Mireia Nicolás

Mitochondrial impact of human immunodeficiency virus and antiretrovirals on infected pediatric patients with or without lipodystrophy.

We determined the mitochondrial status of a group of HIV-infected children, some with body fat abnormalities (BFA). We included 24 controls, 16 HIV-infected untreated, 26 HIV-infected treated, 6 BFA-untreated, and 21 BFA-treated patients. Genetic, translational, and functional mitochondrial values were measured. As compared with controls, mitochondrial DNA depletion and a reduction in functionality were found in BFA groups.

Mitochondrial assessment in asymptomatic HIV-infected paediatric patients on HAART.

BACKGROUND HAART can cause mitochondrial DNA (mtDNA) depletion, which may lead to mitochondrial dysfunction. We aimed to determine whether mtDNA and mitochondrial function abnormalities are present in peripheral blood mononuclear cells from asymptomatic HIV-infected children. METHODS A cross-sectional study in peripheral blood mononuclear cells was performed in 47 asymptomatic (free from any HIV- or AIDS-related active condition or HAART-related toxicity), HIV-infected, HAART-treated children and adolescents and 27 uninfected healthy paediatric patients. We measured mtDNA and mitochondrial RNA (mtRNA) content by quantitative real-time PCR. Mitochondrial respiratory chain enzymatic activity of complex-IV (CIV) and mitochondrial mass (estimated by citrate synthase) were measured spectrophotometrically, and CIV protein subunit content was measured with western blot analysis. RESULTS A reduction in mtDNA levels was observed in HIV-infected children compared with controls (mean ± sem 4.47 ± 0.31 and 5.82 ± 0.48, respectively; 23% depletion; P=0.018), whereas similar levels of mtRNA, CIV protein subunit content and enzymatic activity were found in the two groups. These findings remained unaltered after considering mitochondrial abundance. Among HIV-infected children, mtDNA levels did not correlate with viral load, CD4(+) T-cell counts or lactataemia at the time of assessment. No differences were observed when current or past use of individual antiretroviral drugs or HAART regimens were taken into account. CONCLUSIONS Depletion in mtDNA from asymptomatic HIV-infected children did not lead to differences in mtRNA levels or mitochondrially-encoded CIV proteins, nor to CIV dysfunction. This may be explained by homeostatic-compensatory mechanisms at the transcription level or by the mild depletion we observed.

Evolution of mitochondrial DNA content after planned interruption of HAART in HIV-infected pediatric patients.

HAART-related long-term toxicities, many of them ascribed to mitochondrial (mt) toxicity of the nucleoside analogues, are being increasingly reported in HIV-infected children. HIV infection can also cause mt damage. Case series include 13 vertically HIV-infected pediatric patients (9 girls, median age 10.5 years) with optimal long-term response to a first-line HAART regimen who underwent planned treatment interruption (PTI). MtDNA content from peripheral blood mononuclear cells was assessed by means of a real-time PCR technique at PTI and 12 months later and expressed as an mtDNA/nuclear DNA ratio, together with lactate levels. At PTI, patients had remained a median time of 4.7 years on HAART and 4.3 years with complete suppression of viral replication. The main reason leading to PTI was treatment fatigue. One month after PTI, HIV plasmatic viral load had increased to 4.8 log copies/ml and stabilized thereafter. During the 12-month study period, all children remained free from any HIV-related clinical event. A progressive and significant decrease in median CD4 cell counts and percentages was observed 12 months after PTI. One year after PTI, the median mtDNA/nuclear DNA ratios had increased from 0.76 to 1.08 (p = 0.002) and lactate levels had decreased (from 1.12 to 0.73 mmol/liter; p = 0.019). Changes in mtDNA did not correlate with changes in lactate levels. No relationship was found between the evolution in mt toxicity markers and the rest of the clinical, immunological, and virological variables. In this series, PTI led to a partial restoration of mtDNA levels and a significant decrease in lactate values.

Mitochondrial impairment in HIV-infected children

Purpose of the study Mechanisms of mitochondrial impairment induced by HIV infection itself and highly active antiretroviral therapy (HAART) are well-studied in adults. However, there is more left to know in children, since they are the first following-up generation with the disease. The aim of this study is to determine whether there are alterations in mtDNA content and MRC dysfunctions in peripheral blood mononuclear cells (PBMCs) in HAART-treated and non-HAART-treated HIV-infected children.

Highly active antiretroviral treatment (HAART) interruption leads to an increase in mitochondrial DNA content in HIV-infected children

Purpose of the study HIV infection itself and antiretroviral treatment, especially nucleoside analogue reverse transcriptase inhibitors (NRTIs), cause mitochondrial impairment in HIVinfected patients, due to the inhibition of a-polymerase, the only enzyme responsible for mitochondrial DNA (mtDNA) replication. We investigated whether there are changes in mtDNA content after 1 year of treatment interruption in children.

Mitochondrial toxicity of antiretrovirals in non-HIV-infected patients

Purpose of the study Antiretroviral (ARV) toxicity, especially of nucleoside-analogues, together with HIV-infection have both been demonstrated to induce mitochondrial DNA (mtDNA) depletion and mitochondrial dysfunction. The contribution of each mechanism (either HIV or ARV) to the observed mitochondrial damage present in HIV-infected patients on highly active ARV treatment (HAART) is difficult to elucidate. HIV-induced mitochondrial lesion has been studied in HIV-infected but non-HAART-treated individuals, but ARV-related mitochondrial damage has been poorly explored in non-infected subjects. The aim of the present study is to assess in vivo mitochondrial toxicity of HAART without HIV-infection effects.