Researchers at Weill Cornell Medicine have made significant strides in understanding the cognitive impairments associated with HIV by reprogramming skin cells into neurons. Their findings, published in JCI Insight in March 2025, reveal genetic signatures linked to HIV infection that may help explain why some individuals living with the virus experience cognitive difficulties, even when the virus is effectively controlled.
The study involved skin cells, specifically fibroblasts, collected with informed consent from six individuals who are virologically suppressed due to HIV and seven age- and sex-matched individuals without the virus. By applying advanced cell-reprogramming techniques, researchers transformed these fibroblasts into neurons and discovered notable differences in gene activity between the two groups. The researchers identified that the neurons derived from people with HIV exhibited distinctive gene expression patterns, which were not only consistent with previous studies of post-mortem brain samples but also revealed new potential avenues for investigating the causes of HIV-related cognitive deficits.
Understanding HIV’s Impact on the Brain
The implications of these findings are substantial. According to Dr. Teresa H. Evering, the study’s senior author and an assistant professor in the Division of Infectious Diseases at Weill Cornell Medicine, “These findings give us a foundation for future studies of how certain genes and biological pathways may contribute to this form of cognitive impairment.”
HIV can infiltrate the central nervous system after infection, affecting various brain cells, including immune cells called microglia and supportive astrocytes. Remarkably, even when antiretroviral therapy suppresses HIV to undetectable levels in the bloodstream, the virus can persist within the brain. The chronic nature of this infection and the resultant inflammation can lead to various cognitive issues, including memory loss, difficulty concentrating, mood disorders, and slowed motor functions.
Globally, it is estimated that between 25% and 50% of people living with HIV experience neurocognitive disorders, with prevalence and severity differing based on population and study context. While rates are generally declining in well-treated and virologically suppressed cohorts, the absence of targeted treatments for these neurocognitive effects highlights a critical gap in HIV care.
Innovative Research Approaches
The study led by Weill Cornell Medicine presents a novel research model that could pave the way for understanding the mechanisms behind HIV’s impact on neuronal cells. The fibroblasts were reprogrammed to retain the age-related characteristics of the donors, an essential factor when exploring conditions related to aging.
The significant gene-activity differences observed between the neurons from individuals with HIV and those without suggest that the infection has broader systemic effects on cellular function. Importantly, since the neurons were derived from skin cells, the gene expression differences are unlikely to result from direct exposure to infected brain cells, indicating a more extensive influence of HIV on overall cellular health.
Key Gene Findings and Future Directions
Among the genes identified with altered expression, the inflammatory gene IFI27 was found to be more active in individuals with HIV. Additionally, three other genes—FOXL2NB, FOXL2, and LINC01391—exhibited decreased expression levels associated with cognitive impairment.
The research team plans to conduct further studies to explore the implications of these gene expressions in individuals living with HIV and to investigate their effects in more complex model systems. These efforts could ultimately contribute to identifying effective treatments for the cognitive impairments that often accompany HIV, improving the quality of life for those affected.
The research highlights the ongoing need for innovative approaches to tackle the challenges posed by HIV-related cognitive impairment, emphasizing that even with effective treatment, the virus’s impact on the brain remains a significant concern.
