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T Cells Help HIV Enter and Persist in the Brain

HIV wreaks havoc on health by weakening the immune system. Over time, this damage leaves the body more vulnerable to infection, and even mild illnesses can be life-threatening. A specific type of immune cell, called a T cell, is critical to the body’s ability to fight off infection. Extensive research has been carried out on the role of T cells in targeting HIV, but the relationship between these cells and HIV infection in the brain has been understudied. New research supported by the National Institute of Mental Health sheds light on a unique population of T cells, known as CD4dimCD8bright T cells, that play a role in how HIV enters the brain.

CD4dimCD8bright T cells form when CD8 T cells, which recognize and destroy bacteria and viruses, are activated to express low levels of CD4 T cells, which help initiate an immune response by stimulating other immune cells, on their surface. Like CD8 T cells, CD4dimCD8bright T cells provide a potent immune defense against viral infections by destroying invading cells. Due to their hybrid nature, CD4dimCD8bright T cells also play unique roles in HIV: They can be infected by the virus and act as a source of HIV, yet they show strong anti-HIV responses and are elevated in the blood of long-term nonprogressors—people with HIV who naturally control the virus for long periods without medication.

In a study led by Lena Al-Harthi, Ph.D., at Rush University Medical Center, researchers characterized properties of CD4dimCD8bright T cells in the brain and their role in mediating HIV infection. To do so, they used immunodeficient mice that were injected with human T cells and then either infected with HIV in the blood or left uninfected. The researchers collected T cells from the animals’ brains and spleens and analyzed them using various assay methods to determine the amount of CD4dimCD8bright T cells and how the cells were affected by HIV infection.

Starting with a mouse model is critical to studying human viral infection. These models help advance knowledge of infections like HIV by answering complex questions that are challenging to study in humans. Despite not directly replicating the human immune system, the model includes its fundamental properties, allowing researchers to learn how CD4dimCD8bright T cells may act in humans.

This study revealed several novel findings about CD4dimCD8bright T cells. Notably, the T cells were found in both the brain and spleen of the mice. In the brain, CD4dimCD8bright T cells supported HIV replication. They served as a source of the virus, as evidenced by the integration of HIV into host DNA and the production of infectious viral particles.

Consistent with this, CD4dimCD8bright T cells in the brain expressed the brain-homing receptors, CX3CR1 and CXCR3. These receptors are critical to T cell migration into the brain. In contrast, blocking the movement of T cells into the brain led to a dramatic decrease in the number of CD4dimCD8bright T cells while also reducing the HIV burden there.

Together, the findings indicate that CD4dimCD8bright T cells contribute to part of the challenge in treating HIV. For the first time, the researchers showed that CD4dimCD8bright T cells mediate HIV neuroinvasion, referring to the virus’ entry from the blood into the brain, and act as a latent reservoir for the virus. CD4dimCD8bright T cells as a latent HIV reservoir means that the virus can infect these cells and then remain there in a persistent resting state, at any time becoming active and making more virus.

On the other hand, because they are primarily CD8 cells, CD4dimCD8bright T cells can go after HIV-infected cells and then remember those cells to fight off future infection. CD4dimCD8bright T cells in the brain of HIV-infected mice were also central memory T cells, a type of T cell that protects against organisms that cause disease and triggers a stronger immune response to their reinvasion. Thus, CD4dimCD8bright T cells exert dual actions: mediating HIV entry into the brain and serving as a source of HIV persistence, while also helping control HIV replication and fighting off infection.

This study’s focus on the brain is notable because the brain is a key target of HIV, especially early in infection. Even on medication, people with HIV often experience neurological or cognitive impairments. CD4dimCD8bright T cells in the brain may be a pathway that leads to these impairments. The brain is also an ideal reservoir for HIV because the blood-brain barrier prevents easy access to drugs that treat the virus and control its replication.

This study takes an important step forward in advancing knowledge of these unique T cells and their role in HIV infection. Continuing to characterize CD4dimCD8bright T cells and how they enter the brain and contribute to HIV persistence will help us move toward strategies to better treat HIV, which could include maintaining it in a latent state or removing it altogether.

Reference

Albalawi, Y. A., Narasipura, S. D., Olivares, L. J., & Al-Harthi, L. (2022). CD4dim CD8bright T cells home to the brain and mediate HIV neuroinvasion. Journal of Virology, 96(15), Article e00804-22. https://www.doi.org/10.1128/jvi.00804-22

Grant

MH113425