HIV Protein TAT Dysregulates Multiple Pathways in Human iPSCs-Derived Microglia

TL;DR

This study shows how the HIV protein TAT disrupts brain cell functions in human microglia, contributing to cognitive issues in HIV patients.

Contribution

The study provides direct evidence of HIV-TAT's effects on human microglia, revealing novel miRNA involvement in NeuroHIV.

Findings

HIV-TAT induces lipid droplet accumulation and increases Plin2 levels in human microglia.

TAT upregulates autophagosome formation and p53 levels in human microglia.

TAT activates pro-inflammatory mediators and affects neuroimmune signaling pathways in human microglia.

Abstract

In the era of combined antiretroviral therapy, around 50% of chronic HIV (+) individuals show varying degrees of memory and cognitive deficiency (NeuroHIV), a phenomenon of accelerated brain aging. HIV protein transactivator of transcription (TAT) has been well-accepted as a risk factor contributing to NeuroHIV through dysregulating microglia (Mg) functions. Previous studies have demonstrated that HIV-TAT can affect lipid metabolism, immune responses, autophagy, and senescence in rodent Mg. However, due to the significant species differences between rodent and human Mg (hMg), it is essential to take caution when interpreting the results obtained from rodent models into human conditions. For the unanswered questions, we generated hMg from human inducible pluripotent stem cells (iPSCs) and exposed them to HIV-TAT. The results obtained from Flow analysis and immunostaining experiments reveal that TAT can induce LD accumulation and increase perilipin-2 (Plin2) levels in hMg. Meanwhile, HIV-TAT can upregulate autophagosome formation and p53 levels. Through human immune array assay, we showed that TAT can increase the expression of multiple pro-inflammatory mediators, cytokines, and chemokines in hMg. Extensive bioinformatic analysis shows that HIV-TAT can affect multiple neuroimmune signaling pathways and indicates that microRNAs (miRNAs) are coherently involved in such dysregulation. Overall, our findings provide direct evidence showing that HIV-TAT can affect lipid metabolism, autophagy, senescence signaling, and multiple neuroimmune-related pathways in hMg and indicate the roles of novel miRNAs on NeuroHIV pathogenesis, which deserves further investigations.

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