Factors Associated With Mitochondrial Dysfunction in Circulating Peripheral Blood Lymphocytes From HIV-Infected People

Rosa Polo, Susana Martinez, Pilar Madrigal, Miguel Gonzalez-Muñoz

Disclosures

J Acquir Immune Defic Syndr. 2003;34(1) 

In This Article

Abstract and Introduction

Nucleoside analogue reverse transcriptase inhibitor (NRTI)-associated mitochondrial toxicity is an important issue in the clinical management of HIV infection. The aim of this study was the detection of mitochondrial dysfunction by flow cytometry in lymphocytes from HIV-infected individuals and its association with blood lactate levels, clinical and virologic status, and the different NRTI-based therapies. Lower peripheral blood lymphocytes with mitochondrial dysfunction (PBLmd) percentages were observed in healthy controls (1.2, interquartile range [IQR] = 0.4-1.9) than in patients (2.2, IQR = 0.9-3.7; P < 0.01). Stavudine-containing therapy showed higher PBLmd percentages (3.0, IQR = 1.1-4.5) than no treatment (2.1, IQR = 0.8-2.8; P < 0.05) or zidovudine-based therapy (0.9, IQR = 0.3-1.4; P < 0.01). A significant inverse correlation was found between PBLmd and CD4 T-cell percentage and absolute count. Patients with an AIDS diagnosis had higher PBLmd percentage (2.7, IQR = 1.1-4.4) than HIV-positive non-AIDS patients (1.4, IQR = 0.6-3.0; P = 0.012). In multivariate analysis, use of stavudine (odds ratio [OR] = 5.86, 95% CI = 1.81-19.01, P = 0.003) and CD4 T-cell counts <200/µL (OR = 4.51, 95% CI = 1.38-14.70, P = 0.012) were independent predictors of high PBLmd percentage. This cross-sectional study shows that antiretroviral drugs can impair the in vivo mitochondrial function of PBLs.

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) were the first drugs used in therapy for HIV infection. The development of new therapeutic compounds marked the beginning of the highly active antiretroviral therapy era in the management of HIV infection. Therapy combines typically NRTIs with either HIV protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). The benefits of the NRTI combination therapies in morbidity and mortality of HIV-infected patients are clear; however, adverse effects associated with the therapy have impaired the clinical management of the disease. Inhibition of DNA polymerase γ by NRTIs can cause mitochondrial dysfunction and cellular toxicity, and it seems to be the common pathway underlying the adverse effects of NRTIs on tissues.[1,2] Mitochondria are the main source of ATP by oxidative phosphorylation; therefore mitochondrial dysfunction leads to increased dependence on cytosolic glycolysis to obtain energy. This oxidative pathway results in an increased production and accumulation of lactate, which indicates mitochondrial dysfunction. NRTI-associated hyperlactatemia has been detected in HIV-infected patients.[3,4,5] In general, this finding represents a mild, asymptomatic, and nonprogressive hyperlactatemia. An approach for directly studying mitochondrial dysfunction is the measurement of mitochondrial membrane potential (Δψ) loss at cellular level. Depolarization of mitochondria is detected by using cationic lipophilic fluorochromes that enter in the mitochondria and are retained by the Δψ. Therefore, diminished fluorescence indicates a decreased mitochondrial potential and mitochondrial dysfunction.[6] Significant Δψ loss has been observed in peripheral blood lymphocytes (PBLs) during acute HIV syndrome[7] and chronic HIV-infected patients without antiretroviral treatment or taking zidovudine.[8,9]

To our knowledge, no studies have been published on Δψ changes associated with NRTI combination therapy in peripheral lymphocytes in chronic HIV infection. The objective of this study was the detection of Δψ decreases in freshly collected peripheral blood lymphocytes from HIV-infected patients and to determine their association with blood lactate levels, clinical and virologic status, and antiretroviral therapy.

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