Study reveals how HIV infection and some antiretrovirals affect cognition and the central nervous system

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Though many negative repercussions of human immunodeficiency virus infection can be mitigated with the use of antiretroviral therapy (ART), one area where medical advances haven’t made as much progress is in the reduction of cognitive impacts.

Half of HIV patients have HIV-associated neurocognitive disorders (HAND), which can manifest in a variety of ways, from forgetfulness and confusion to behavior changes and motor deficiencies.

To better understand the mechanisms underlying HAND, researchers from Penn’s School of Dental Medicine and Perelman School of Medicine and from the Children’s Hospital of Philadelphia (CHOP) brought together their complementary expertise to create a laboratory model system using three of the types of brain cells thought to be involved.

Led by doctoral student Sean Ryan, who was co-mentored by Kelly Jordan-Sciutto of Penn Dental Medicine and Stewart Anderson of CHOP and Penn Medicine, the model recapitulates important features of how HIV infection and ART affect the brain.

“Frankly the models we generally use in the HIV field have a lot of weaknesses,” says Jordan-Sciutto, co-corresponding author on the paper, which appears in the journal Stem Cell Reports.

“The power of this system is it allows us to look at the interaction between different cell types of human origin in a way that is more relevant to patients than other models.”

In addition to studying HIV, members of the team plan to use the same model to shed light on the neurological mechanisms that underlie other conditions, such as schizophrenia, Alzheimer’s, and even normal aging.

“We’re collaborating with a variety of colleagues to use this system to study Alzheimer’s disease as well as schizophrenia,” says Anderson, co-corresponding author on the paper.

“We have the components in a dish that we know are interacting in these diseases, and this gives us a new mix-and-match way to understand how certain cells are contributing to neuronal damage.”

Indeed, the impetus to create the model grew not out of HIV research but work that Ryan was pursuing in Anderson’s lab on schizophrenia.

“We had been looking at the role of microglia, the resident immune cells of the central nervous system,” says Ryan, first author on the work.

“We wanted to see if we could see the mechanistic changes that occur with microglia in schizophrenia.”

To do so, Ryan and Anderson were interested in using human-induced pluripotent stem cells–adult cells that are reprogrammed to resemble embryonic stem cells–which can be coaxed into differentiating into a variety of different cell types.

But schizophrenia is a complicated disease with a variety of contributing genetic and environmental factors and a broad spectrum of presentations.

Rather than looking at something complex, they sought to apply their new system to a disease that likewise causes neurological damage but does so in a more dramatic way and in which microglia are also implicated: HIV/AIDS infection.

They reached out to Jordan-Sciutto, who has deep experience investigating the mechanisms of HAND and was eager for the opportunity to develop a model superior to those currently available.

Together, the scientists identified the three cell types they were most interested in studying: neurons, astrocytes, and microglia.

Neurons aren’t directly infected by HIV but are known to be damaged during infection. Meanwhile astrocytes are believed to interact with neurons, causing damage by sending pro-inflammatory factors into the spaces between cells, called synapses.

And microglia, which are responsible for maintaining a healthy environment in the absence of disease, are seen to expand and contribute to inflammation during HIV infection.

After nailing the technical challenge of creating this tractable model in which each cell type is generated independently and then mixed together, the team used it to probe how HIV infection and ART impact the cells, both alone and in combination.

“A lot of people are taking PreEP [pre-exposure prophylaxis] if they’re in a situation where their risk of contracting HIV is heightened,” says Ryan. “Just as we want to understand the cognitive impacts of HIV, we also want to see whether thes

e drugs alone are impacting the brain health of otherwise healthy people.”

The researchers looked at RNA expression in their cultures to get a sense of what proteins and signaling pathways were becoming activated in each scenario.

During infection, they saw inflammatory pathways that had previously been implicated in HIV in earlier research.

When they introduced the antiretroviral drug EFZ, which is not in common use in the United States but remains a frontline therapy in many other areas of the world, with an infection, the activity of most of these pathways was reduced.

“But this scenario involved its own unique response,” says Ryan. Certain pathways associated with inflammation and damage remained despite the introduction of EFZ.

“EFZ treatment of the tri-cultures that included HIV-infected microglia reduces inflammation by around 70%,” Ryan says. Interestingly, EFZ by itself also triggered inflammation, though to a lesser extent than infection.

“It seems a combination of infection and ART is creating its own unique response that is different from the sum of its parts,” Ryan says.

“Knowing what pathways are still active due to ART could help us appropriately target additional therapies so patients don’t develop HAND.”

In addition to studying HIV, members of the team plan to use the same model to shed light on the neurological mechanisms that underlie other conditions, such as schizophrenia, Alzheimer’s, and even normal aging.

Many features of infection seen in the three-cell culture mirror what is known from HIV infection and ART treatment in people, giving the researchers confidence in the reliability of their model.

“Just looking at the microglia,” says Anderson, “we see in our system that they are taking on both of their normal roles in keeping key signaling systems balanced during their normal state and activating and causing damage when they’re fighting infection.

We’re able to model normality and abnormality in a way we haven’t been able to before.”

For Jordan-Sciutto, the new system “is really going to change the way my lab operates going into the future.”

She’s hopeful many other HIV scientists will take it up to further their studies as she also explores more aspects of HIV’s impact on the brain, such as how it navigates through the blood-brain barrier that normally protects the central nervous system from inflammation and infection.

The study authors give credit to the collaborative environment at Penn for this cross-disciplinary project.

“Tentacles of this project extend from CHOP to the dental school to the vet school to the medical school,” says Anderson.

“Penn is a very special place where people seem to be more likely to share their technologies around and let other people work with and develop them. This project is a great example of that.”

Kelly L. Jordan-Sciutto is vice chair and professor in the Department of Basic and Translational Sciences in Penn’s School of Dental Medicine, associate dean of graduate education, and director of biomedical graduate studies at the Perelman School of Medicine.

Stewart A. Anderson is director of research in the Department of Child and Adolescent Psychiatry and Behavioral Services at the Children’s Hospital of Philadelphia and a professor of psychiatry at the Perelman School of Medicine.

Sean K. Ryan was a graduate student in Penn’s Cell and Molecular Biology Graduate Group in the Genomics and Epigenetics program, co-mentored by Jordan-Sciutto and Anderson. He is now a postdoctoral researcher at the Perelman School of Medicine.

Jordan-Sciutto, Anderson, and Ryan’s coauthors on the study were CHOP’s Michael V. Gonzalez, James P. Garifallou, Nathaniel P. Sotuyo, Kieona Cook, and Hakon Hakonarson; Penn Medicine’s Frederick C. Bennett and Eugene Mironets; and Spelman College’s Kimberly S. Williams.

Funding: The research was supported by the National Institute of Neurological Disorders and Stroke (Grant NS107594), Penn Center for AIDS Research, and Penn Mental Health AIDS Research Center.


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Human immunodeficiency virus (HIV) is widely recognized for its deleterious impact on the immune system. Fortunately, the introduction and implementation of combination antiretroviral therapy (CART) has transformed HIV infection into a manageable chronic disease instead of the death sentence it was when it emerged thirty-five years ago.

Although CART has been extremely successful in reducing viral replication in the periphery to undetectable levels in many people with HIV (PWH), HIV reservoirs still persist.

The central nervous system (CNS) is a target organ system of HIV and neuroinvasion occurs shortly after infection. A major consequence of persistent HIV infection in the CNS is the development of HIV-associated neurocognitive disorders (HAND), which is estimated to effect 30–60% of PWH (Heaton et al., 2011). HAND is a research diagnosis based on neuropsychological testing and a functional assessment of activities of daily living.

At minimum, a person with HIV is diagnosed with HAND when they show abnormal test performance (< 1 standard deviation (SD) below best available population norms) on at least 2 cognitive domains.

The most common domains impacted in the CART era include deficits in processing speed, executive function, and memory retrieval deficits [12]. However, there is considerable heterogeneity in the patterns of cognitive impairment demonstrated [3], which can be impacted by numerous factors including viral suppression and adherence to antiretroviral medication [2].

Classification of HAND comprises a range of cognitive impairments increasing in severity. Asymptomatic neurocognitive impairment (ANI) is defined as mild cognitive difficulties involving two cognitive domains that fall below 1 SD of population norms without overt functional impairment in daily life activities.

Similarly, mild neurocognitive disorders (MND) are marked by cognitive impairments in two cognitive domains that score below 1 SD of norms, yet mild to moderate interference in daily functioning is observed.

HIV-associated dementia (HAD), the most severe form of HAND, requires a score below 2 SD of population norms with significant functional impairments [45].

It is widely accepted that HIV enters the brain via infected macrophage/monocytes and lymphocytes that cross the blood brain barrier (BBB). Once inside the brain, infected monocytes/macrophages facilitate productive infection and release free virions into the brain parenchyma that infect neighboring microglia and to some degree, astrocytes.

This infection leads to the release of neurotoxic viral proteins and to the activation of resident glia. There is substantial evidence that this inflammatory response is a major driver for the development and progression of HAND.

Although neurons are not infected by HIV, the pathophysiology of HAND ultimately impacts neurons. Loss of synaptic complexity, neuronal damage and death are documented during HIV infection [68].

Much attention has been given to direct neurotoxicity associated with the release of viral proteins from infected cells and indirect neurotoxicity mediated by the inflammatory response mounted by both infected and uninfected non-neuronal cells.

However, recently it has become increasingly important to examine how neurotoxic factors and inflammation are associated with alterations in cellular metabolism in the context of neurodegenerative disorders.

The brain is a complex organ requiring a vast amount of energy to sustain its basic functions. At baseline, the brain consumes over 20% of the oxygen and 25% of the glucose taken in by the body, although it makes up only 2% of the body’s weight [911].

This is a 10-fold greater energy requirement than any other organ. Glucose is the primary energy substrate of the brain. The majority of glucose is used to transduce energy through glycolysis and mitochondrial oxidative phosphorylation to generate the large amounts of ATP required to maintain membrane potentials, facilitate synaptic transmission and other neural cell activities.

The brain undergoes a steady decline in energy metabolism during normal aging. Since the brain requires substantial amounts of energy, a shortage of metabolic supply can contribute to cognitive decline.

There is a body of evidence demonstrating that a loss of energy homeostasis may be an early event that primes the CNS for functional impairments. Chronic HIV infection is associated with metabolic disturbances in the brain, even in PWH on effective CART regimens [1215]. In this review, we aim to summarize the current understanding of how HIV infection contributes to energy disturbances involved in HAND pathology.

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Figure 1.
Proposed model of overall metabolic status of CNS during HIV infection. HIV enters the CNS likely in HIV-infected peripheral monocytes. Infected microglia undergo a proinflammatory response. Subsequently, HIV particles, viral proteins, and proinflammatory mediators released by microglia can activate other microglia and neighboring astrocytes thus creating a state of chronic inflammation. Maintenance of HIV-induced inflammation is metabolically expensive and thus, induces a metabolic switch in glia cells. As astrocytes and oligodendrocytes work to fulfill their own enhanced energy requirements, these cells are less able to provide metabolic support to neurons. Compromised glia support in combination with direct neurotoxicity of HIV challenges neuronal metabolism, which can lead to neuronal energy deficits, hinder neuronal fitness and present as neurocognitive impairments. (Abbreviations: OXPHOS- oxidative phosphorylation, ATP-adenosine triphosphate, MMP- mitochondrial membrane potential, LDH-lactate dehydrogenase, FAO-fatty acid oxidation, TCA-tricarboxylic acid, NAA- N-acetylaspartate, ROS-reactive oxygen species).

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Despite effective antiretroviral (ARV) therapy, people living with HIV continue to report memory and mental acuity problems and demonstrate impairment on standard measures of neuropsychological functioning.1,2

 For example, in the Women’s Interagency HIV Study (WIHS), HIV-infected (HIV+) women on effective ARVs show persistent vulnerabilities in global neuropsychological functioning as well as in verbal learning, memory, attention/working memory, and verbal fluency compared to HIV-uninfected (HIV−) women.3 

Moreover, issues in motor function become apparent over time among HIV+ women on ARVs versus HIV− women. Given the persistence of neurocognitive vulnerabilities despite combined antiretroviral therapy (cART) and their relationship to function4,5, identifying potential contributors to neurocognitive performance is an important clinical priority.

One factor that may influence some of the variability in neuropsychological test performance among HIV+ individuals is the effects of non-ARV medications with known neurocognitive adverse effects (NC-AE) including agents with anticholinergic properties, anxiolytics, antipsychotics, antiepileptics, and opiates.2,611 

The possible contribution of non-ARV medications to neurocognitive performance in HIV+ individuals is particularly important to consider since cART recipients are living longer and using multiple non-ARV medications with age.12,13

 On average, HIV+ individuals report using 7–14 non-ARV medications many of which are NC-AE medications.1416 

Importantly, concomitant medication use or “polypharmacy” is associated with lower performance on rapid screening tests for cognitive impairment in both HIV+17 and HIV− individuals.18

An important first step before investigating NC-AE medication associations with neuropsychological test performance is to:

1) characterize the patterns and prevalence of NC-AE medication use ;

2) determine socio-demographic, behavioral, and clinical predictors of NC-AE medication use; and

3) to determine whether NC-AE medication use predicts HIV-related treatment outcomes.

We addressed these aims within the WIHS and hypothesized that HIV-serostatus would predict NC-AE medication use and that NC-AE medication use would predict lower cART adherence and virologic suppression.

CONCLUSION

The use of NC-AE medications in women living with HIV is high and more common than in women without HIV infection. NC-AE medication use also appears to be associated with cART use and viral suppression in HIV+ women.

The causal direction of these associations remains unclear. Further research is needed to determine if NC-AE medication use exacerbates neurocognitive impairment or if discontinuation of NC-AE medications in cognitively impaired HIV+ individuals leads to improved function. Nonetheless, results from this work further the understanding of non-ARV medication use patterns among HIV+ women.

The benefits and harms of NC-AE medications are important clinical considerations for the treatment of comorbid conditions in HIV+ individuals.


Source:
University of Pennsylvania

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