A recent study from Weill Cornell Medicine has unveiled genetic signatures linked to cognitive impairment in individuals living with HIV, even when the virus is well-controlled. Researchers utilized skin cells from participants, transforming them into neurons to investigate the underlying mechanisms of HIV-related cognitive deficits. The findings, published in JCI Insight, may pave the way for future research on how HIV affects the brain.
The study involved skin samples, known as fibroblasts, taken from six individuals with suppressed HIV and seven age- and sex-matched control subjects. By applying advanced cell-reprogramming techniques, the researchers successfully converted these fibroblasts into neurons. They discovered significant differences in gene activity between the neurons derived from HIV-positive individuals and those from the control group. Notably, some of these gene-activity discrepancies echoed previous findings from post-mortem brain samples, while others were identified for the first time, offering fresh insights into the causes of cognitive impairment associated with HIV.
Understanding the impact of HIV on the brain is crucial, as the virus can infiltrate the central nervous system and infect various brain cells, including microglia and astrocytes. Although antiretroviral therapy can suppress HIV to undetectable levels in the bloodstream, the virus may persist in the brain. This chronic infection and the resulting inflammation can lead to issues such as memory problems, concentration difficulties, and mood disorders. Studies indicate that neurocognitive disorders affect between 25% and 50% of people living with HIV globally, with prevalence varying across different populations and settings.
Despite improvements in treatment, no effective therapies currently exist for the neurocognitive effects of HIV. The challenge lies in understanding the mechanisms through which the virus impacts neurons, as traditional models, such as mouse studies and post-mortem analyses, have proven inadequate. Dr. Teresa H. Evering, senior author of the study and assistant professor of medicine in the Division of Infectious Diseases at Weill Cornell Medicine, emphasizes that this new model offers promising avenues for future research.
The reprogramming technique used in this study produces neurons that retain age-related characteristics of the donors, a vital aspect for studying age-associated conditions. The clear differences in gene activity suggest that HIV infection has systemic effects on cells, even in the absence of detectable viral loads. Importantly, the changes in gene expression observed in these neurons are not due to direct exposure to the virus but reflect broader impacts of HIV infection.
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 reduced expression associated with cognitive impairment. The research team intends to conduct further studies to explore the implications of these findings in individuals living with HIV and utilize more complex model systems.
The study represents a significant step forward in understanding how HIV can lead to cognitive challenges, even in well-managed cases. As researchers continue to unravel these genetic signatures, they hope to develop targeted strategies for addressing the cognitive impairments faced by many living with HIV.
For more detailed information, the study can be referenced as: Philipp N. Ostermann et al, “Transcriptional signature of induced neurons differentiates virologically suppressed people with HIV from people without HIV,” published in JCI Insight, DOI: 10.1172/jci.insight.190445.
