• Research Highlight
Despite decades of research and the availability of antiretroviral medications, HIV continues to pose a significant health challenge. While these medications can be used to eliminate the symptoms of HIV and prevent its spread to others, a cure has yet to be found.
One major challenge is that HIV can enter a dormant-like state, hiding in the body and evading treatments, only to reactivate later. HIV hiding in the brain is particularly difficult to access, as the blood-brain barrier—the protective membrane surrounding the brain—often prevents treatments from entering those tissues.
In a recent NIMH-funded study, researchers explored a potential solution by testing a drug called BLZ945 that targets a type of immune cell known as macrophages.
How does the treatment work?
Macrophages are a major way that HIV multiplies and spreads in the brain. HIV-infected macrophages can also persist in the brain during antiretroviral treatment, making them a source of long-lasting HIV infection. Because macrophages help spread and maintain HIV infection, targeting these cells could be a way to successfully eliminate HIV from the brain.
BLZ945 is a small molecule capable of entering into 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 for Research at the Tulane University National Primate Research Center, treated primates infected with SIV with a daily oral dose of either 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 declined after treatment with BLZ945, and this reduction was associated with a significant decline in brain-based SIV. These results confirm BLZ945 as a potential treatment for HIV by targeting macrophages. Importantly, treatment with BLZ945 did not significantly affect other immune cells in the brain that support brain health, such as microglia.
The researchers found that factors associated with antiviral immune response were increased in the brains of animals treated with BLZ495, suggesting the drug may help activate the immune system to target and eliminate SIV. The researchers also found evidence of reduced neuroinflammation in treated animals. The medication did not impact SIV levels in the blood or plasma, where macrophages don’t contribute as much to the production of the virus, suggesting this treatment specifically targets the brain.
CSF1R inhibitors, like BLZ945, can sometimes cause liver damage. However, the researchers found no evidence of this in animals treated with either dose during the study, suggesting the medication is safe when given at therapeutic levels.
What do the results mean?
The results suggest that using medications like BLZ945 to target macrophages—a major source of the spread and replication of HIV in the brain—may be a promising strategy for removing infection from these tissues. BLZ945 is currently being tested in human clinical trials for solid tumors, providing a roadmap for studying the effectiveness and safety of this drug for treating HIV in humans. This research represents a step forward in the ongoing battle against HIV, providing hope for a future where the virus can be eliminated from the brain.
Reference
Bohannon, D. G., Zablocki-Thomas, L. D., Leung, E. S., Dupont, J. K., Hattler, J. B., Kowalewska, J., Zhao, M., Luo, J., Salemi, M., Amedee, A. M., Li, Q., Kuroda, M. J., & Kim, W. K. (2024). CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques. Brain: A Journal of Neurology, 147(9), 3059–3069. https://doi.org/10.1093/brain/awae153
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