Polyomavirus Drives Cerebellar Lesions in AIDS Monkeys With Ataxia

ABSTRACT Cognitive and motor dysfunction occurs in 30%–50% of people with HIV/AIDS. Within this clinical spectrum, HIV‐associated ataxia is an uncommon but debilitating disorder with poorly defined neuropathological mechanisms. This study investigated two rhesus macaques with chronic simian immunodeficiency virus (SIV) infection that developed progressive ataxia, characterized by postural imbalance and nystagmus. Comparative neuropathological profiling of cerebellar tissue from ataxic SIV‐infected macaques, non‐ataxic SIV‐infected macaques, and uninfected controls revealed that ataxia was associated with diffuse cerebellar atrophy, disrupted tissue organization, Purkinje cell degeneration, demyelination, glial nodule formation, and prominent microglial neuroinflammation. Cerebellar infection with simian polyomavirus 40 (SV40), a member of the Polyomaviridae family, was identified as the cause of the lesions, with viral tropism primarily involving cerebellar granule neurons. Mechanistically, SV40 infection induced neuronal pyroptosis and inflammatory cytokine release, promoting microglial recruitment and activation, amplifying local neuroinflammation, and culminating in nodular aggregate formation. Collectively, these findings establish SV40 infection as a direct driver of cerebellar pathology in SIV‐associated ataxia and define a pathogenic sequence linking granule neuron pyroptosis, microglial activation, and progressive cerebellar injury—a cascade that may parallel polyomavirus‐induced ataxia in people living with HIV‐1.