The Double-Edged Sword of HIV Treatment

May 1, 2018

Written by: Carolyn Keating

 

When you hear the words human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), you probably think about how the virus attacks and damages the immune system, making it harder for patients to fight off infections.  But did you know that HIV also impacts the brain?

HIV in the brain can cause a variety of conditions collectively called HIV-associated neurocognitive disorders, or HAND. People with HAND can experience symptoms such as loss of attention and concentration, poor memory, slowed or uncoordinated movements, and personality changes. These symptoms can range in intensity from hardly noticeable with no impact on daily life to severely disruptive dementia. Fortunately, the prevalence of the most severe forms of HAND have decreased drastically since the introduction of antiretroviral therapies (ART) in the late 1980’s1. ART (sometimes written as combined ART, or cART), consists of a multiple drug treatment approach that targets different steps in the HIV replication process in order to prevent the virus from reproducing. Despite this advance, milder cognitive, behavioral, and motor deficits persist in 30-50% of patients2.

Although damage to and loss of neurons causes many of these symptoms, interestingly, HIV does not directly infect neurons.  Instead, immune cells outside of the brain become infected, then enter the brain and infect the brain’s local immune cells. These infected cells then release toxic factors that lead to the progressive loss of structure and function of neurons3.

Neurons aren’t the only thing in the brain harmed by HIV, however. Cells called oligodendrocytes are also damaged.  These support cells wrap a fatty white substance called myelin around the axons of neurons (Figure 1).

Myelination
Figure 1: Oligodendrocytes wrap around the axons of neurons, creating myelin that acts as insulation so that neurons can transmit electrical signals faster, resulting in better communication between cells. Image from Concepts of Biology-1st Canadian Edition, 16.1 Neurons and Glial Cells by Charles Molnar and Jane Gair.

This myelin sheath acts as insulation, enabling the neuron to better conduct electrical signals. People with HIV, however, have changes in myelin: the structure can be damaged, and the insulation wrapping around axons can be thinner or destroyed all together. As a result of these changes, some HIV-infected brains undergo degradation of a structure called the corpus callosum, which is a large, heavily myelinated group of axons that connects the left and right halves of the cerebral cortex and allows them to communicate with each other4.

And unfortunately, the virus isn’t the only thing leading to myelin damage. The same antiretroviral therapy (ART) drugs that have enabled people with HIV to live much longer lives (and decreased the most severe forms of HAND), also appear themselves to be disrupting myelin!  HIV patients taking ART have more damaged corpus callosums compared to patients not taking ART5.  Additionally, it appears that the longer people take these drugs, the less myelin they have6.

What could be causing these changes in myelin?  Research from right here at Penn has begun to shed some light on the problem.  When certain commonly prescribed ART drugs (Ritonavir and Lopinavir) were applied to mouse cells that would normally grow up to become oligodendrocytes, those cells instead remained immature and did not produce myelin. What’s more, when Ritonavir was given to adult mice, the animals were found to have decreased components of myelin in their cerebral cortices compared to mice not receiving the drug.  Similarly, when the researchers looked at cortex from humans, they found that people with HIV who had been taking ART also had decreased components of myelin compared to both healthy individuals and HIV patients who hadn’t taken these drugs7. These findings suggest that ART drugs themselves can damage myelin and the cells that produce it.

These recent findings about ART and myelin put us in a sticky situation. On the one hand, ART has enabled HIV patients to live long lives free from the most severe forms of HAND. On the other hand, ART seems to be damaging myelin and the cells that create it. Myelin is important for enabling neurons to communicate with each other effectively, and without it, neurological problems can develop. Since people with HIV take ART for the rest of their lives, it is necessary to consider how the drugs may be impacting their myelination. And possibly more concerning is the fate of children with HIV who begin taking ART at a very young age. Childhood is the period when the most myelination in the brain occurs, meaning children born with HIV could be even more impacted than adults (due to both living longer with infection and longer exposure to potentially damaging ART). In fact, there is evidence that children treated with ART experience developmental delay, behavioral issues, and low cognitive abilities8.

Since the very drugs designed to treat HIV also contribute to HAND, scientists hope to discover drugs with fewer side effects or find a therapy they can add to current treatments that will promote oligodendrocyte and myelin health. Due to scientific research and medical advancements, HIV/AIDS is no longer a death sentence, and hopefully in the future these patients will be able to lead completely normal lives free from HAND as well!

References:

  1. Sacktor, N. et al. HIV-associated neurologic disease incidence changes: Neurology 56, 257 LP-260 (2001).
  2. Heaton, R. K. et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J. Neurovirol. 17, 3–16 (2011).
  3. Kaul, M., Zheng, J., Okamoto, S., Gendelman, H. E. & Lipton, S. A. HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death Differ. 12 Suppl 1, 878–892 (2005).
  4. Muller-Oehring, E. M., Schulte, T., Rosenbloom, M. J., Pfefferbaum, A. & Sullivan, E. V. Callosal degradation in HIV-1 infection predicts hierarchical perception: a DTI study. Neuropsychologia 48, 1133–1143 (2010).
  5. Kelly, S. G. et al. Early suppressive antiretroviral therapy in HIV infection is associated with measurable changes in the corpus callosum. J. Neurovirol. 20, 514–520 (2014).
  6. Tate, D. F. et al. Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies. J. Neurovirol. 17, 368–379 (2011).
  7. Jensen, B. K. et al. Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders. J. Neuropathol. Exp. Neurol. 74, 1093–1118 (2015).
  8. Crowell, C. S., Malee, K. M., Yogev, R. & Muller, W. J. Neurologic disease in HIV‐infected children and the impact of combination antiretroviral therapy. Rev. Med. Virol. 24, 316–331

Images:

Figure 1: Concepts of Biology-1st Canadian Edition, 16.1 Neurons and Glial Cells by Charles Molnar and Jane Gair, (CC BY 4.0).

 

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