Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition

Trends Pharmacol Sci. 2011 Dec;32(12):715-25. doi: 10.1016/ Epub 2011 Sep 6.


The combined pharmacological approach to the treatment of HIV infection, known as highly active antiretroviral therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, its use has been associated with serious adverse reactions, of which those resulting from mitochondrial dysfunction are particularly widespread. Nucleos(t)ide-reverse transcriptase inhibitors (NRTIs) have long been considered the main source of HAART-related mitochondrial toxicity due to their ability to inhibit Pol-γ, the DNA polymerase responsible for the synthesis of mitochondrial DNA. Nevertheless, accumulating evidence points to a more complex relationship between these organelles and NRTIs. Also, alternative pathways by which other groups of anti-HIV drugs (non-nucleoside reverse transcriptase inhibitors and protease inhibitors) interfere with mitochondria have been suggested, although their implications, both pharmacological and clinical, are open to debate. This review aims to provide a comprehensive overview of the mechanisms and factors which influence the mitochondrial involvement in the toxicity of all three major classes of anti-HIV drugs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / pharmacology*
  • Antiretroviral Therapy, Highly Active / adverse effects
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Mitochondrial Diseases / chemically induced*
  • Mitochondrial Diseases / enzymology
  • Mitochondrial Diseases / metabolism
  • Nucleic Acid Synthesis Inhibitors
  • Reverse Transcriptase Inhibitors / adverse effects
  • Reverse Transcriptase Inhibitors / pharmacology


  • Anti-HIV Agents
  • Nucleic Acid Synthesis Inhibitors
  • Reverse Transcriptase Inhibitors
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase