Targeting Brain Macrophages Reduces SIV Viral Load
Original Title
CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques.
- Brain : a journal of neurology
- 4:02 Min.
Overview
This study investigated a potential new approach to addressing the persistence of HIV and its simian counterpart,
Background
One of the major challenges in treating HIV and SIV infections is that the viruses can hide out in certain parts of the body, including the brain. Even when patients are taking effective
Previous research has shown that certain immune cells in the brain, called macrophages, can become infected with HIV and SIV and act as reservoirs for the virus, even during ART. These infected macrophages, particularly a subtype called
Targeting CSF1R to Deplete Brain Macrophages
In this study, the researchers used a drug called BLZ945 to target the
The researchers found that high-dose treatment with BLZ945 (30 mg/kg per day) significantly reduced the numbers of two key macrophage markers, CD163 and CD206, across different regions of the brain. Importantly, this depletion of macrophages was closely correlated with a 95-99% reduction in the levels of SIV DNA in the brain tissue of the treated animals, with some areas even reaching undetectable levels of the virus.
Interestingly, the BLZ945 treatment did not affect the numbers of another type of brain immune cell, called
Reducing Viral Burden in the Brain
The researchers found that the reduction in brain macrophages and viral DNA levels was most pronounced in the animals that received the high-dose BLZ945 treatment. In contrast, the lower dose of 10 mg/kg per day did not have as dramatic an effect on macrophage numbers or viral loads in the brain.
Importantly, the decrease in brain viral burden was specifically linked to the depletion of PVMs, and not the resting microglia population. This suggests that the infected PVMs are a major source of SIV in the brain during acute infection, and that targeting these cells with CSF1R inhibition can effectively reduce the viral reservoir.
Interestingly, the BLZ945 treatment did not significantly affect the levels of SIV in the blood or
Safety and Neuroimmune Effects
The researchers also examined the safety of BLZ945 treatment in the SIV-infected monkeys. While they did observe moderate increases in some liver enzymes, there was no evidence of actual liver damage based on histological examination. This suggests the enzyme increases may have been due to changes in liver function rather than direct toxicity from the drug.
In addition to reducing the viral burden, the BLZ945 treatment also appeared to have beneficial effects on the overall
Interestingly, the high-dose BLZ945 treatment also caused an increase in the levels of the CSF1 protein in the cerebrospinal fluid, but not in the blood. This suggests that the drug may be specifically modulating CSF1 signaling within the brain environment.
Implications and Future Directions
Overall, this study demonstrates that targeting the CSF1R receptor on brain macrophages, particularly the PVM subtype, can be an effective strategy for reducing the viral reservoir in the brain during acute SIV infection. The selective depletion of these infected macrophages by the CSF1R inhibitor BLZ945 led to a significant decrease in viral DNA levels in the brain tissue, without impacting the essential microglia population.
These findings highlight the potential of CSF1R-targeted therapies as part of a broader approach to addressing the persistence of HIV in the brain, even in patients on effective antiretroviral therapy. By reducing the viral burden in this important sanctuary site, such therapies could help prevent or mitigate the neurological complications that can still occur in some HIV-infected individuals.
Further research is still needed to fully understand the long-term effects of CSF1R inhibition on the brain's immune environment and to evaluate the potential of this approach for clearing HIV from the brain during chronic infection. Nevertheless, this study provides important proof-of-concept evidence that targeting macrophage survival pathways may be a promising new strategy in the ongoing fight against HIV and its neurological impacts.