Mechanisms of Nucleoside Analogue Toxicity
Mechanisms of Nucleoside Analogue Toxicity
Abstract & Commentary
By Dean L. Winslow, MD, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, and Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert
Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron, and is on the speaker’s bureau for Pfizer/Agouron.
Synopsis: Nucleoside analogue reverse transcriptase inhibitors have long been recognized as causal in a number of significant toxicities seen in patients with HIV infection who have been treated with these agents for long periods of time. Altered gene expression induced by these agents is a more significant mechanism than is depletion of mitochondrial DNA.
Source: Mallon PWG, et al. In Vivo, Nucleoside Reverse-Transcriptase Inhibitors Alter Expression of Both Mitochondrial and Lipid Metabolism Genes in the Absence of Depletion of Mitochondrial DNA. J Infect Dis. 2005;191:1686-1696.
This prospective study recruited 20 healthy, HIV-uninfected subjects to receive a 6-week course of either stavudine (d4T) plus lamivudine (3TC) or zidovudine (ZDV) plus lamivudine. Subjects underwent clinical assessment, routine laboratory studies, and assessment of body composition using 3-slice abdominal CT imaging and dual-energy X-ray absorptiometry (DEXA) scan at 0, 1, 2, 3, 6, and 12 weeks. In addition, subjects underwent subcutaneous (sc) fat biopsy at weeks 0 and 2. Monocytes were examined as a surrogate for NRTI-induced mitochondrial toxicity due to the importance of lipid metabolism genes in the regulation of monocyte cholesterol metabolism and their high expression of mitochondrial RNA (mtRNA).1
Adipose expression of 3 different mtRNA’s (MTCO1, MTCO3, and MTCYB) all decreased significantly by week 2, and were significantly correlated. No significant change in mtDNA levels were observed. Adipose tissue expression of nuclear genes was examined. These studies demonstrated increased expression of PPARGC1A (the gene for PPAR gamma coactivator 1), NRF1 (the gene for nuclear respiratory factor 1), and TFAM (the gene for mt transcription factor A). Expression of PPAR gamma decreased by 50% and correlated with reduced mtRNA expression. Expression of SREBF1 (the gene for steroid regulatory element binding protein 1) did not change. Expression of LPL (the gene for lipoprotein lipase, involved in recruitment of circulating lipid substrate for oxidative phosphorylation) increased significantly. Expression of LEP (the gene for leptin) significantly increased as well.
Monocyte expression of MTCO1 decreased significantly at week 6 and remained low for 6 weeks after discontinuation of nucleoside analogues.
Larger decreases in adipose tissue expression of mtRNA’s were observed in the d4T plus 3TC group than in the ZDV plus 3TC group, but did not reach statistical significance.
Body composition as determined by CT or DEXA imaging did not change significantly in this short term study, nor did sc fat histopathology, as determined by light microscopy.
Comment by Dean Winslow, MD, FACP
Lipodystrophy (encompassing plasma dyslipidemias, lipoatrophy/fat wasting, and lipo-accumulation) have all been observed in patients receiving longterm antiretroviral therapy. In addition, peripheral neuropathy, hepatic steatosis/lactic acidosis, myopathy, and perinatal encephalopathy have all been observed in association with NRTIs2-8 and are consistent with mitochondrial toxicity as a general mechanism. However, the precise mechanisms underlying the causality of these conditions have eluded understanding when studied in complicated HIV-infected patients who have significant comorbid conditions, often high endogenous levels of inflammatory cytokines, and who have received numerous antiretroviral drugs and other medications. The literature in this area has frankly been confusing and often has shown contradictory results. While not answering all the potentially relevant mechanistic questions, this study goes a long way toward doing so, and highlights the importance of conducting carefully controlled studies in healthy HIV-negative controls when possible.
This study does not address directly the mechanisms of protease inhibitor-associated lipodystrophy/lipoaccumulation. (Proposed mechanisms for this include direct inhibition of SREBP1 and PPAR gamma.)
The study does show conclusively that independent of HIV, NRTI’s cause decreased transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTI’s cause mitochondrial dysfunction by a mechanism other than the widely-believed inhibition of DNA polymerase gamma. Also, reduced expression of lipid metabolism genes provides a rational explanation for NRTI--induced lipoatrophy.
References
- Moore KJ, et al. The Role of PPAR-Gamma in Macrophage Differentiation and Cholesterol Uptake. Nat Med. 2001;7:41-47.
- Carr A, et al. A Syndrome of Peripheral Lipodystrophy, Hyperlipidaemia and Insulin Resistance in Patients Receiving HIV Protease Inhibitors. AIDS. 1998;12:F51-58.
- Mallon PWG, et al. Prospective Evaluation of the Effects of Antiretroviral Therapy on Body Composition in HIV-1 Infected Men Starting Therapy. AIDS 2003;17:971-979.
- Cossarizza A, et al. Antiretroviral Nucleoside and Nucleotide Analogues and Mitochondria. AIDS 2004; 18:137-151.
- Barret B, et al. Persistent Mitochondrial Dysfunction in HIV-1 Exposed but Uninfected Infants: Clinical Screening in a Large Prospective Cohort. AIDS. 2003; 17:1769-1785.
- Carr A, et al. A Syndrome of Lipoatrophy, Lactic Acidaemia and Liver Dysfunction Associated with HIV Nucleoside Analogue Therapy: Contribution to Protease Inhibitor-Related Lipodystrophy Syndrome. AIDS 2000;14:F25-32.
- Nolan D, et al. Mitochondrial DNA Depletion and Morphologic Changes in Adipocytes Associated with Nucleoside Reverse Transcriptase Inhibitor Therapy. AIDS. 2003;17:1329-1338.
- Carr A, et al. Fatal Portal Hypertension, Liver Failure, and Mitochondrial Dysfunction After HIV-1 Nucleoside Analogue-Induced Hepatitis and Lactic Acidaemia. Lancet. 2001;357:1412-1414.
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