Mitochondrial functionalism in HIV-infected children receiving antiretroviral therapy

Abstract

It is widely known that HIV and ARV drugs trigger mitochondrial impairment in adults. However, their effects in perinatally-infected children have been poorly explored. For this reason, the main hypothesis of the present Thesis was to demonstrate that mitochondrial abnormalities are present in HIV-infected pediatric patients treated with ARV.

It is expected to find mitochondrial alterations in asymptomatic perinatally HIV-infected children. This mitochondrial lesion, manifested in a depletion of the mitochondrial genome, would lead to a reduction of the mitochondrial protein synthesis or to a mitochondrial dysfunction and, as a last resort, compromising the cellular viability. However, it is also possible that the presence of homeostatic mechanisms in mitochondria entails a proper function of some complexes, even in the presence of mitochondrial genome depletion.

Rather than a localized mitochondrial alteration in a specific enzymatic activity, it is possible that HIV and ARV cause a diffuse damage in the organelle which may be observed in a general assessment of the respiratory chain. In case of a mitochondrial alteration, either in asymptomatic or symptomatic patients, it would be expected a more evident presentation of mitochondrial toxicity in case of the latter.

If our hypothesis of an evidence of mitochondrial toxicity derived from HIV and ARV in children is confirmed, we believe that, once the detrimental agent is withdrawn, a recover of the mitochondrial affectation is possible.

Mitochondrial impairment may change depending on the type of HAART regimen, leading us to use mitochondrial parameters as a biomarker or a trail to find the best therapeutic options in the choice of different HAART schedules. In this context, the intensity of mitochondrial impairment over time would be higher in children receiving first generation NRTI which, in turn, have been demonstrated to present a higher mitochondrial toxicity in vitro, than those under second generation NRTI.

In order to study and test our hypothesis, the main objectives of the present Thesis are:

A) General Objective

To test if HIV and ARV mechanisms of mitochondrial toxicity found in adults are present in perinatally HIV-infected children.

B) Specific Objectives

- Objective 1: To elucidate whether ARV treatment or HIV infection were exerting a mitochondrial toxic effect in asymptomatic perinatally HIV-infected pediatric patients receiving HAART. - Objective 2: To investigate if hypothetic alterations in the mitochondrial genome of asymptomatic HIV-infected children receiving ARV are downstream reflected at transcriptional, translational and functional levels. In case of mitochondrial dysfunction was present, to test whether MRC alterations are focalized or diffuse.

- Objective 3: To determine mitochondrial status in lipodystrophic HIV-children and compare them to a group of asymptomatic children and to a group of uninfected controls.

- Objective 4: To evaluate whether a 12-month interruption of ARV is able to improve or revert these hypothetic mitochondrial alterations at molecular and/or clinical level.

- Objective 5: To compare mitochondrial toxicity derived from different HAART schedules in a longitudinal 2-year follow-up assessment of immunovirological and mitochondrial status under first or second generation NRTI. To elucidate whether those NRTI demonstrated to present high mitochondrial toxicity in vitro present a major toxicity in vivo as well.