How is the brain fighting HIV?
or technically,
Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV
[See Original Abstract on Pubmed]
Authors of the study: Analise L. Gruenewald, Yoelvis Garcia-Mesa, Alexander J Gill, Rolando Garza, Benjamin B. Gelman, Dennis L. Kolson
You might be familiar with Human Immunodeficiency Virus (HIV), but did you know that approximately half of those living with HIV also experience impairments in cognition?1
HIV is a virus capable of invading our cells, specifically those that play vital roles in our immune system. The immune system is the body’s security force, fighting off invaders and preventing you from getting sick. If HIV is not treated, it will progress into Acquired Immunodeficiency Syndrome (AIDS), in which the immune system is severely weakened and patients become highly vulnerable to complications from other illnesses. While untreated HIV/AIDS is fatal, there have been amazing scientific developments in antiretroviral therapies, which substantially prevent the progression of HIV into AIDS. This therapy prevents the virus from making lots of copies of itself inside cells so that the immune system does not get overwhelmed and can still do its job.2
Despite these advancements, there is still much more progress that needs to be made to improve HIV treatment. At the end of 2019, there were roughly 38 million people suffering from HIV/AIDS around the world, and over half a million people died from illnesses related to AIDS. While therapies such as antiretroviral therapy can be successful, a third of people living with HIV still do not have access to these life-saving treatments.3
But how does HIV impact your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.? Besides weakening the immune system, HIV can also impact cognition (the way our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. thinks and functions). About half of people with HIV also suffer from HIV-associated neurocognitive disorder (HAND). HAND can impair memory, attention, and decision making. How much a person’s cognition is impaired can vary widely, with mild effects in some cases but detrimental effects to a person’s life in others, such as being unable to learn new things or remember important dates and appointments. Why some with HIV develop HAND, and others do not, is still not well understood, but discoveries made by scientists are starting to shed some light on this question.
Dr. Analise Gruenewald is a recent graduate of the Neuroscience Graduate Group at the University of Pennsylvania and member of the Kolson Lab who is intent on building science’s understanding of why HAND develops in only a subset of people living with HIV. Previous work in the Kolson Lab has suggested that a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. called heme-oxygenase 1 (HO-1) might be key. HO-1 helps the body handle both oxidative stressdamage done to the body due to a build-up of unstable oxygen-containing molecules and inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system, which are both responses of the body to HIV that are thought to contribute to some of its harmful effects. Those with HAND have been shown to have a lower amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in a specific brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region called the prefrontal cortex.4 The prefrontal cortex is a part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that is important for decision making, which is disrupted in HAND. Analise built upon these findings to understand how HO-1 might be important in the development of HAND in HIV patients. Specifically, Analise sought to determine how much HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. is in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue of patients and how this relates to signs of inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.
Analise examined the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue of those who had HIV (but specifically did not have HAND) compared to those who did not have HIV. By examining the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of those who had HIV but not HAND, she aimed to identify a particular factor that may function to prevent or protect against it. She first observed that the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of those with HIV but not HAND was higher than the amount in those without HIV. This exciting finding supports the hypothesis that HO-1 is an important factor in how our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. defend against HIV, suggesting high levels of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. provide protection against the development of HIV-related HAND. Further understanding of HO-1’s role in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s defense against HAND could enable the development of preventative treatments. Encouraged, Analise decided to explore the connection between HO-1 and HIV-related brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.
But how does HIV impact your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.? Besides weakening the immune system, HIV can also impact cognition (the way our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. thinks and functions). About half of people with HIV also suffer from HIV-associated neurocognitive disorder (HAND). HAND can impair memory, attention, and decision making. How much a person’s cognition is impaired can vary widely, with mild effects in some cases but detrimental effects to a person’s life in others, such as being unable to learn new things or remember important dates and appointments. Why some with HIV develop HAND, and others do not, is still not well understood, but discoveries made by scientists are starting to shed some light on this question.
Dr. Analise Gruenewald is a recent graduate of the Neuroscience Graduate Group at the University of Pennsylvania and member of the Kolson Lab who is intent on building science’s understanding of why HAND develops in only a subset of people living with HIV. Previous work in the Kolson Lab has suggested that a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. called heme-oxygenase 1 (HO-1) might be key. HO-1 helps the body handle both oxidative stressdamage done to the body due to a build-up of unstable oxygen-containing molecules and inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system, which are both responses of the body to HIV that are thought to contribute to some of its harmful effects. Those with HAND have been shown to have a lower amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in a specific brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region called the prefrontal cortex.4 The prefrontal cortex is a part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that is important for decision making, which is disrupted in HAND. Analise built upon these findings to understand how HO-1 might be important in the development of HAND in HIV patients. Specifically, Analise sought to determine how much HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. is in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue of patients and how this relates to signs of inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.
Analise examined the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue of those who had HIV (but specifically did not have HAND) compared to those who did not have HIV. By examining the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of those who had HIV but not HAND, she aimed to identify a particular factor that may function to prevent or protect against it. She first observed that the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of those with HIV but not HAND was higher than the amount in those without HIV. This exciting finding supports the hypothesis that HO-1 is an important factor in how our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. defend against HIV, suggesting high levels of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. provide protection against the development of HIV-related HAND. Further understanding of HO-1’s role in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s defense against HAND could enable the development of preventative treatments. Encouraged, Analise decided to explore the connection between HO-1 and HIV-related brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.
Figure 1: Potential mechanism by which HO-1 prevents development of HAND.
HIV leads to inflammation (which involves immune cell activation), and whether or not the individual then develops HAND might depend on the level of HO-1 protein they have. (A) If an individual has a high level of HO-1 protein this might enable them to maintain normal cognition. (B) An individual with a low level of HO-1 protein might not be able to properly respond to the inflammation, and will develop HAND. Image created with BioRender.com
To explore this idea further, Analise investigated how the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. correlated with the presence of inflammatory signals. If HO-1 prevents HAND by mediating the body’s response to infection, one might expect these two to be connected. She chose to measure the levels of various proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. involved in inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system – so if the levels of these proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. are higher, that would indicate that there is more inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system present. She found that if the levels of these inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system-related proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. were higher in a given individual, the amount of HO-1 also tended to be higher. These findings provided even stronger support for Analise’s hypothesis that HO-1 might be important in preventing HAND via compensating for the body’s inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.
To recap how this might work: HIV causes an inflammatory response in infected patients. HO-1 is a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. that is important for ensuring the body can be healthy even during this inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system. Higher HO-1 levels should be protective and allow a person to successfully handle high levels of inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system without a lot of serious negative effects (such as on cognition). In those without HAND, this appears to hold true: if the patient has high inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system, they also have high levels of HO-1.
Analise’s work provides a fascinating insight into a poorly understood yet critical topic: why some people with HIV develop HAND, but others don’t. There is still more work to be done to fully confirm her initial findings; however, her work presents a strong foundation for future research. Her findings indicate that HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. might be critical in preventing the development of HAND. Not only is this work thrilling in terms of simply furthering scientific understanding of HAND, but it also has promising therapeutic potential. If HO-1 is important for preventing HAND, this opens up the exciting possibility that a treatment that increases the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in those with HIV could prevent HAND. Analise’s work is a wonderful step toward significantly improving the lives of millions of people affected by HIV around the world.
To recap how this might work: HIV causes an inflammatory response in infected patients. HO-1 is a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. that is important for ensuring the body can be healthy even during this inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system. Higher HO-1 levels should be protective and allow a person to successfully handle high levels of inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system without a lot of serious negative effects (such as on cognition). In those without HAND, this appears to hold true: if the patient has high inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system, they also have high levels of HO-1.
Analise’s work provides a fascinating insight into a poorly understood yet critical topic: why some people with HIV develop HAND, but others don’t. There is still more work to be done to fully confirm her initial findings; however, her work presents a strong foundation for future research. Her findings indicate that HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. might be critical in preventing the development of HAND. Not only is this work thrilling in terms of simply furthering scientific understanding of HAND, but it also has promising therapeutic potential. If HO-1 is important for preventing HAND, this opens up the exciting possibility that a treatment that increases the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in those with HIV could prevent HAND. Analise’s work is a wonderful step toward significantly improving the lives of millions of people affected by HIV around the world.
Citations:
Saylor, D., Dickens, A. M., Sacktor, N., Haughey, N., Slusher, B., Pletnikov, M., Mankowski, J. L., Brown, A., Volsky, D. J., & McArthur, J. C. (2016). HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nature reviews. Neurology, 12(4), 234–248. https://doi.org/10.1038/nrneurol.2016.27
Deeks, S., Overbaugh, J., Phillips, A. & Buchbinder, S. (2015). HIV infection. Nat Rev Dis Primers, 1, 15035. https://doi.org/10.1038/nrdp.2015.35
The Global HIV/AIDS Epidemic. (2020, November 25). HIV.gov. Retrieved January 2, 2021, from https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics
Gill, A. J., Kovacsics, C. E., Cross, S. A., Vance, P. J., Kolson, L. L., Jordan-Sciutto, K. L., Gelman, B. B., & Kolson, D. L. (2014). Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders. The Journal of clinical investigation, 124(10), 4459–4472. https://doi.org/10.1172/JCI72279
About the brief writer: Katie Copley
Katie is a PhD student in Dr. Jim Shorter’s lab.