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Despite the decades of research and the availability of antiretroviral medications, HIV continues to raise a significant health challenge. While these medications can be used to eliminate HIV symptoms and prevent their spread to others, a cure has not yet been found.
An important challenge is that HIV can enter a latent state, hide in the body and evade treatments, just to reactivate later. The HIV that is hidden in the brain is particularly difficult to access, since the blood brain barrier, the protective membrane that surrounds the brain, often prevents treatments from entering those tissues.
In a recent study funded by NIMH, the researchers explored a potential solution when trying a medicine called BLZ945 that is directed to an immune cell type known as macrophages.
How does the treatment work?
Macrophages are an important way in which HIV multiplies and spreads in the brain. Macrophages infected with HIV can also persist in the brain during antiretroviral treatment, which makes them a long -term HIV infection source. Because macrophages help spread and maintain HIV infection, addressing these cells could be a way to successfully eliminate HIV from the brain.
BLZ945 is a small molecule capable of entering the brain. It stops the activity of a protein on the cell surface of macrophages called CSF1R, preventing them from multiplying and becoming active.
What did the researchers do in the study?
The researchers examined the effect of BLZ945 on Simian immunodeficiency virus (SIV): A virus found in primates that is closely related to HIV. The study team, led by Woong-Ki Kim, Ph.D. Associate Director of Research at the National Primates Research Center of the University of Tulane, treated with primates infected with SIV with a daily oral dose of 10 or 30 mg/kg of BLZ945 for 20 to 30 days.
What did the researchers find?
The researchers found that macrophage levels in the brain decreased after treatment with BLZ945, and this reduction was associated with a significant decrease in the SIV based on the brain. These results confirm BLZ945 as a potential treatment for HIV when addressing macrophages. It is important to highlight that BLZ945 treatment did not significantly affect other immune cells in the brain that support brain health, such as microglia.
The researchers found that the factors associated with the antiviral immune response increased in the brains of the animals treated with BLZ495, which suggests that the drug can help activate the immune system to point and eliminate SIV. The researchers also found evidence of reduced neuroinflammation in treated animals. The medication did not affect the SIV levels in the blood or plasma, where macrophages do not contribute both to the production of the virus, which suggests that this treatment is specifically directed to the brain.
CSF1R inhibitors, such as BLZ945, can sometimes cause liver damage. However, the researchers did not find evidence of this in animals treated with dose during the study, which suggests that the medication is safe when administered at the therapeutic level.
What do the results mean?
The results suggest that the use of medicines such as BLZ945 to direct macrophages, an important source of the propagation and replication of HIV in the brain, can be a promising strategy to eliminate infection of these tissues. BLZ945 is currently being tested in human clinical trials for solid tumors, providing a road map to study the effectiveness and safety of this medication to treat HIV in humans. This investigation represents a step forward in the battle against HIV, which provides hope for a future in which the virus can be eliminated from the brain.
Reference
Bohannon, DG, Zablock-Thomas, LD, Leung, Es, Dupont, JK, Hattler, JB, Kowalewska, J., Zhao, M., Luo, J., Salemi, M., Amedee, Am, Li, Q., Kuroda, MJ, & Kim, WK (2024). CSF1R inhibition exhausts brain macrophages and reduces brain virus load in macaques infected with SIV. Brain: A Journal of Neurology, 147(9), 3059–3069. https://doi.org/10.1093/brain/awae153
