Impact of HIV on the Brain and Immune Function
HIV is known to adversely affect the brain, contributing to cognitive and memory issues. Once the virus infiltrates the brain, it tends to stay there.
The virus primarily targets a specific immune cell type known as helper T cells. These cells roam throughout the body, including the brain, searching for foreign proteins called antigens, which usually signify an infection. When they identify antigens, helper T cells activate other immune responses to eliminate threats.
However, since HIV infects and depletes these helper T cells, it compromises the immune system, increasing vulnerability to opportunistic infections and ultimately leading to AIDS.
Fortunately, there are antiviral medications that help manage HIV and maintain helper T cells. However, these drugs struggle to penetrate the brain and spinal cord effectively.
In my lab, we focus on understanding how helper T cells function, aiming to create better HIV vaccines and therapies for neurodegenerative diseases. We’ve found that when helper T cells transport HIV into the brain, the virus conceals itself within cells, leading to persistent inflammation that can accelerate aging of the brain.
As of now, there are no therapies to eliminate HIV from the brain or spinal cord. Researchers are actively investigating avenues to mitigate chronic inflammation induced by HIV within the central nervous system. Collaborating with our colleagues in the Morrison Lab at UC Davis and the Raeman Lab at the University of Pittsburgh, we discovered that a therapy intended to alleviate inflammation might inadvertently increase viral levels in the brain instead.
Integrins’ Role in Viral Control
T cells monitor the brain and spinal cord through proteins called integrins. These proteins, located on cell surfaces, allow immune cells to access various regions in the body.
Our research is exploring whether inhibiting integrins might help address inflammation in the brain by preventing immune cells from bringing HIV into the central nervous system. We tested this concept on rhesus macaque monkeys infected with SIV, a primate strain of HIV, administering a multiple sclerosis drug that targets integrins.
However, even after blocking an integrin called alpha-4, which facilitates T cell migration into the brain, we observed no reduction in viral presence. In some brain regions, the viral load actually increased.
Reevaluating the Strategy Against the Virus
Curious about the unexpected rise in viral levels, we delved deeper. Blocking the alpha-4 integrin didn’t lower the number of helper T cells in the brain; instead, it decreased the count of killer T cells.
Killer T cells play a crucial role by destroying infected cells, while helper T cells activate other immune responses. So, with fewer killer T cells around, helper T cells continue transporting the virus into the brain unhindered.
To validate our hypothesis, we isolated immune cells from the brain to check for viral presence and assess their communication. We also examined these factors in the hippocampus, a region integral to memory and cognitive functions.
Both methods produced similar findings. First, we noted an increase in viral levels in helper T cells following treatment. Second, the interaction capabilities of killer T cells with key immune cells in the brain were hindered, contributing to perpetual inflammation.
Lastly, we investigated mice genetically modified to lack the alpha-4 integrin. It turned out helper T cells that carry HIV do not rely on this integrin to access the brain, but activated killer T cells do.
Enhancing Killer T Cell Function
Addressing systemic inflammation alongside antiviral treatments might lessen the impact of HIV on the brain. Our findings indicate that treatments r targeting immune cells with more precision could be more effective in alleviating neurodegeneration, rather than exacerbating it.
HIV remains one of the top three deadliest infectious diseases around the globe. In fact, over 40 million individuals worldwide were living with HIV in 2024, with more than 22% lacking access to treatment. The funding cuts for global HIV programs during the Trump administration are predicted to lead to increased rates of infections and fatalities.
Greater support for research into how to better utilize and adapt the immune system in combatting HIV and other infectious diseases could significantly improve outcomes for millions.
