Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells

Int J Mol Sci. 2023 Jul 31;24(15):12242. doi: 10.3390/ijms241512242.

Abstract

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus and in SH-SY5Y cells after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with the most pronounced effects in latently infected HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

Keywords: HIV; antiretroviral drug; combination antiretroviral therapy; human microglia; iron; metabolic reprogramming; mitochondrial dysfunction; neural cell.

MeSH terms

  • DNA, Mitochondrial / metabolism
  • HIV Infections* / complications
  • HIV Infections* / drug therapy
  • HIV Infections* / metabolism
  • Humans
  • Iron / metabolism
  • Microglia / metabolism
  • Mitochondria / metabolism
  • Neuroblastoma* / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Iron
  • DNA, Mitochondrial