UC Riverside Researchers Identify Brain Protein Driving NeuroHIV Damage

Researchers at the University of California, Riverside, identified MAPK14 as a critical brain protein driving inflammation and memory problems in long-term HIV infections, a condition known as neuroHIV. The discovery points to potential new treatments for neurological complications that persist even when antiretroviral therapies successfully suppress the virus.

MAPK14 and the Mechanism of NeuroHIV Brain Damage

While powerful medications effectively suppress the spread of HIV and prevent its progression to AIDS, no cure exists for the virus, and many individuals living with HIV experience persistent nervous system problems according to findings published in the journal Brain, Behavior, and Immunity. Termed neuroHIV, these complications occur when infection compromises the function and structural integrity of the brain, spinal cord, and peripheral nervous system. The resulting conditions, including dementia and neuropathy, trigger memory and cognitive deficits that interfere with daily life.

Research led by biomedical scientists at the University of California, Riverside, has pinned down a specific brain protein driving this damage. The investigative team focused on the role of MAPK14—also known as p38α mitogen-activated protein kinase—a gene and protein integral to the inflammatory responses associated with viral infections.

Unlike the viral infection itself, the resulting neurological harm occurs when MAPK14 is activated in microglial cells simply by exposure to a surface component of the human immunodeficiency virus. These resident immune cells of the central nervous system carry vital receptors for the pathogen.

“This is because microglia carry three critical binding sites for the HIV envelope protein gp120. This interaction is sufficient for HIV to induce a neurotoxic state in microglia and compromise brain function.”

Marcus Kaul, professor of biomedical sciences in the School of Medicine at the University of California, Riverside

Genetic Deletion Prevents Synaptic Injury in Mouse Models

Because MAPK14/p38α operates across various cells throughout the body and fulfills numerous biological functions, the UCR research team adopted a targeted genetic approach. Spearheaded by Deepika Bhullar, a former associate specialist in the lab, alongside biomedical sciences professor Monica Carson, the team examined transgenic animals engineered to express the HIV envelope protein as a transgene in their brains.

By removing MAPK14 specifically from microglial cells in these neuroHIV model mice and in human cell models, the researchers observed whether the typical neurological deterioration still occurred.

“NeuroHIV mice in which microglia possess p38α have reduced nerve cell processes and connections compared with control animals. Dendrites and synapses in the cerebral cortex and hippocampus are affected, indicating brain injury. If the microglia in neuroHIV mice lack p38α, this injury is absent.”

Marcus Kaul, professor of biomedical sciences at the University of California, Riverside

This genetic knockout demonstrated that microglial MAPK14 is required for the virus to trigger brain injury and memory problems. The research team plans to confirm these insights by examining human post-mortem tissues from people with HIV.

Establishing New Research Centers to Tackle Brain Inflammation

The identification of cellular pathways driving neuroinflammation coincides with broader institutional investments aimed at combating neurological decline among individuals with suppressed viral loads. Antiretroviral drugs successfully extend lifespans, but cognitive problems persist in a significant portion of patients, ranging from mild memory impairment to difficulties holding a job.

To close critical research gaps, the National Institute of Mental Health awarded Rutgers Health and Weill Cornell Medicine a $3 million grant to establish the New York-New Jersey Center for Actionable NeuroHIV Biomarkers as detailed in an announcement by Rutgers University.

“HIV reaches the brain within days of infection, often before people even know they have HIV. And once it gets there, it can persist even after treatment begins, hiding in the DNA of infected cells where antiretroviral drugs can’t reach it.”

Tricia Burdo, associate director of the Rutgers Institute for Translational Medicine and Science

Infected cells continuously release toxic viral proteins and maintain low levels of replication despite drug therapy. Before antiretroviral regimens became available, patients experienced severe brain damage; modern treatment makes these effects milder, but cognitive impairment remains widespread.

Personalized Medicine and Biomarker Discovery

Because neuroHIV affects patients differently—some lose executive function, while others experience memory loss, depression, or motor difficulties—the newly formed research center aims to leverage machine learning to parse diverse clinical datasets.

UC Riverside Researchers Identify Brain Protein Driving NeuroHIV Damage — Photo: Rutgers University

The four-year grant funds shared infrastructure rather than a single standalone study, including multi-omics platforms and cerebral organoids, which are lab-grown clusters of human brain cells allowing scientists to observe viral activity without animal subjects. Additionally, the funding allocates $20,000 in pilot grants for junior faculty and investigators entering the field.

“If we can identify a subgroup of people with certain cognitive phenotypes such as memory impairment or loss of cognitive function and find a biomarker that tracks with that phenotype, we can then ask what mechanism is driving it and, ultimately, how to target that mechanism with treatment. That’s the path toward a more personalized approach to treatment.”

Tricia Burdo, Henry Rutgers Endowed Professor of Translational Medicine

With no current therapies specifically designed to prevent or mitigate ongoing brain injury, researchers at both academic institutions emphasize that identifying precise drivers like microglial MAPK14 and establishing actionable clinical biomarkers represent essential steps toward targeted interventions for chronic viral survivors.

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