Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune...

Area of Science:

• Immunology
• Mitochondrial Biology
• Virology

Background:

• HIV treatment with ART has improved outcomes, but chronic immune activation and inflammation persist in people living with HIV (PLWH).
• This residual inflammation contributes to long-term comorbidities like neurocognitive impairment and cardiovascular disease.
• Mitochondria play a crucial role in regulating cellular metabolism and immune responses, and their function is disrupted in PLWH.

Purpose of the Study:

• To review the role of the mito-immune axis in HIV pathogenesis.
• To explore how HIV and ART impact mitochondrial function and inflammatory signaling.
• To discuss potential therapeutic interventions targeting mitochondrial dysfunction and inflammation.

Main Methods:

• Literature review focusing on the interplay between mitochondria and the immune system in HIV.
• Analysis of mechanisms including oxidative phosphorylation (OxPhos) dysregulation, inflammasome activation, and purinergic receptor signaling.
• Examination of potential therapeutic strategies, such as purinergic antagonists.

Main Results:

• HIV and ART disrupt mitochondrial function, leading to the release of reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA).
• These mitochondrial-derived signals activate the NLRP3 inflammasome, promoting the secretion of IL-1β and other pro-inflammatory cytokines.
• Excess mitochondrial ATP activates purinergic receptors (P2X1, P2X7), further propagating inflammatory signaling.

Conclusions:

• Mitochondria are central regulators of immune function in HIV.
• Targeting the mito-immune axis, including OxPhos, inflammasomes, and purinergic signaling, offers a promising approach to address chronic inflammation in PLWH.
• A paradigm shift towards restoring immunometabolic balance, beyond viral suppression, is needed for comprehensive HIV treatment.