Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-γ inhibition

Area of Science:

• Biochemistry
• Cell Biology
• Virology

Background:

• Nucleotide reverse-transcriptase inhibitors (NRTIs) are crucial in HIV treatment.
• Mitochondrial toxicity is a known complication of NRTI therapy.
• The exact mechanisms underlying NRTI-induced mitochondrial dysfunction are not fully understood.

Purpose of the Study:

• To investigate the hypothesis that competition between NRTI triphosphates and endogenous deoxyribonucleotide triphosphate (dNTP) pools leads to mitochondrial dysfunction.
• To determine if this toxicity is independent of polymerase-gamma (pol-γ) inhibition.

Main Methods:

• Peripheral blood mononuclear cells were collected from 75 adults: 25 HIV-infected patients with mitochondrial toxicity (cases), 25 HIV-infected controls, and 25 HIV-negative controls.
• Ribonucleotide (RN) and deoxyribonucleotide (dRN) pools were quantified.
• Mitochondrial DNA copy number was assessed.
• Expression levels of key proteins including pol-γ, nucleotide transporters, kinases, and ATP-binding cassette (ABC) proteins were measured.

Main Results:

• Significant differences in RN and dRN pools were observed between cases, controls, and HIV-negative individuals.
• Cases exhibited significantly higher mitochondrial DNA copy number compared to negative controls.
• Cases showed significantly elevated expression of pol-γ, nucleotide transporters, kinases, and ABC proteins.

Conclusions:

• Antiretroviral therapy (ART) perturbs both RN and dRN pools.
• Depletion of these nucleotide pools is associated with ART-induced mitochondrial toxicity.
• This toxicity may occur independently of pol-γ inhibition, highlighting a potential new therapeutic target.