HIV infection in microglia leads to senescence, triggering activation of neurotoxicity pathways

Area of Science:

• Neuroscience
• Immunology
• Gerontology

Background:

• HIV-associated neurocognitive disorders (HAND) persist despite antiretroviral therapy, contributing to premature brain aging.
• Microglia, the primary brain HIV reservoir, play a crucial role in neuroinflammation and cognitive decline.
• Understanding the molecular mechanisms linking HIV infection and brain aging is critical for developing effective treatments.

Purpose of the Study:

• To investigate the transcriptomic interplay between HIV infection and normal aging in microglia.
• To determine if HIV infection induces cellular senescence in microglia and compare it to aging-associated senescence.
• To identify potential therapeutic targets for HAND by examining senescence-associated pathways.

Main Methods:

• Comparative transcriptomic analysis (single-cell and bulk) of microglia from healthy aging humans and HIV-infected ex vivo and in vivo models.
• Analysis of key molecular pathways, including p53, inflammation, proliferation, and mTOR signaling.
• Assessment of senescence patterns in both actively HIV-infected and bystander microglia.

Main Results:

• HIV infection in microglia induces a transcriptomic pattern of cellular senescence that closely resembles normal aging.
• Both HIV-infected and bystander microglia exhibit this senescence signature.
• Shared characteristics include p53 pathway activation, increased inflammatory gene expression, decreased proliferative gene expression, and maintained mTOR signaling.

Conclusions:

• HIV infection accelerates brain aging through microglia-induced cellular senescence, providing a mechanistic link to HAND.
• Cellular senescence pathways in microglia represent promising therapeutic targets for mitigating HAND and premature brain aging.
• Targeting senescence pathways could offer novel treatment strategies for patients with HIV-associated neurocognitive disorders.