HIV-1 Tat drives genotype-dependent neuroimmune programs that promote Parkinson Disease–like neurodegeneration in the hSNCAA53T Gba1 mouse model

: Human immunodeficiency virus type I (HIV-1) infection can induce both motor and cognitive impairments even in patients receiving combination antiretroviral therapy (cART). These neurological alterations are related to direct and indirect mechanisms represented by viral and immune mediated processes, respectively. HIV-1 directly elicits neurological damages through some viral proteins including transactivator of transcription (Tat), a protein involved in the HIV-1 replication and able to affect neural cell through autocrine and paracrine pathways. In this study, we investigated the functional and transcriptional effects of intrastriatal Tat injection in pre-symptomatic mice carrying the hSNCAA53TGba1+/+ and hSNCAA53TGba1+/L444P mutations, common genetic risk factors for Parkinson's disease (PD). Behavioural assessment revealed that Tat administration anticipated motor symptoms onset in both genotypes, with some behavioural measures suggesting greater impairment in mice carrying both mutations, whereas spatial memory was not affected. In line with these findings, Tat injection induced significant loss of tyrosine hydroxylase (TH)-positive cells and fibre density in hSNCAA53TGba1+/L444P mice. HIV-1 Tat injection did not significantly modify TH-positive fibre density in hSNCAA53TGba1+/+ mice, whereas a marked reduction was observed in hSNCAA53TGba1+/L444P mice. Transcriptomic analysis revealed genotype-dependent responses, with a predominant innate immune-related signatures in hSNCAA53TGba1+/+ mice and transcriptional alterations involving immune, lysosomal, proteostatic, and autophagy-related pathways hSNCAA53TGba1+/L444P mice. Altogether, these findings indicate that HIV-1 Tat administration is associated with genotype-dependent PD-related motor deficits and that the Gba1 deficiency is linked to a more pronounced dopaminergic and transcriptional response to Tat exposure.