Targeting Brain Macrophages Reduces SIV Viral Load

Overview

This study investigated a potential new approach to addressing the persistence of HIV and its simian counterpart,

, in the brain. The researchers focused on targeting a specific receptor called CSF1R, which is important for the survival of certain types of brain immune cells called

macrophages

A type of immune cell that helps fight infections and remove damaged or dead cells in the body.

 

. By using a drug called

BLZ945

A drug that can block the activity of the CSF1 receptor, which may help reduce the number of certain types of macrophages in the brain.

 

to block CSF1R, the researchers were able to selectively deplete a particular group of macrophages in the brains of SIV-infected monkeys. Interestingly, this depletion of macrophages led to a significant reduction in the amount of SIV virus found in the brain tissue, suggesting that these macrophages are a key reservoir for the virus during infection.

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

that suppresses the virus in the blood, HIV and SIV may still persist in the brain. This is because the brain is a kind of "sanctuary" where the viruses can evade the effects of the drugs, which have difficulty crossing the protective

blood-brain barrier

A protective barrier that helps prevent harmful substances from entering the brain from the bloodstream.

 

.

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

, are thought to be an important target for new therapies aimed at clearing the virus from the brain.

Targeting CSF1R to Deplete Brain Macrophages

In this study, the researchers used a drug called BLZ945 to target the

, which is crucial for the survival and function of macrophages in the brain. By inhibiting CSF1R, the researchers were able to selectively deplete the PVMs and other macrophages in the brains of rhesus monkeys that were acutely infected with SIV.

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

, which express lower levels of CSF1R. This selective depletion of macrophages without impacting microglia is an important finding, as microglia play a crucial role in maintaining a healthy immune environment in the brain.

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

(the fluid surrounding the brain and spinal cord). This indicates that the infected PVMs in the brain are not a major contributor to the virus found in these other compartments during acute infection.

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

environment. The researchers found that BLZ945 led to the upregulation of factors associated with an antiviral immune response, as well as a reduction in markers of

neuroinflammation

Inflammation in the brain and nervous system, which can occur in response to infections, injuries, or other conditions. This inflammation can affect the normal functioning of the brain and nervous system.

 

and peripheral immune cell infiltration. This indicates that targeting CSF1R may help reactivate the brain's innate immune defenses against the virus while also dampening the harmful inflammatory processes that can contribute to neurological complications of HIV/SIV infection.

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.