BLZ945 Offers New Possibilities for Eradicating HIV From the Brain

Researchers from the Tulane National Primate Research Center found that BLZ945, an experimental small molecule inhibitor used in amyotrophic lateral sclerosis and brain cancer, may help eliminate HIV from infected brains cells. The findings, published in Brain, showed that a high dose treatment of the cancer medication substantially reduced levels of simian immunodeficiency virus (SIV), the nonhuman primate equivalent of HIV, in the brain. Although further research is needed, the initial results show the promising ability of BLZ945 to penetrate the hard-to-reach reservoirs where HIV persists, improving long-term outcomes and mitigating brain-related complications for patients.

It is believed that this is the cause of neurocognitive dysfunction associated with HIV infection, meaning comprehensive treatment options that clear the virus from the brain is crucial for patients. Image Credit: © ActionGP - stock.adobe.com

According to the World Health Organization, an estimated 40 million individuals around the world were living with HIV at the end of 2023. Since the HIV epidemic of the 1980s, substantial medical advancements have been made that evolved the infection from a terminal illness to a manageable, chronic condition. The development of antiretroviral therapy (ART) dramatically improved outcomes for patients and is the standard of care for HIV management. It is relatively successful at maintaining the virus at undetectable levels in the blood but is incapable of fully eliminating it from the liver, lymph nodes, and brain.^1,2

There are various persistent, adverse neurological symptoms associated with HIV, including confusion and forgetfulness, headaches, difficulty concentrating, and anxiety or depression, among others. Due to the blood-brain barrier, it is challenging to attack the virus, thereby allowing the infection to persist. The HIV infection is harbored by macrophages, which are long-lived white blood cells in the brain, making it difficult to eradicate them once infected. It is believed that this is the cause of neurocognitive dysfunction associated with HIV infection, meaning comprehensive treatment options that clear the virus from the brain is crucial.^3,4

The researchers targeted the macrophages using BLZ945, a brain-penetrant CSF1R kinase inhibitor that hasn’t yet been considered for use in HIV treatment. They utilized 3 groups to model human HIV infection and treatment, consisting of an untreated control group, and 2 groups treated with either a low (10 mg/kg/day) or high (30 mg/kg/day) dose of the small molecule inhibitor for 30 days.⁵

The findings demonstrated a significant reduction in cells expressing HIV receptor sites CD163 and CD206 across all 4 brain regions examined by researchers. Additionally, there was a 95% to 99% decrease in viral DNA loads. BLZ945 treatment had little impact on microglia and did not show signs of liver toxicity.⁵

The initial results are promising for patients and marks a crucial advancement in HIV treatment. In future studies, the researchers plan to investigate use of BLZ945 in conjunction with ART, potentially paving the way for more targeted treatments capable of eradicating HIV from the body.⁴

"This research is an important step in tackling brain-related issues caused by HIV, which still affect people even when they are on effective HIV medication," said lead study author Woong-Ki Kim, PhD, associate director for research at Tulane National Primate Research Center, in a press release. "By specifically targeting the infected cells in the brain, we may be able to clear the virus from these hidden areas, which has been a major challenge in HIV treatment."⁴

REFERENCES

1. Why the HIV epidemic is not over. World Health Organization. Accessed August 2, 2024. https://www.who.int/news-room/spotlight/why-the-hiv-epidemic-is-not-over
2. HIV data and statistics. World Health Organization. 2024. Accessed August 2, 2024. https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/strategic-information/hiv-data-and-statistics
3. Neurological complications of HIV. National Institute of Neurological Disorders and Stroke. Accessed August 2, 2024. https://www.ninds.nih.gov/health-information/disorders/neurological-complications-hiv
4. Tulane study says new drug shows promise in clearing hiv from brain. News Release. July 25, 2024. Accessed August 1, 2024. https://www.eurekalert.org/news-releases/1052665
5. Bohannon D, Zablocki-Thomas L, Leung E, et al. CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques. Brain. July 25, 2024. doi:10.1093/brain/awae153