Hydrogen Sulfide Rescues Microglia From HIV Tat-Driven Ferroptosis: Implications for HIV-Associated Neuroinflammation

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• HIV-associated neurocognitive disorders (HAND) involve neuroinflammation and glial dysfunction.
• Ferroptosis, a form of iron-dependent cell death, contributes to HAND pathogenesis.
• Oxidative stress induced by HIV transactivator of transcription (Tat) protein is a key factor in NeuroHIV.

Purpose of the Study:

• To investigate the protective role of hydrogen sulfide (H2S) against HIV Tat-induced ferroptosis in microglial cells.
• To determine if H2S can mitigate oxidative stress, lipid peroxidation, and inflammation in the context of NeuroHIV.

Main Methods:

• BV2 microglial cells were treated with an H2S donor (NaHS) followed by exposure to HIV Tat protein.
• Ferroptosis markers (Fe2+ accumulation, lipid peroxidation, ROS, LDH release) were measured.
• Protein and cytokine expression related to ferroptosis and inflammation were analyzed.

Main Results:

• H2S treatment significantly reduced Tat-induced ferroptosis markers, including Fe2+ accumulation, ROS generation, and lipid peroxidation.
• H2S suppressed pro-ferroptotic proteins (ACSL4, 4-HNE) and restored anti-ferroptotic proteins (SLC7A11, GPX4).
• H2S attenuated the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) induced by HIV Tat.

Conclusions:

• Hydrogen sulfide (H2S) effectively protects microglia from HIV Tat-induced ferroptosis.
• H2S signaling restores cellular homeostasis and reduces neuroinflammation in a model of NeuroHIV.
• H2S represents a promising therapeutic target for managing NeuroHIV-associated neuroinflammation.