New Insights into the Intersection of HIV and Alzheimer's Disease at the Molecular Level

Recent research from Northwestern Medicine has uncovered a surprising connection between HIV-1 and proteins associated with Alzheimer's disease. Published in the Proceedings of the National Academy of Sciences, the study reveals how a fragment of amyloid precursor protein (APP), known as C99, interferes with HIV-1's ability to assemble and release new viral particles within brain cells, specifically macrophages and microglia. These immune cells act as reservoirs for the virus in the brain, where infection can lead to neurocognitive disorders.

The research highlights that C99 blocks HIV-1 from accessing multivesicular bodies (MVBs), the cellular compartments where the virus typically assembles, thereby hindering its replication. This interference occurs because C99 and HIV-1 Gag proteins compete for vital host proteins like TSG101 and VPS4A, which are crucial for vesicular sorting processes. Interestingly, depletion of TSG101 impairs HIV-1 replication unless C99 is also reduced, implying a direct competition for these cellular factors.

The findings suggest a complex interplay: while processing through MVBs is necessary for HIV replication, it also leads to the production of neurotoxic amyloid peptides linked to Alzheimer’s disease. This creates a conflict within infected brain cells, balancing viral propagation and neurodegeneration.

Furthermore, the virus may promote the breakdown of C99 to evade its inhibitory effects, but this process inadvertently increases the production of amyloidogenic toxins, which damage brain cells. The team is now investigating how these mechanisms function in neurons, using stem cell-derived models to better understand the implications for neurodegenerative conditions.

Overall, this research sheds new light on the molecular crosstalk between HIV infection and neurodegeneration, potentially opening new avenues for treatments that address both viral reservoirs and neurodegenerative pathology. It emphasizes the importance of understanding vesicular sorting pathways in brain health and disease.

Source: https://medicalxpress.com/news/2025-09-hiv-alzheimer-pathways-collide-protein.html