HIV-1 Protein Tat1–72 Impairs Neuronal Dendrites via Activation of PP1 and Regulation of the CREB/BDNF Pathway

Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus (HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly reducing the health-related quality of their lives. Although neurons cannot be infected by HIV-1, shed viral proteins such as transactivator of transcription (Tat) can cause dendritic damage. However, the detailed molecular mechanism of Tat-induced neuronal impairment remains unknown. In this study, we first showed that recombinant Tat (1–72 aa) induced neurotoxicity in primary cultured mouse neurons. Second, exposure to Tat1–72 was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat1–72 (0–6 h) modulates protein phosphatase 1 (PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat1–72 (24 h) downregulates CREB activity and CREB-mediated gene (BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat1–72 might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.