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Genetic and Functional Mitochondrial Assessment of HIV-Infected Patients Developing HAART-Related Hyperlactatemia

Garrabou, Glòria PhD*; Morén, Constanza PhD student*; Gallego-Escuredo, Jose Miguel PhD student; Milinkovic, Ana MD; Villarroya, Francesc PhD; Negredo, Eugenia MD§; Giralt, Marta PhD; Vidal, Francesc MD; Pedrol, Enric MD; Martínez, Esteban MD; Cardellach, Francesc MD*; Gatell, Josep Maria MD; Miró, Òscar MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: December 2009 - Volume 52 - Issue 4 - p 443-451
doi: 10.1097/QAI.0b013e3181bd564c
Basic Science

Background: Mitochondrial damage of HIV and antiretrovirals, especially nucleoside-analogue interference on mitochondrial DNA (mtDNA) replication, is reported to underlay highly active antiretroviral therapy (HAART)-related hyperlactatemia, but scarce approaches have been performed to correlate clinical manifestations and mitochondrial abnormalities.

Methods: We obtained lymphocytes and monocytes of 26 HIV-infected and treated patients who developed hyperlactatemia and after recovery, 28 nonhyperlactatemic HIV subjects on HAART, 31 naive individuals, and 20 uninfected controls. Mitochondrial replication and transcription analysis were performed by quantitative real-time PCR, mitochondrial translation quantification by western blot and mitochondrial enzymatic activities by spectrophotometry.

Results: Mitochondrial parameters decreased during hyperlactatemia and improved at recovery. Mitochondrial replication and transcription species were reduced (P = 0.16 and P = 0.71), but the most significant decay was observed on mitochondrial protein content (P < 0.05) and mitochondrial complexes III and IV activities (P < 0.01 and P < 0.001). During hyperlactatemia lactate level correlated complexes III and IV function (P < 0.05). After recovery mitochondrial parameters achieved values of nonhyperlactatemic HIV individuals, which were lower than ranges of naive subjects and uninfected controls.

Conclusions: HIV and HAART-related hyperlactatemia is associated with a general mitochondrial impairment which reverts after recovery. Mitochondrial biochemistry show a better correlation with lactate levels than mitochondrial genetics suggesting that mitochondrial function could be a better marker of hyperlactatemia development than mtDNA content.

From the *Mitochondrial Research Laboratory, Internal Medicine Department, Hospital Clínic of Barcelona, IDIBAPS, University of Barcelona and CIBER de Enfermedades Raras, CIBERER, Barcelona, Spain; †Biochemical and Molecular Biology Department and Institute of Biomedicine (IBUB), University of Barcelona, and CIBER de Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain; ‡Infectious Diseases Department, Hospital Clinic of Barcelona, Barcelona, Spain; §Infectious Diseases Department, Hospital Germans Trias i Pujol of Badalona, Spain; ¶Infectious Diseases and HIV/AIDS Section, Department of Internal Medicine, Hospital Universitari of Tarragona Joan XXIII, IISPV, University Rovira i Virgili, Tarragona, Spain; and ‖HIV Unit, Hospital de Sant Pau i Santa Tecla, Tarragona, Spain.

Received for publication April 7, 2009; accepted August 18, 2009.

Preliminary data which represent only a small part of the information contained on the present manuscript have been presented as poster communication to the following meetings: (1) Congress: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention by Garrabou G, López S, Morén C, Rodriguez V, Milinkovic A, Martinez E, Riba J, Casademont J, Cardellach F, Gatell JM, Miró Ò. “Mitochondrial impairment in mononuclear cells of hyperlactatemic patients on HAART.” Sydney (Australia), July 22-25, 2007. (2) At the same time it was co-submitted to the 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV by Garrabou G, López S, Morén C, Rodriguez V, Milinkovic A, Martinez E, Riba J, Casademont J, Cardellach F, Gatell JM, Miró Ò. Mitochondrial impairment in mononuclear cells of hyperlactatemic patients on HAART. Sydney (Australia), July 19-22, 2007.

Supported by Fundació la Marató de TV3 (02/0210 and 02/0631), Fundación para la Investigación y la Prevención del SIDA en España (FIPSE 36612/06 and 36572/06), Fondo de Investigación Sanitaria (FIS 0381/04, 1239/04 0229/08 and 1715/08), Red de Sida (RD 06/006), Suports a Grups de Recerca de la Generalitat de Catalunya (2009/SGR/1158) and CIBER de Enfermedades Raras and CIBER de Fisiopatología de la Obesidad y Nutrición (initiatives of the ISCIII). Dr. Òscar Miró has been depositary of a Research Intensification grant from ISCIII (Spain) during 2009.

Disclosure statement/conflict of interest: This work has not been supported by pharmaceutical funding which could have commercial interest on the present results. None of the authors has a financial or beneficial interest in the products or concepts mentioned in the present article or in competing products that might bias his/her judgment. None of them is in association with any organization that could pose a conflict of interest on the points described on the present manuscript.

Correspondence to: Òscar Miró, MD, Mitochondrial Research Laboratory, Muscle Research Unit, Internal Medicine Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Catalonia, Spain (e-mail: omiro@clinic.ub.es).

© 2009 Lippincott Williams & Wilkins, Inc.