Monday, September 30, 2013

HIV and Neurocognitive Dysfunction

            HIV, human immunodeficiency virus, infection is one of the largest public health problems we face today. The WHO estimates that currently over 35 million people worldwide are infected with HIV. HIV primarily infects and kills helper T cells, cells that have the critical role of activating and supporting other cells of the immune system, thus impairing the immune response on a broad level. It is well known for causing AIDS, the acquired immunodeficiency syndrome, which severely weakens the body’s immune response and leaves it open to attack by foreign antigens. However, less widely known, HIV also causes neurocognitive impairment and encephalitis (swelling of the brain), estimated by Heaton et al to affect one third of individuals infected with HIV. This facet of HIV infection, which affects a whopping 10 million people worldwide, is an important concern and is now receiving more attention.
            Recently, the Section of Infectious Diseases of the Nervous System at NIH, led by Dr. Avindra Nath, and their colleagues at Johns Hopkins School of Medicine have discovered possible mechanisms for HIV-mediated neurocognitive impairment. In a recent paper in the Journal of Neurovirology, these researchers looked at the impairment of adult neurogenesis and neurite outgrowth in the hippocampus using a HIV mouse model. They believe that the growth patterns of neurons in this part of the brain, which deals with processes such as memory consolidation, may be disrupted during HIV infection and underlie the cognitive dysfunction seen in HIV infected patients. While previous research had found that HIV infects glial cells and not neurons, it was shown that HIV infection lead to synaptic pruning and apoptosis (Ellis et al 2007).

            The investigators used a transgenic mouse model that expressed the HIV envelope glycoprotein gp120 under the control of the GFAP promoter (glial fibrillary acidic protein, a protein expressed by glial cells in the brain). HIV gp120 is part of the HIV viral envelope “spike,” a device used to bind host cell receptors and enter the cell. Briefly, the spike consists of three gp120 units bound to three gp41 units; gp120 binds to the CD4 co-receptor on a helper T cell, allowing the HIV envelope glycoprotein gp41 to contact the host cell membrane and promote viral fusion. Thus, the investigators used this mouse model to simulate HIV infection, during which gp120 would be circulating in the body.
            These investigators first looked at the proliferation of neural progenitor cells (NPCs) in the hippocampus that give rise to neurons (and other neural cell types) using an assay where only newly divided cells incorporate a modified nucleotide, BrdU, into their DNA during DNA synthesis. They found that the HIV gp120 mice showed significantly fewer proliferating NPCs compared to control mice. They also found decreased neurogenesis in the transgenic mice. This means that not only are NPCs proliferating less during HIV infection, fewer NPCs are differentiating into neurons. On the other hand, the authors of this article found more elaborate dendritic trees and longer dendritic length in the transgenic mice; dendrites are the processes that extend from neurons and link onto other neurons. You might ask why increased dendritic growth and complexity is bad, since dendrites mediate neuronal activity; however, we must keep in mind that the brain is very sensitive to changes, and a balance must be established. Thus, more dendrites may overcrowd brain regions and may even interfere with normal neuronal communication . Along with structural differences, the authors saw decreased BDNF levels in the whole brain and hippocampus of the transgenic animals and increased Cdk5 kinase activity; BDNF promotes neuronal survival and growth and Cdk5, along with other proteins, promotes neuronal maturation and stabilization. Thus, the authors showed that during HIV infection, neuronal structures changed, possibly caused by the negative impact on the proteins that regulate neural. These findings are backed by the finding of others, who have seen similar changes in neural structure or protein (such as Cdk5) in both mouse models of HIV and in HIV-infected patients.

            However, these investigators also found a silver lining, a possible treatment for these aberrant processes that occur in the brain during HIV infection. They decided to put their transgenic and control mice on exercise regimens, which have been shown to improve cognitive function in other diseases and promote general health. After a 20 day running regimen, NPC proliferation, neurogenesis, and neuronal survival increased in both the transgenic and control animals. Similarly, this exercise regimen increased BDNF levels and normalized Cdk5 activity to that of control mice in the HIV gp120 mice. Lastly, this exercise regimen was able to normalize dendritic development in the transgenic mice to levels comparable to control mice. Surprisingly, a 10 day running-10 day resting exercise regimen only showed positive effects during the running phase, which was promptly abolished after the mice stopped exercising.
            The findings these investigators present have elucidated some of the possible mechanisms and effects of HIV infection of the brain that may lead to cognitive dyfunction seen in over 10 million HIV infected individuals. The authors showed that HIV infection alters brain chemistry and cellular activity, which may lead to the altered brain structuring seen in HIV mouse models and patients. However, they also propose a significant solution that may ameliorate some of these negative neural effects: exercise. The benefits of exercise regimens as a treatment for HIV cognitive decline are very evident. Exercise is a natural process that is cost-effective to implement and can be performed throughout a patient’s lifetime; as a natural process, exercise is less likely to interfere with brain chemistry as pharmacological agents and promotes brain health in a more controlled manner, not to mention its beneficial effects for general health. However, the downside of this treatment for HIV infected individuals is simply their impaired health and their ability to exercise. For patients who have progressed to AIDS and are constantly assaulted by foreign invaders (viruses, bacteria, etc.), patient health may not allow strict exercise regimens. Even those who have not converted fully to AIDS, many hard-to-control factors such as location, willpower, occupation, and free time limit the implementation of exercise regimens. While the exact mechanisms behind HIV induction of neural chemical and structural dysfunction need further elucidation, and future studies are needed to confirm the effects of exercise found by these investigators, we may now have another, more natural way to combat the neurocognitive dysfunction caused by HIV infection.

Main article:
Lee, M. H., Amin, N. D., Venkatesan, A., Wang, T., Tyagi, R., Pant, H. C., & Nath, A. (2013). Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is reversed by exercise via BDNF production and Cdk5 regulation. Journal of Neurovirology,

Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44
http://www.who.int/hiv/en/ (WHO general HIV/AIDS page)

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