An experimental drug originally developed to treat cancer may help clear HIV from infected cells in the brain, according to a new study from Tulane University.
For the first time, researchers at the Tulane National Primate Research Center have found that a cancer drug significantly reduced levels of SIV, the nonhuman primate equivalent of HIV, in the brain by targeting and depleting certain immune cells that harbor the virus.
Published in the magazine Brain, This discovery marks a significant step toward eliminating HIV from hard-to-reach reservoirs where the virus evades otherwise effective treatment.
“This research is an important step toward addressing brain-related problems caused by HIV, which continue to affect people even when they are taking effective HIV medications,” said study senior author Dr. Woong-Ki Kim, associate director of research at the Tulane National Primate Research Center. “By specifically targeting infected cells in the brain, we might be able to clear the virus from these hidden areas, which has been a major challenge in HIV treatment.”
Antiretroviral therapy (ART) is an essential component of successful HIV treatment, keeping the virus at undetectable levels in the blood and transforming HIV from a terminal illness to a manageable condition. However, ART does not completely eradicate HIV, so lifelong treatment is necessary. The virus persists in “viral reservoirs” in the brain, liver, and lymph nodes, where it remains beyond the reach of ART.
The brain has been a particularly tricky area to treat because of the blood-brain barrier, a protective membrane that shields it from harmful substances but also blocks treatments, allowing the virus to persist. Additionally, brain cells known as macrophages are extremely long-lived, making them difficult to eradicate once infected.
Infection of macrophages is thought to contribute to neurocognitive dysfunction, which affects nearly half of people living with HIV. Eradication of the virus from the brain is essential for comprehensive HIV treatment and could significantly improve the quality of life of people with HIV-related neurocognitive problems.
The researchers focused on macrophages, a type of white blood cell that harbors HIV in the brain. By using a small-molecule inhibitor to block a receptor that is upregulated on HIV-infected macrophages, the team was able to reduce the viral load in the brain. This approach essentially eliminated the virus from brain tissue, offering a potential new treatment avenue for HIV.
The small molecule inhibitor used, BLZ945, has previously been studied for therapeutic use in amyotrophic lateral sclerosis (ALS) and brain cancer, but never before in the context of clearing HIV from the brain.
The study, conducted at the Tulane National Primate Research Center, used three groups to model HIV infection and treatment in humans: an untreated control group and two groups treated with either a low or high dose of the small molecule inhibitor for 30 days. The high-dose treatment produced a marked reduction in cells expressing HIV receptor sites, as well as a 95-99% decrease in viral DNA loads in the brain.
In addition to reducing viral load, the treatment had no significant impact on microglia, the immune cells resident in the brain, which are essential for maintaining a healthy neuroimmune environment. It also showed no signs of liver toxicity at the doses tested.
The research team’s next step is to test this therapy alongside antiretroviral therapy to assess its efficacy in a combination treatment approach. This could pave the way for more comprehensive strategies to completely eradicate HIV from the body.
This research was funded by the National Institutes of Health, including grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, and was supported by resources from the National Institutes of Health Tulane National Primate Research Center core grant, P51 OD011104.