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

Abstract

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 Tat was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat (0-6 h) modulates protein phosphatase 1 (PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat (24 h) downregulates CREB activity and CREB-mediated gene (BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

“…33 Conversely, BDNF has been found to support the stability of dendritic spines by increasing the density of dendritic spines possibly through the mechanism of increasing F-actin in spines. 31 Similar to gp120, tat also decreases the conversion of proBDNF to mBDNF. 30 Tat increases the activity of NF-kβ which triggers the activation of immune cells.…”

“…Liu et al demonstrated a 50% decrease in BDNF mRNA levels when neurons were exposed to Tat for 24 hrs. 31 As a result, HIV tat decreases long-term potentiation (LTP), which is a long-lasting increase in synaptic strength that is critical for learning and memory. HIV Tat achieves this is by decreasing the phosphorylation of the transcription factor cAMP response element binding protein (CREB) thereby downregulating BDNF mRNA levels.…”

HIV-1 gp120 impairs spatial memory through CREB

“…HIV-1 Tat has been shown to utilize CREB to promote IL-10 production, though the significance of this functional interaction regarding HIV pathogenesis remains unclear (49). Further, several studies showed a decreased expression of CREB in neurons treated with HIV-Tat and/or gp120 proteins, however, CREB has never been the subject of these studies, and the mechanisms involved were not examined (50,51). Hence, this current study presents a novel hypothesis and it clarifies the relationship between gp120 and CREB.…”

Interaction of Structural Glycoprotein E2 of Classical Swine Fever Virus with Protein Phosphatase 1 Catalytic Subunit Beta (PPP1CB)

“…Several viruses have been previously determined to directly bind PP1 catalytic subunits, similar to what was observed in this report. For example, HIV Tat protein directly binds PP1α, regulating its activity in mouse neurons, suggesting that the Tat-PP1α protein interaction could be the cause of impaired cognitive function in people living with HIV [39]. Several studies have also shown that inhibitors of PP1, such as small molecules that bind RVxF motifs, have inhibited HIV viral transcription [39].…”