Induction of a Senescence-Like Phenotype in Cultured Human Fetal Microglia During HIV-1 Infection

Area of Science:

• Neuroscience
• Immunology
• Virology

Background:

• Chronic human immunodeficiency virus type 1 (HIV-1) infection is linked to premature aging and HIV-associated neurocognitive disorders (HAND).
• Microglia, the brain's resident immune cells, are crucial for HIV-1 infection in the central nervous system.
• Cellular senescence markers (p53, p21) are elevated in HAND patients, but their role in microglia during HIV-1 infection is unknown.

Purpose of the Study:

• To investigate whether HIV-1 infection induces cellular senescence in human microglia.
• To explore the mechanisms and consequences of HIV-1-induced microglial senescence.

Main Methods:

• Primary human fetal microglia were exposed to HIV-1 pseudotypes.
• Senescence markers (β-galactosidase, p21, p53 foci), cytokine production (IL-6, IL-8), mitochondrial function (ROS, respiration), and supernatant transfer effects were assessed.
• The impact of nucleoside treatment on senescence markers was evaluated.

Main Results:

• HIV-1 infection significantly increased senescence markers, including β-galactosidase activity and p21 levels.
• Infected microglia exhibited elevated IL-6 and IL-8 production, suggesting a senescence-associated secretory phenotype.
• Mitochondrial dysfunction, characterized by increased ROS and decreased respiration, was observed in HIV-1-infected microglia.
• Transfer of supernatant from infected microglia induced senescence markers in naïve microglia.
• Nucleoside treatment partially reversed HIV-1-induced senescence marker upregulation.

Conclusions:

• HIV-1 infection induces a senescence-like phenotype in human microglia.
• This microglial senescence may contribute to the pathogenesis of HAND and accelerated aging in HIV-1 patients.
• Targeting microglial senescence could be a therapeutic strategy for HAND.