HIV-1 Tat expression drives progressive synaptic decline: evidence from longitudinal [ ¹¹ C]-UCB-J PET imaging

Abstract Objectives In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic condition that continues to affect the brain. As synaptodendritic injury occurs early, often years before the onset of clinical symptoms, noninvasive neuroimaging methods such as positron emission tomography (PET) hold promise for early detection. Methods A doxycycline (DOX)-inducible HIV-1 Tat 1-86 transgenic mouse model was used to examine the longitudinal impact of Tat expression on synaptic density in vivo. PET imaging with [ 11 C]-UCB-J, a radiotracer targeting synaptic vesicle glycoprotein 2A (SV2A), was performed at 0-, 2-, and 12-weeks after Tat induction via DOX to assess progressive changes in synaptic density in the cerebrum. Complementary Western blot analyses were conducted at 12 weeks of Tat induction to measure SV2A and PSD-95 protein levels across the cortex, prefrontal cortex, striatum, and cerebellum. Results Longitudinal [ 11 C]-UCB-J PET imaging revealed a progressive decline of SV2A in the cerebrum of DOX treated Tat(+) mice compared to Tat(−) controls. Western blot analyses demonstrated a significant genotype x sex interaction in the cortex in which Tat expression reduced SV2A protein levels in females, without affecting males. Further, lower SV2A protein levels were noted overall in males relative to females in the cortex, prefrontal cortex, and cerebellum. No significant effects were detected for PSD-95 protein expression. Conclusions These findings provide in vivo evidence that HIV-1 Tat expression contributes to progressive synaptic density decline and highlight sex-dependent differences in SV2A regulation, supporting SV2A as a biomarker for synaptic alterations in neuroHIV.