Researchers from the University of Pittsburgh Schools of Public Health and Medicine have developed advanced cellular models that closely mimic the structure and function of the human brain, providing a powerful new platform to study how human immunodeficiency virus (HIV) and other neurotropic viruses damage the brain and spinal cord.
For more than a decade, miniature, three-dimensional structures known as brain organoids grown from human induced pluripotent stem cells (hiPSCs) have accelerated scientific understanding of brain development and neurodegenerative disease. Reporting in an open-access journal from the publishers of Nature, Velpandi Ayyavoo, PhD, and colleagues highlight how these next-generation organoid models can be used to study viral effects on the central nervous system and test potential therapeutic interventions.
“This model brings us much closer to replicating the human brain environment in the lab,” says Ayyavoo, senior author of the Scientific Reports manuscript and professor and vice chair of education, Department of Infectious Diseases and Microbiology. “It allows us to directly study how HIV enters into the brain and why the virus can persist despite effective antiviral treatment.”
Ayyavoo and colleagues developed the model by culturing normal stem cells with cells engineered to overexpress ETS variant 2 (ETV2), a transcription factor that promotes the formation of endothelial cells—the cells that line blood vessels. “This model provides a unique opportunity to investigate how HIV-1 disrupts endothelial integrity within the central nervous system,” Ayyavoo says, explaining that the new vascularized organoids better exemplify the blood–brain barrier and neurovascular integrity.
The team incorporated HIV-1-infected cells into their brain organoids and confirmed infection and viral replication, assessing viral activity in the presence and absence of antiretroviral therapy (ART). Despite ART treatment, however, viral replication persisted in vascularized organoids, highlighting the difficulty eliminating HIV from the brain, says Ayyavoo.
In addition to Ayyavoo, study authors include Sathish Selvam, PhD; Roberta S. Dos Reis, PhD; Marc C.E. Wagner and Rishi Krishnakumar, all of the Department of Infectious Diseases and Microbiology; and Kamyar Keshavarz, PharmD; and Mo R. Ebrahimkani, MD, Department of Pathology, Pitt School of Medicine.
-Michele Dula Baum