HIV-1 Tat adversely affects neurogenesis through Notch signaling

Alterations in adult neurogenesis appear to be a common hallmark in several neurodegenerative diseases including human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND). HIV-1 Tat is a major pathogenic factor in HIV-associated neuropathogenesis. In vitro study have revealed that Tat severely reduces the proliferation of NPCs and impacts neurogenesis. But adult neurogenesis is limited to specific brain regions in the mammalian brain, so further investigations on the in vivo effect of Tat on NPCs proliferation and differentiation, and the molecular mechanisms are still urgent and necessary. In this study, we took advantage of the Doxycycline (Dox)-inducible brain-specific HIV-1 Tat transgenic mouse model (iTat) to investigate how Tat affected neural progenitor cell (NPC) proliferation and differentiation in the dentate gyrus of hippocampus of the mouse brain. We found that Tat decreased NPC proliferation and impacted NPC differentiation by leading dynamic imbalance of neurogenesis and astrogliogenesis. When investigated the underlying mechanism, we demonstrated that HIV-1 Tat was sufficient for Hes1 activation, which is the critical molecular downstream pathway of Notch signaling. In this process, the cysteine-rich domain of Tat plays an essential role in Hes1 activation and modulating neurogenesis and astrogliogenesis. Lastly, we determined that Notch signaling was directly involved in HIV-1 Tat induced dynamic imbalance of neurogenesis and astrogliogenesis.