• Research Highlight
Despite decades of research and the availability of antiretroviral drugs, 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 other people, a cure has not yet been found.
A major challenge is that HIV can enter a latent-like state, hiding in the body and evading treatments, only to reactivate later. HIV hidden 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 possible solution by testing a drug called BLZ945 that targets a type of immune cell known as macrophages.
How does the treatment work?
Macrophages are an important way to multiply and spread HIV 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 clear 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 Primate Research Center at Tulane University, treated SIV-infected primates 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 SIV in the brain. These results confirm that BLZ945 is a potential macrophage-targeting treatment for HIV. Importantly, BLZ945 treatment did not significantly affect other brain immune cells that support brain health, such as microglia.
The researchers found that factors associated with the antiviral immune response increased in the brains of animals treated with BLZ495, suggesting that the drug may help activate the immune system to attack and eliminate SIV. The researchers also found evidence of a reduction in neuroinflammation in the treated animals. The drug did not affect SIV levels in blood or plasma, where macrophages do not contribute as much to virus production, suggesting that this treatment specifically targets the brain.
CSF1R inhibitors, such as BLZ945, can sometimes cause liver damage. However, the researchers found no evidence of this in animals treated with either dose during the study, suggesting that the drug is safe when given at therapeutic levels.
What do the results mean?
The results suggest that using drugs such as BLZ945 to target macrophages (a major source of HIV spread and replication in the brain) may be a promising strategy to clear infection from these tissues. BLZ945 is currently being tested in human clinical trials for solid tumors, providing a roadmap to study the efficacy and safety of this drug for the treatment of HIV in humans. This research represents a step forward in the ongoing battle against HIV and provides hope for a future in which 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., and Kim, W.K. (2024). Inhibition of CSF1R depletes brain macrophages and reduces brain virus load in SIV-infected macaques. Brain: a journal of neurology, 147(9), 3059–3069. https://doi.org/10.1093/brain/awae153
