A new way to study HIV's impact on the brain

March 27, 2020

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 these 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."

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.
-end-
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.

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.

University of Pennsylvania

Related HIV Articles from Brightsurf:

BEAT-HIV Delaney collaboratory issues recommendations measuring persistent HIV reservoirs
Spearheaded by Wistar scientists, top worldwide HIV researchers from the BEAT-HIV Martin Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Collaboratory) compiled the first comprehensive set of recommendations on how to best measure the size of persistent HIV reservoirs during cure-directed clinical studies.

The Lancet HIV: Study suggests a second patient has been cured of HIV
A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient's blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Children with HIV score below HIV-negative peers in cognitive, motor function tests
Children who acquired HIV in utero or during birth or breastfeeding did not perform as well as their peers who do not have HIV on tests measuring cognitive ability, motor function and attention, according to a report published online today in Clinical Infectious Diseases.

Efforts to end the HIV epidemic must not ignore people already living with HIV
Efforts to prevent new HIV transmissions in the US must be accompanied by addressing HIV-associated comorbidities to improve the health of people already living with HIV, NIH experts assert in the third of a series of JAMA commentaries.

The Lancet HIV: Severe anti-LGBT legislations associated with lower testing and awareness of HIV in African countries
This first systematic review to investigate HIV testing, treatment and viral suppression in men who have sex with men in Africa finds that among the most recent studies (conducted after 2011) only half of men have been tested for HIV in the past 12 months.

The Lancet HIV: Tenfold increase in number of adolescents on HIV treatment in South Africa since 2010, but many still untreated
A new study of more than 700,000 one to 19-year olds being treated for HIV infection suggests a ten-fold increase in the number of adolescents aged 15 to 19 receiving HIV treatment in South Africa, according to results published in The Lancet HIV journal.

Starting HIV treatment in ERs may be key to ending HIV spread worldwide
In a follow-up study conducted in South Africa, Johns Hopkins Medicine researchers say they have evidence that hospital emergency departments (EDs) worldwide may be key strategic settings for curbing the spread of HIV infections in hard-to-reach populations if the EDs jump-start treatment and case management as well as diagnosis of the disease.

NIH HIV experts prioritize research to achieve sustained ART-free HIV remission
Achieving sustained remission of HIV without life-long antiretroviral therapy (ART) is a top HIV research priority, according to a new commentary in JAMA by experts at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The Lancet HIV: PrEP implementation is associated with a rapid decline in new HIV infections
Study from Australia is the first to evaluate a population-level roll-out of pre-exposure prophylaxis (PrEP) in men who have sex with men.

Researchers date 'hibernating' HIV strains, advancing BC's leadership in HIV cure research
Researchers have developed a novel way for dating 'hibernating' HIV strains, in an advancement for HIV cure research.

Read More: HIV News and HIV Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.