Why HIV patients develop dementia: Researchers track harmful immune reactions in the brain

September 3, 2014

Since the introduction of the combination anti-retroviral therapy (cART) in the mid-90s, the life expectancy of HIV patients has significantly improved. As a result, long-term complications are becoming more relevant: almost every second HIV patient is affected by neurocognitive disorders, which can lead to dementia. It has not as yet been fully understood how these disorders occur. Researchers from Bochum have now successfully identified mechanisms how infected cells can activate brain-specific immune cells which subsequently display harmful behaviour and lead to the destruction of neurons. These findings may help develop biomarkers to identify risk patients and to make a therapeutic strategy possible in the long term. The study was published in the trade journal Experimental Neurology.

"HIV-associated neurocognitive disorders" (HAND) include disorders of the cognitive functions, motor capacities as well as behavioural changes. How exactly HAND occur has not, as yet, been fully understood. "Scientists assume that HIV is harmful to directly and that is also triggers indirect mechanisms that lead to nerve cell damage," explains Dr Simon Faissner (RUB clinic for neurology, St. Josef-Hospital). The researchers strongly suspect that, once activated in the brain and the spinal cord, immune cells keep up a chronic inflammation level which then results in the destruction of . An immune activation in peripheral tissue as well as therapeutic consequences may likewise contribute to nerve cell damage in the brain.

First steps of HIV infection are sufficient

The HI virus overcomes the blood-brain barrier hitchhiking on infected immune cells, the monocytes and probably the T cells. The researchers from Bochum tested the hypothesis that HIV-infected monocytes activate specific in the brain, the so-called microglial cells. These cells, in turn, respond by releasing harmful substances, such as reactive oxygen metabolites and inflammatory signalling molecules, i.e. cytokines. To test this hypothesis, the researchers developed a cell culture system in which they initially examined the effect of HIV-infected monocytes on microglial cells. The researchers simulated the individual steps of HIV infection and measured the volume of the cytokines released at each stage. Thus, they were able to demonstrate that releasing the viral RNA in the monocytes was a sufficient trigger for maximal microglial activation. Subsequent infection phases – reverse transcription into DNA and the resulting formation of HIV proteins – did not augment activation any further.

Released substances result in neuronal cell death

In the second step, they analysed nerve cells from rat brains to determine if the substances released by the microglial cells could lead to cell death. Compared with the control group, the number of cell deaths was indeed twice as high. Studies of liquor cerebrospinalis received from HIV-infected patients have shown a positive correlation with marker of neuronal degeneration in patients who did not as yet present any neurocognitive disorders.

Detailed understanding necessary for therapeutic strategies

"Thanks to our research, we have gained a better understanding of the mechanisms of HIV-associated neurodegeneration," concludes Prof Dr Andrew Chan. "These results are likely to contribute to HAND biomarkers becoming established. In the long term, these data will be used to develop therapeutic strategies aiming at retarding HAND progression in HIV-infected patients." Starting points may include activation of – a method that is applied in other autoimmune diseases of the central nervous system, for example in multiple sclerosis.

Start-up through FoRUM funds

The research, which was initiated following a collaboration between clinics for neurology and dermatology, St. Josef Hospital, as well as the Department for Molecular and Medical Virology, has been made possible through start-up funding provided by the Faculty of Medicine at Ruhr-Universität (FoRUM). The collaboration has evolved into an international consortium of clinics and basic research organisations in Bochum, Langen, Strasbourg and Mailand. One objective of the follow-up study, for which an application for EU funds is pending, is going to be an in-depth analysis of inflammatory processes in the central nervous system. The researchers will attempt to inhibit inflammatory processes with different drugs. They are, moreover, planning to study direct cell-cell interaction by means of state-of-the-art microscopy, in collaboration with the University of Strasbourg.

Explore further: Scientists uncover features of antibody-producing cells in people infected with HIV

More information: Faissner, S. et al.: "Cytoplasmic HIV-RNA in monocytes determines microglial activation and neuronal cell death in HIV-associated neurodegeneration." In: Exp Neurol. 2014 Aug 19. pii: S0014-4886(14)00263-5. DOI: 10.1016/j.expneurol.2014.08.011. [Epub ahead of print],
Link to the article: www.ncbi.nlm.nih.gov/pubmed/25150097

Related Stories

Scientists uncover features of antibody-producing cells in people infected with HIV

June 3, 2014
By analyzing the blood of almost 100 treated and untreated HIV-infected volunteers, a team of scientists has identified previously unknown characteristics of B cells in the context of HIV infection. B cells are the immune ...

Why the immune system fails to kill HIV

July 18, 2014
Our immune system contains CD8+ T cells which protect us from various diseases such as cancer and viruses. Some of them are specifically tasked with killing cells infected with the HIV virus – and researchers from Karolinska ...

HIV antibodies block infection by reservoir-derived virus in laboratory study

August 26, 2014
A laboratory study led by scientists from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), lends further weight to the potential effectiveness of passive immunotherapy ...

Scientists discover how HIV kills immune cells

June 5, 2013
Untreated HIV infection destroys a person's immune system by killing infection-fighting cells, but precisely when and how HIV wreaks this destruction has been a mystery until now. New research by scientists at the National ...

Hemophilia and long-term HIV infection—is there a protective link?

December 11, 2013
People with the genetic blood clotting disorder hemophilia who have been infected with HIV for decades have an increased proportion of immune cells in their blood that specifically target HIV. This protective immune response ...

Researchers find HIV protein may impact neurocognitive impairment in infected patients

November 15, 2013
A protein shed by HIV-infected brain cells alters synaptic connections between networks of nerve cells, according to new research out of the University of Minnesota. The findings could explain why nearly half of all patients ...

Recommended for you

Investigating patterns of degeneration in Alzheimer's disease

November 17, 2017
Alzheimer's disease (AD) is known to cause memory loss and cognitive decline, but other functions of the brain can remain intact. The reasons cells in some brain regions degenerate while others are protected is largely unknown. ...

Study may point to new treatment approach for ASD

November 17, 2017
Using sophisticated genome mining and gene manipulation techniques, researchers at Vanderbilt University Medical Center (VUMC) have solved a mystery that could lead to a new treatment approach for autism spectrum disorder ...

Paraplegic rats walk and regain feeling after stem cell treatment

November 16, 2017
Engineered tissue containing human stem cells has allowed paraplegic rats to walk independently and regain sensory perception. The implanted rats also show some degree of healing in their spinal cords. The research, published ...

Brain implant tested in human patients found to improve memory recall

November 15, 2017
(Medical Xpress)—A team of researchers with the University of Southern California and the Wake Forest School of Medicine has conducted experiments involving implanting electrodes into the brains of human volunteers to see ...

Researchers identify potential mediator for social memory formation

November 15, 2017
Research by a group of scientists at the Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) have discovered that a tiny brain region plays a critical role in the formation ...

Improving clinical trials with machine learning

November 15, 2017
Machine learning could improve our ability to determine whether a new drug works in the brain, potentially enabling researchers to detect drug effects that would be missed entirely by conventional statistical tests, finds ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.