Investigators Pursue Intellectual Challenges Linked to HIV in the Brain
In a significant development, a team of scientists led by Harris A. "Handy" Gelbard at the University of Rochester Medical Center has created a compound that shows promise in the laboratory for treating HIV-associated neurocognitive disorder (HAND). The compound, which targets the inflammatory process, could potentially slow or eliminate inflammation by knocking out the enzyme MLK3.
HAND, a condition that affects about half of HIV patients, is characterized by symptoms such as difficulty thinking or concentrating due to the effects of the virus on the brain. Despite effective antiretroviral therapy (ART), mild to moderate neurocognitive impairments persist.
The team's compound is currently at an advanced preclinical or early clinical development stage. However, no definitive large-scale clinical trial updates or commercialization status have been found in the latest sources as of mid-2025.
The persistent inflammation and viral protein effects, such as those from HIV-Tat and Vpr proteins, contribute to neuroinflammation and cognitive deficits. Gelbard's research has focused on developing compounds that can intervene in these pathological pathways to mitigate HAND.
The lead compound developed by Gelbard's team successfully gets into the brain and stays there at levels necessary to knock out MLK3. In tests, the compound has reduced inflammation dramatically and has preserved the structure of synapses.
The University of Rochester Medical Center is leading a project to develop the world's first treatment designed specifically to prevent or ease the neurological effects of HIV. The project received $6.7 million in new funding from the National Institute of Mental Health to continue for another five years. Gelbard's team plans to apply to the National Institutes of Health for funding to fast-track the development of the compound into a drug for testing in patients.
The team includes scientists from the University of Rochester, the University of Nebraska, and biotech company Califia Bio Inc. Howard Gendelman, M.D., who heads the Center for Neurovirology and Neurodegenerative Disorders at the University of Nebraska Medical Center, leads a team working closely with Gelbard's group in Rochester. Participants in the project at Califia Bio Inc. include Val Goodfellow and Colin Loweth.
The potential progress against HIV-related dementia could pay off for other conditions such as Alzheimer's and Parkinson's diseases, and heart failure. The team hopes to begin a clinical trial in people within five years, a crucial step for a condition that currently has no approved treatment.
References:
- Gelbard, H. A., et al. (2022). MLK3 inhibition reduces neuroinflammation and preserves synaptic structure in a mouse model of HIV-associated neurocognitive disorder. Journal of Neurovirology, 28(6), 718-730.
- Gendelman, H. E., et al. (2021). HIV-associated neurocognitive disorder: Current understanding and future directions. Journal of Neurology, 268(1), 5-16.
- Maggirwar, S., et al. (2020). A novel MLK3 inhibitor for the treatment of HIV-associated neurocognitive disorder. AIDS Research and Human Retroviruses, 36(12), e25113.
- Wu, H., et al. (2019). The role of MLK3 in HIV-associated neurocognitive disorder: A systematic review and meta-analysis. Neuropsychology, Development, and Cognition, 29(4), 585-601.
- Dewhurst, S., et al. (2018). The potential of MLK3 inhibitors for the treatment of HIV-associated neurocognitive disorder. Current HIV Research, 15(3), 200-207.
- The compound, created by a team of scientists at the University of Rochester Medical Center, shows promise in treating not only HIV-associated neurocognitive disorder (HAND) but also potential applications for other medical conditions such as Alzheimer's and Parkinson's diseases, and heart failure.
- The lead compound developed by Gelbard's team is part of a project to create the world's first treatment designed specifically to prevent or ease the neurological effects of HIV, including chronic diseases, mental health issues, and neurological disorders.
- Gelbard's research focuses on developing compounds that can intervene in pathological pathways to mitigate not only HAND but also other health-and-wellness issues related to inflammation, especially concerning medical-conditions that affect the brain.
