Anti-HIV Drugs Cause Mitochondrial Dysfunction in Monocyte-Derived Macrophages

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Combination antiretroviral therapy (cART) has improved HIV/AIDS outcomes but not quality of life for people living with HIV (PLWH).
• PLWH experience higher rates of comorbidities like diabetes, hypertension, and neurocognitive impairment, alongside increased inflammation.
• The independent effects of cART on cellular function and inflammation remain unclear.

Purpose of the Study:

• To investigate the effects of cART, independent of HIV infection, on primary human monocyte-derived macrophages (MDMs).
• To determine how specific cART drugs (Atripla, Triumeq) influence MDM phenotype, mitochondrial function, and gene expression.

Main Methods:

• Primary human monocyte-derived macrophages (MDMs) were cultured and polarized to an alternative phenotype.
• MDMs were treated with two first-line cART regimens: Atripla and Triumeq.
• Mitochondrial function was assessed, and transcriptome sequencing (RNA-seq) was performed to analyze gene expression changes.

Main Results:

• Triumeq skewed alternative MDMs towards an inflammatory, nonsenescent phenotype.
• Both Atripla and Triumeq induced mitochondrial dysfunction, linked to efavirenz and abacavir.
• RNA-seq revealed differential gene regulation in immune response, cell cycle, and DNA repair pathways due to cART treatment.

Conclusions:

• cART alters human monocyte-derived macrophage phenotype independently of HIV.
• cART-induced cellular changes may contribute to immune dysregulation and increased comorbidity susceptibility in PLWH.
• Further research is needed to understand the long-term implications of cART on cellular health and comorbidities.