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

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. The image is in the public domain.

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.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source:
University of Pennsylvania
Media Contacts:
Katherine Unger Baillie – University of Pennsylvania
Image Source:
The image is in the public domain.

Original Research: Open access
“Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection”. Sean Ryan at al.
Stem Cell Reports doi:10.1016/j.stemcr.2020.02.010.

Abstract

Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection

Highlights
• Describes a tri-culture of hiPSC-derived microglia, astrocytes, and neurons
• HIV infection leads to increased EIF2 signaling in all three cell types
• Efavirenz treatment alone creates an inflammatory signature by RNA expression
• Infected iMicroglia increased inflammation response and reduced synaptophagocytosis

Summary
HIV-associated neurocognitive disorders (HAND) affect over half of HIV-infected individuals, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive, partly due to a lack of a representative model. We developed a human-induced pluripotent stem cell (hiPSC)-based model, independently differentiating hiPSCs into neurons, astrocytes, and microglia, and systematically combining to generate a tri-culture with or without HIV infection and ART. Single-cell RNA sequencing analysis on tri-cultures with HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Treatment with the antiretroviral compound efavirenz (EFZ) mostly resolved these signatures. However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in transforming growth factor α production by microglia. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of infection, its treatment, and other co-morbid conditions.