Microglial reactivity and nodule formation are associated with Synaptodendritic damage in the brains of people with HIV-1.

Despite the success of combination antiretroviral therapy (ART) in suppressing systemic HIV replication, neurocognitive impairment (NCI) remains common among people with HIV (PWH). In the pre-ART era, severe forms such as HIV-associated dementia (HAD) were prevalent and characterized by distinct neuropathological features, including multinucleated giant cells, microglial nodules, and extensive neuronal loss. In the ART era, milder forms of NCI are more frequent; however, the underlying histopathology remains poorly understood. These milder impairments are primarily associated with synaptodendritic damage and neuronal dysregulation, typically in the absence of productive infection in neurons. Instead, microglia and macrophages are implicated as key drivers of neuroinflammation and neuronal injury. In this study, we investigated the neuropathological features of brain tissue from PWH with and without symptomatic cognitive impairment. Immunohistochemical analysis revealed microglial nodules with active neuronal phagocytosis, which was associated with dendritic loss and neuronal damage. Complementary in vitro studies demonstrated that HIV-infected microglia demonstrated enhanced phagocytic activity, supporting their direct role in neurodegeneration beyond cytokine-mediated mechanisms. Together, these findings highlight microglial phagocytosis as one of the critical contributors of HIV-associated NCI in the ART era.