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Mitochondrial Dysfunction in HIV/AIDS

10 Chronic Diseases linked to mitochondrial dysfunction

Listed below are current articles and published clinical studies documenting the
strong link between Mitochondrial Dysfunction and HIV/AIDS.
Journal of Endocrinology, Metabolism and Diabetes of South Africa.   ISSN: 003-8-2469
Mitochondrial dysfunction and human immunodeficiency virus infection
Human immunodeficiency virus (HIV) infection and the pharmacological treatment thereof have both been shown to affect mitochondrial function in a number of tissues, and each may cause specific organ pathology through specific mitochondrial pathways. HIV has been shown to kill various tissue cells by activation of mitochondrial apoptosis. Nucleoside analogues, used extensively to treat HIV infection, are known to influence a number of steps affecting mitochondrial DNA integrity. This review describes the basic physiology, pharmacology and pathophysiology of HIV infection and the nucleoside analogues regarding mitochondrial function and discusses the progress made in this field with respect to the measurement of these effects and the prediction of potential drug toxicity.
2012 International AIDS Conference
Mitochondrial function and metabolic abnormalities in children with
perinatally-aquired HIV infection in the Pediatric HIV/AIDS Cohort Study (PHACS)
Background:  Metabolic abnormalities, common among perinatally HIV-infected children (HIV+), may be caused by mitochondrial dysfunction that is induced by antiretroviral therapy (ARV) or chronic viral infection. We compared mitochondrial function [oxidative phosphorylation (OXPHOS) enzyme activities and lactate levels] of HIV+ and HIV-exposed, uninfected (HEU) children and, among HIV+, determined associations with fasting glucose, insulin, and homeostatic model assessment of insulin-resistance (HOMA-IR).
Methods:  HIV+ and HEU were enrolled from the PHACS Adolescent Master Protocol. Children with known, non-HIV-associated mitochondrial disorders were excluded. Demographic and BMI [all] and CD4, HIV viral load, ARV exposures, and fasting insulin/glucose [HIV+ only] were collected. Main outcomes included venous and point-of-care (POC) lactate, venous pyruvate, and PBMC NADH dehydrogenase (CI) and cytochrome c oxidase (CIV) enzyme activities. A Wilcoxon test was used to compare outcomes between HIV+ and HEU; Spearman correlations were determined between insulin/glucose and OXPHOS activity in HIV+.
Results: 112 HIV+ and 66 HEU children were enrolled as of December 2011. HIV+ were older than HEU (15.8yr vs 12.4yr) with similar gender and racial distributions. BMI-Z was lower in HIV+ (0.41SD vs 0.54SD). Among HIV+, 45% were CDC stage B/C and 74% had CD4 >500 cell/mm3 with 60% having viral load < 400cp/mL. 56% were on HAART, PI-based ARVs. Median glucose was 87mg/dL (range 74-110), insulin was 13.6IU (range 4.7-83) and HOMA-IR was 3.1 (range 1-20.7). POC lactate was higher and venous pyruvate lower among HIV+ vs HEU (Table), while C1 and CIV activities did not differ between groups. Among HIV+ with measures available, we observed a negative correlation of fasting glucose with CI OXPHOS activity (n=26; r=-0.38; p=0.06) and a positive correlation with venous lactate (n=34; r=0.31; p=0.07).
Conclusions:  Preliminary analyses show higher POC lactate in HIV+ compared to HEU children and that mitochondrial dysfunction may be associated with metabolic abnormalities in HIV+ children.
XIX International AIDS Conference
July 22-27, 2012, Washington, DC
Mitochondrial Upsets May Underlie Metabolic
Disorders in HIV-Positive Adolescents
A US study comparing HIV-infected youngsters with HIV-exposed but uninfected (HEU) youth yielded data suggesting that mitochondrial dysfunction lies behind metabolic abnormalities in HIV-positive adolescents [1]. This Pediatric HIV/AIDS Cohort Study (PHACS) linked every 1 mg/dL higher venous lactate to an 18-mg/dL higher triglyceride reading.
Metabolic abnormalities often affect HIV-positive people, including perinatally infected children and adolescents taking antiretrovirals for a decade or more. These metabolic derangements may be caused by mitochondrial dysfunction fostered by antiretroviral therapy or chronic HIV infection, PHACS researchers suggested. To test those hypotheses, they gauged mitochondrial function as oxidative phosphorylation (OSPHOS) enzyme activities and lactate levels, then compared those measures in HIV-infected and HEU adolescents. In the HIV-positive group, the researchers also determined associations between mitochondrial function and fasting glucose, insulin, and HOMA-defined insulin resistance.
Researchers recruited youngsters without known non-HIV mitochondrial disorders from the PHACS Adolescent Master Protocol. The investigators gathered demographic and body mass index data in both HIV-positive and HEU youth, and they recorded CD4 counts, viral loads, antiretroviral exposure, and fasting insulin and glucose in HIV-positive youngsters. Principal outcomes were venous and point-of-care (fingerprick) lactate, venous pyruvate, and PBMC NADH dehydrogenase (CI) and cytochrome c oxidase (CIV) enzyme activities.
The PHACS team enrolled 191 HIV-positive adolescents and 117 HEU youngsters. The HIV-positive adolescents were older than HEU youth (average 15.8 versus 12.7 years, P < 0.001), and a higher proportion of HIV-positive youngsters were non-Hispanic blacks (70% versus 56%, P = 0.05). But the gender distribution was similar in the two groups (54% and 51% boys). Body mass index Z scores were significantly lower in adolescents with HIV (average 0.46 versus 0.91, P = 0.005).
In the HIV group, 50% had CDC stage B or C HIV infection, 58% were taking a protease inhibitor (PI)-based antiretroviral combination, only 11% had a viral load below 400 copies, and median CD4 count stood at 624. HIV-positive youngsters had a median fasting glucose of 86 mg/dL (interquartile range [IQR] 81 to 91), median fasting insulin of 12.1 uu/mL (IQR 8.0 to 20.9), and HOMA insulin resistance of 2.5 (IQR 1.7 to 4.5). Median total cholesterol stood at 159 mg/dL (IQR 137 to 186) and median triglycerides at 86.5 mg/dL (IQR 63 to 116).
Median point-of-care lactate levels (measured by fingerprick) were marginally higher in adolescents with HIV (1.45 mg/dL, IQR 1.0 to 1.9) than in HEU youth (1.4 mmol/L, IQR 1.1 to 1.9), and that difference was not significant (P = 0.98). But median venous lactates were significantly lower in the HIV group (1.0 mg/dL, IQR 0.79 to 1.40) than in HEU youngsters (1.26 mg/dL, IQR 0.89 to 1.70) (P < 0.001).
Median venous pyruvate was also significantly lower in the HIV group (0.09 mg/dL, IQR 0.05 to 0.11) than in the HEU group (0.10 mmol/L, IQR 0.07 to 0.13) (P = 0.005). Pyruvate may be metabolized to lactate or to acetyl CoA.
Median CI OXPHOS enzyme activity was similar in HIV-positive and HEU adolescents (37.9 and 36.9 OD/min/ug e-6, P = 0.71), but median CIV OXPHOS enzyme activity was higher in the HIV group (69.4 versus 60.8 OD/min/ug e-6, P = 0.048).
In children with HIV, insulin resistance was associated with higher venous lactate (P = 0.046) and pyruvate (P = 0.028), while high triglycerides were associated with higher point-of-care lactate (P = 0.024) and venous lactate (P < 0.001). Venous lactate correlated positively with total cholesterol (r = 0.16, P = 0.04) and with triglycerides (r = 0.37, P < 0.0001) in HIV-positive children. Low "good" high-density lipoprotein (HDL) cholesterol was associated with lower PBMC OXPHOS CI enzyme activity (P = 0.024) and lower OXPHOS CIV enzyme activity (P = 0.085).
Multivariate analysis identified associations between longer PI duration and higher triglycerides (+2.63 mg/dL per year of PIs, P = 0.03) and longer nonnucleoside duration and higher triglycerides (+4.19 mg/dL per year of nonnucleosides, P = 0.004). Higher venous lactate was also associated with higher triglycerides (+17.7 mg/dL per 1 mg/dL lactate, P = 0.0008).
The PHACS investigators concluded that (1) insulin resistance is associated with higher lactates and pyruvate in HIV-positive children, (2) high triglycerides are associated with higher lactates, (3) low HDL cholesterol is associated with lower OXPHOS CI and CIV enzyme activities, and (4) venous lactate is independently associated with higher triglycerides. They proposed the overall conclusion that "mitochondrial dysfunction induced by either HIV or antiretrovirals may be responsible for the observed metabolic changes" in HIV-positive youngsters.
Previous studies yielded additional findings on mitochondrial function in HIV-positive, HIV-exposed, and HIV-negative youth. A Spanish cross-sectional comparison of 47 asymptomatic antiretroviral-treated youngsters and 27 healthy HIV-negative controls found significantly lower mitochondrial DNA (mtDNA) in PBMCs from the HIV group, but similar levels of mitochondrial RNA in the two groups [2]. CIV protein subunit content and enzymatic activity were also similar in the two groups.
J Infect Dis. (2010)  
Possible Mitochondrial Dysfunction and Its Association with
Antiretroviral Therapy Use in Children Perinatally Infected with HIV
Background. Mitochondrial dysfunction has been associated with both human immunodeficiency virus (HIV) infection and exposure to antiretroviral therapy. Mitochondrial dysfunction has not been widely studied in HIV-infected children. We estimated the incidence of clinically defined mitochondrial dysfunction among children with perinatal HIV infection.
Methods. Children with perinatal HIV infection enrolled in a prospective cohort study (Pediatric AIDS Clinical Trials Group protocols 219 and 219C) from 1993 through 2004 were included. Two clinical case definitions of mitochondrial dysfunction, the Enquête Périnatale Française criteria and the Mitochondrial Disease Classification criteria, were used to classify signs and symptoms that were consistent with possible mitochondrial dysfunction. Adjusted odds ratios of the associations between single and dual nucleoside reverse-transcriptase inhibitor use and possible mitochondrial dysfunction were estimated using logistic regression.
Results. Overall, 982 (33.5%) of 2931 children met 1 or both case definitions of possible mitochondrial dysfunction. Mortality was highest among the 96 children who met both case definitions (20%). After adjusting for confounders, there was a higher risk of possible mitochondrial dysfunction among children who received stavudine regardless of exposure to other medications (odds ratio, 3.44 [95% confidence interval, 1.91–6.20]) or who received stavudine-didanosine combination therapy (odds ratio, 2.23 [95% confidence interval, 1.19–4.21]). Exposure to lamivudine and to lamivudine-stavudine were also associated with an increased risk of mitochondrial dysfunction.
Conclusions. Receipt of nucleoside reverse-transcriptase inhibitors, especially stavudine and lamivudine, was associated with possible mitochondrial dysfunction in children with perinatal HIV infection. Further studies are warranted to elucidate potential mechanisms of nucleoside reverse-transcriptase inhibitor toxicities.
2003 - J Acquir Immune Defic Syndr.
Factors Associated With Mitochondrial Dysfunction in Circulating
Peripheral Blood Lymphocytes From HIV-Infected People
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.[3-5] 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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