Changes in Mitochondrial DNA as a Marker of Nucleoside Toxicity in HIV-Infected Patients
Hélène C.F. Côté, Ph.D., Zabrina L. Brumme, B.S., Kevin J.P. Craib, M.Math., Christopher S. Alexander, Ph.D., Brian Wynhoven, B.S., Lillian Ting, B.S., Hubert Wong, Ph.D., Marianne Harris, M.D., P. Richard Harrigan, Ph.D., Michael V. O'Shaughnessy, Ph.D., and Julio S.G. Montaner, M.D.
Background Nucleoside analogues can induce toxic effects onmitochondria by inhibiting the human DNA polymerase . The toxiceffects can range from increased serum lactate levels to potentiallyfatal lactic acidosis. We studied changes in mitochondrial DNArelative to nuclear DNA in the peripheral-blood cells of patientswith symptomatic, nucleoside-induced hyperlactatemia.
Methods Total DNA was extracted from blood cells. A nucleargene and a mitochondrial gene were quantified by real-time polymerasechain reaction. Three groups were studied: 24 controls not infectedwith the human immunodeficiency virus (HIV), 47 HIV-infectedasymptomatic patients who had never been treated with antiretroviraldrugs, and 8 HIV-infected patients who were receiving antiretroviraldrugs and had symptomatic hyperlactatemia. The patients in thelast group were studied longitudinally before, during, and afterantiretroviral therapy.
Results Symptomatic hyperlactatemia was associated with markedreductions in the ratios of mitochondrial to nuclear DNA, which,during therapy, averaged 68 percent lower than those of non–HIV-infectedcontrols and 43 percent lower than those of HIV-infected asymptomaticpatients never treated with antiretroviral drugs. After thediscontinuation of antiretroviral therapy, there was a statisticallysignificant increase in the ratio of mitochondrial to nuclearDNA (P=0.02). In the patients followed longitudinally, the declinein mitochondrial DNA preceded the increase in venous lactatelevels.
Conclusions Mitochondrial DNA levels are significantly decreasedin patients with symptomatic, nucleoside-related hyperlactatemia,an effect that resolves on the discontinuation of therapy.
Source Information
From the British Columbia Centre for Excellence in HIV/AIDS (H.C.F.C., Z.L.B., K.J.P.C., C.S.A., B.W., L.T., M.H., P.R.H., M.V.O., J.S.G.M.) and the Canadian HIV Trials Network (H.W.), University of British Columbia, St. Paul's Hospital, Providence Health Care, Vancouver, B.C., Canada.
Address reprint requests to Dr. Montaner at St. Paul's Hospital, 667-1081 Burrard St., Vancouver, BC V6Z 1Y6, Canada, or at jmontaner{at}hivnet.ubc.ca.
Mitochondrial DNA and Nucleoside Toxicity
Chariot P., Bourokba N., Brivet F., Rastegar D. A., Casademont J., Miró O, Cardellach F., Montaner J. S.G., Coté H. C.F., Harrigan P. R.
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N Engl J Med 2002;
347:216-218, Jul 18, 2002.
Correspondence
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. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia. 
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