Image shows an activated microglial cell next to other cells in a mouse brain.
Image Credit: UCR/Kaul lab AI generated / Gemini
Scientific Frontline: Extended "At a Glance" Summary: MAPK14 and NeuroHIV
The Core Concept: A specific brain protein, MAPK14 (or p38α mitogen-activated protein kinase), has been identified as a critical driver of the inflammatory response that causes brain damage and cognitive impairment in long-term HIV infections, a condition known as neuroHIV.
Key Distinction/Mechanism: Unlike the viral infection itself, the damage is caused when MAPK14 is activated in microglial cells (the brain's resident immune cells) simply by exposure to a component of the HIV envelope (gp120), inducing a neurotoxic state that harms dendrites and synapses.
Major Frameworks/Components:
- Microglia: The brain's resident immune cells, which carry binding sites for the HIV envelope protein.
- MAPK14 (p38α): A gene and protein integral to inflammatory responses.
- HIV Envelope Protein gp120: The viral component that interacts with microglia to trigger the neurotoxic cascade.
- NeuroHIV Mouse Model (HIVgp120tg): A transgenic model expressing the HIV envelope protein, used to demonstrate that removing MAPK14 from microglia prevents brain injury.
Branch of Science: Biomedical Sciences, Neuroscience, Virology, Immunology.
Future Application: The findings point toward a potential therapeutic target (MAPK14 in microglia) to treat or prevent the cognitive decline, dementia, and neuropathy associated with neuroHIV, with the next steps involving confirmation in human post-mortem tissues.
Why It Matters: While current antiretroviral therapies effectively suppress HIV spread, they do not prevent neuroHIV; identifying the mechanism of brain injury offers a pathway to improving the quality of life and cognitive function for people living with chronic HIV.
While powerful medications can suppress the spread of HIV and its progression to AIDS, there is no cure, and many people living with HIV experience nervous system problems.
Called neuroHIV, these complications occur when HIV infection affects the function and structural integrity of the brain and, to some extent, the spinal cord and peripheral nervous system. The complications, including dementia and neuropathy, can cause problems with memory and thinking that make it difficult for individuals to lead normal lives.
Research led by biomedical scientists at the University of California, Riverside, has identified a brain protein driving this damage, pointing toward a possible treatment.
The research team studied the role of MAPK14, a gene integral to the inflammatory responses associated with viral infections. They found in a mouse model of neuroHIV that MAPK14’s presence and activity in specific brain cells, called microglia, are required for HIV to cause brain injury and memory problems. The research is published in the journal Brain, Behavior, and Immunity.
Marcus Kaul, a professor of biomedical sciences in the School of Medicine who led the study, explained that MAPK14, also known as p38α mitogen-activated protein kinase, becomes activated in microglial cells by exposure to a component on the surface of HIV, whether or not infection occurs.
“This is because microglia carry three critical binding sites for the HIV envelope protein gp120,” Kaul said. “This interaction is sufficient for HIV to induce a neurotoxic state in microglia and compromise brain function.”
MAPK14/p38α is present in other cells of the body as well as the brain, and it has many other functions. Kaul’s team used a genetically driven approach to remove MAPK14/p38α specifically from microglial cells in the mouse model of neuroHIV and a human cell model. The team used neuroHIV mice, which express the HIV envelope protein as a transgene in their brains (HIVgp120tg). A transgene is a gene that has been transferred from one organism to another.
“NeuroHIV mice in which microglia possess p38α have reduced nerve cell processes and connections compared with control animals,” Kaul said. “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.”
According to the researchers, the work adds important aspects to scientists’ understanding of how a specific cellular signaling mechanism affects the brain during chronic HIV and possibly other viral infections.
The findings are noteworthy because the mouse model of neuroHIV that Kaul and his team used shares key features of brain injury and compromised function, such as impaired memory, with people with HIV infection (PWH).
The research was spearheaded by Deepika Bhullar, a former associate specialist in Kaul’s lab and the first author of the research paper, in collaboration with Monica Carson, a professor of biomedical sciences at UCR.
Next, the team plans to confirm the findings from the neuroHIV model in PWH.
“For this, we will need to investigate tissues of PWH who consented to donate them for research after death,” Kaul said.
Funding: The study was funded by grants to Kaul from the National Institutes of Health. Kaul, Bhullar, and Carson were joined in the research by scientists at UCR, the Sanford Burnham Prebys Medical Discovery Institute, and The Scripps Research Institute.
Published in journal: Brain, Behavior, and Immunity
Title: A critical in vivo role for microglial p38α MAPK in HIV-1 associated inflammatory brain injury
Authors: Deepika Bhullar, Ricky Maung, Amanda J. Roberts, Rabi Murad, Monica J. Carson, and Marcus Kaul
Source/Credit: University of California, Riverside | Iqbal Pittalwala
Edited by: Scientific Frontline
Reference Number: bmed092226_01
