings demonstrate that the Nef protein kicks off this harmful chain of events via cellular signalling: it activates protein kinases of the Src family, 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,” Professor Kalle Saksela said.
Inhibiting protein kinases
Drugs that block Src, Raf, and MAPK protein kinases are already in clinical use and may provide a solution to treating HIV patients whose immunity is not restored by antiretroviral therapy, which the researchers are now investigating.
While studying the drugs in tissue cultures, they have discovered that it is possible to prevent the production of inflammatory extracellular vesicles caused by the Nef protein using the same levels of the inhibitors as is currently clinically used.
Saksela commented: “Our findings make it possible to explore novel therapies without delay in patients whose immunodeficiency is not reversed to a sufficient degree with current antiretroviral therapies. The repurposing of kinase inhibitors for treating HIV infection appears to be a very promising way of solving this significant medical challenge.”