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

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• NeuroHIV, characterized by cognitive deficits and accelerated brain aging, affects approximately 50% of individuals with chronic HIV.
• The HIV protein transactivator of transcription (TAT) is implicated in NeuroHIV by dysregulating microglia (Mg) function.
• Rodent Mg studies show TAT affects lipid metabolism, immune responses, autophagy, and senescence, but human Mg (hMg) responses require investigation due to species differences.

Purpose of the Study:

• To investigate the direct effects of HIV-TAT on human microglia (hMg) derived from induced pluripotent stem cells (iPSCs).
• To elucidate the molecular mechanisms by which TAT contributes to NeuroHIV pathogenesis in hMg.

Main Methods:

• Generation of hMg from human iPSCs.
• Exposure of hMg to HIV-TAT.
• Flow cytometry and immunostaining for lipid droplets (LDs) and perilipin-2 (Plin2).
• Analysis of autophagosome formation and p53 levels.
• Human immune array assay for inflammatory mediators.
• Bioinformatic analysis of neuroimmune signaling pathways and microRNAs (miRNAs).

Main Results:

• TAT induced lipid droplet accumulation and increased Plin2 levels in hMg.
• HIV-TAT upregulated autophagosome formation and p53 levels, indicating effects on autophagy and senescence.
• TAT increased the expression of pro-inflammatory mediators, cytokines, and chemokines in hMg.
• Bioinformatic analysis revealed TAT's impact on neuroimmune pathways and suggested involvement of miRNAs.

Conclusions:

• HIV-TAT directly impacts lipid metabolism, autophagy, and senescence signaling in human microglia.
• TAT dysregulates multiple neuroimmune pathways in hMg, contributing to NeuroHIV pathogenesis.
• Novel miRNAs may play a significant role in NeuroHIV pathogenesis, warranting further research.