A brief overview of mechanisms of mitochondrial toxicity from NRTIs

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) in combinations with other antiretrovirals (highly active antiretroviral therapy, HAART) are the cornerstones of AIDS therapy, turning HIV infection into a manageable clinical entity. Despite the initial positive impact of NRTIs, therapeutic experience revealed serious side effects that appeared to originate in the mitochondria and which ultimately manifested as dysfunction of that organelle. It may be reasonable to consider that as the AIDS epidemic continues and as survival with HIV infection is prolonged by treatment with HAART, long-term side effects of NRTIs may become increasingly common. This consideration may be underscored in children who are born to HIV-infected mothers who received NRTI therapy in utero during gestation. The long-term effect of that NRTI exposure in utero is not clear yet. This review examines some proposed mechanisms of NRTI mitochondrial toxicity, including genetic predisposition, defects in mitochondria DNA replication, the encompassing "DNA pol-gamma hypothesis," the relationship between mitochondrial nucleotide and NRTI pools, mitochondrial DNA mutation and dysfunction, and oxidative stresses related to HIV infection and NRTIs. Mechanisms of mitochondrial toxicity are reviewed with respect to key cell biological, pathological, and pharmacological events.

Targeted Transgenic Overexpression of Mitochondrial Thymidine Kinase (TK2) Alters Mitochondrial DNA (mtDNA) and Mitochondrial Polypeptide Abundance

“…The DNA pol-␥ hypothesis 2 has been developed and refined throughout the years 1,47 to help define events in acquired mtDNA depletion caused by antiretroviral nucleosides for AIDS. 28 Pharmacological and cellular events that relate to abundance of phosphorylated NRTIs and normal mtDNA precursors in the intramitochondrial compartment were considered important initially but now are becoming crucial biological factors in understanding the downstream events in inhibition of DNA pol-␥ and in resultant mtDNA depletion.…”

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa

“…[3] The 140 kDa catalytic protein is translated from the 22 exons of the POLG1 gene on chromosome 15q25, and possesses both polymerase and 3´ -5´ exonuclease activities. [4] Primary mutations in the POLG1 gene lead to secondary defects in the maintenance of the mitochondrial genome, depletion of mtDNA, [5,6] damage to oxidative phosphorylation [6] and elevation of serum lactate, [5,7] thus making the POLG1 gene a strong candidate for NRTI-induced mitochondrial-toxicity-related disorders such as hyperlactataemia. Literature reports from developed countries suggest an incidence rate for SHL of 5 -10/1 000 patients per year on NRTIs and 1/1 000 patients per year for the very severe form (LA), which is associated with a high expected mortality.…”

Antiretroviral Therapy and HIV-Associated Neurocognitive Disorders

“…The emergence of these strains along with the severe NRTI/NtRTI-associated side effects, including lactic acidosis, lipoatrophy, and peripheral neuropathy, usually necessitates changes in the regimen, which can include switching ARVs, adding more ARVs, and/or adjusting dosing (Kohler and Lewis 2007). Interestingly, individual NRTIs/NtRTIs are associated with specific side effects.…”

“…For example, d4T, and to a lesser extent, AZT, are associated with lipoatrophy, while TDF does not appear to cause this particular side effect. Peripheral neuropathy, which manifests in approximately 40% patients on cART, is associated with regimens that include d4T (Kohler and Lewis 2007). On the other hand, TDF is associated with increased risk of nephropathy and loss of bone density (Duarte-Rojo and Heathcote 2010).…”