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Mitochondrial damage in adipose tissue of untreated HIV-infected patients - publication pdf attached
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Published Ahead-of-Print
AIDS:
POST AUTHOR CORRECTIONS, 9 December 2010
Gloria Garraboua,M, Sonia Lo peza,M, Constanza More na, Esteban Mart nezb, Joan Fontdevilac, Francesc Cardellacha, Josep Maria Gatellb and O scar Miro a
aMitochondrial Research Laboratory, Internal Medicine Department, Muscle Research Unit, IDIBAPS, University of Barcelona, Barcelona, Centro de Investigacio n Biome dica en Red de Enfermedades Raras (CIBERER, Valencia), bInfectious Diseases Department, and cPlastic Surgery Department, Hospital Clinic of Barcelona, Barcelona, Catalonia, Spain. Correspondence to Dr Glo ria Garrabou, Mitochondrial Research Laboratory 413 IDIBAPS, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Catalonia, Spain.
"Our results indicate that mtDNA depletion and associated mitochondrial dysfunction are present in SAT of naive patients, even just after 18 months of infection. Such finding corroborates our hypothesis that HIV itself may play a role in adipose tissue mitochondrial lesion, classically considered a characteristic feature of lipody- strophy. However, most of the studies performed on adipose tissue did not find mitochondrial differences between seronegative and naive [18,20,24,25] or treated HIV patients [25,26], except when tNRTI-treated individuals were individually compared. These studies mainly concluded that ART led to adipose tissue mitochondrial impairment [18-20,22-26] and demon- strated mitochondrial benefits of tNRTI interruption or switching to less mitotoxic schedules [7,17,27]. Based on our findings, mitochondrial damage in fat of naive individuals suggests that the virus itself may contribute to the mitochondrial dysfunction present in the target tissue of lipodystrophy, which is indeed confirmed by the negative correlation found between viral load and SAT mitochondrial function."
Abstract
Objective: Antiretrovirals, especially thymidine-analogue nucleoside reverse transcriptase inhibitors (tNRTIs), may cause the mitochondrial damage in adipose tissue that has been associated with lipodystrophy development. HIV itself may damage blood cell mitochondria. However, the viral capacity to induce adipose tissue mitochondrial lesion is still a matter of doubt. We aimed to assess whether untreated HIV infection was associated with adipose tissue mitochondrial abnormalities.
Design: Single-site, cross-sectional, controlled observational and exploratory study without intervention.
Methods: We included 24 uninfected controls and 18 HIV-infected patients with undetectable viral load and no clinical signs of lipodystrophy stratified as antiretroviral naive (n = 11) or at least 6-month antiviral-treated with a double NRTI combination, including lamivudine plus one tNRTI (n = 7). Subcutaneous adipose tissue was homogenated to determine mtDNA content by rtPCR and mitochondrial function per mitochondria through the spectrophotometric measurement of cytochrome c oxidase activity normalized by citrate synthase amount (COX/citrate synthase). Differences in mitochondrial parameters among groups were sought to determine the contribution of HIV and antiretrovirals to mitochondrial alterations.
Results: Compared with uninfected controls (arbitrarily assigned 100%), naive individuals presented a marked decrease in adipose tissue mtDNA content and COX/citrate synthase function (62 and 75% remaining content/activity, P < 0.001 and P < 0.05). Antiretrovirals did not increase this impairment (69 and 70% remaining content/activity, P < 0.05 compared to controls and P = not significant compared to naives). Additionally, molecular and functional mitochondrial parameters were positively correlated (P < 0.05).
Conclusion: In nonlipodystrophic HIV-infected naive patients, viral infection is associated with adipose tissue mtDNA decrease and mitochondrial dysfunction independently of antiretroviral treatment.
DISCUSSION
As an exploratory study, the number of included patients was small. The reduced sample size was due to the invasiveness of the approach, which required adipose tissue biopsy collection. Unfortunately, this is a common characteristic of many other studies in the literature [17- 20,25,26]. However, despite the reduced number of cases, we were able to obtain conclusive results for the testing of our hypothesis. Other limitation of our study could be the different location of SAT. We did not use visceral adipose tissue or SAT susceptible to containing brown adipocytes (present on the buffalo hump depots of lipodystrophy patients). We analyzed periumbilical SAT of nonlipody- strophy individuals, unless clinician or patient advice asked for an alternative location. In those few cases, SAT was obtained from the arm. Therefore, we think that dual SAT location should not affect our findings because both kinds of samples are constituted by white adipocytes and were always present in all the groups of patients analyzed.
Our results indicate that mtDNA depletion and associated mitochondrial dysfunction are present in SAT of naive patients, even just after 18 months of infection. Such finding corroborates our hypothesis that HIV itself may play a role in adipose tissue mitochondrial lesion, classically considered a characteristic feature of lipody- strophy. However, most of the studies performed on adipose tissue did not find mitochondrial differences between seronegative and naive [18,20,24,25] or treated HIV patients [25,26], except when tNRTI-treated individuals were individually compared. These studies mainly concluded that ART led to adipose tissue mitochondrial impairment [18-20,22-26] and demon- strated mitochondrial benefits of tNRTI interruption or switching to less mitotoxic schedules [7,17,27].
Based on our findings, mitochondrial damage in fat of naive individuals suggests that the virus itself may contribute to the mitochondrial dysfunction present in the target tissue of lipodystrophy, which is indeed confirmed by the negative correlation found between viral load and SAT mitochondrial function. These results corroborate previous findings of altered mito- chondrial function in adipocytes [10,11] and PBMC [13,14] of naive patients. According to the present findings, HIV could be contributing to the mitochon- drial impairment found on adipose tissue of lipody- strophy patients, together with ART. That fact could explain rare cases of lipodystrophy in naive individuals and, above all, would explain reported association between decreased number of CD4¥ T lymphocytes and higher risk of lipodystrophy [28]. Such finding abrogates for the current established guidelines of early treatment management of HIV infection to avoid deleterious effects triggered by the virus and to prevent reservoirs constitution.
We did not observe additive mitochondrial toxicity when considering dual presence of HIV and ART, though considering tNRTI drugs with well known mitochon- drial toxicity. This may be explained because ART- negative effects exerted against mitochondria may be balanced by ART-positive mitochondrial effects decreas- ing viral load and its derived mitotoxic capacity, thereby leading to similar levels of mitochondrial lesion in naive and treated patients. Such finding is in agreement with results of clinical trials reporting SAT increase in HIV individuals after tNRTI introduction [29,30]. However, we do not know future consequences of HIV-induced mitochondrial dysfunction compensated by ART into lipodystrophy development.
Both molecular and functional mitochondrial parameters were positively correlated confirming the strong dependence of mitochondrial function on mitochondrial genome [5,14]. A similar correlation was observed by Hammond et al. [24] in adipose tissue of HIV-treated patients concomitant with evidence of cellular toxicity. Homeostatic transcriptional and translational upregulatory mechanisms can compensate HIV and ART-induced mtDNA depletion in PBMCs [31]. However, observed adipose tissue mitochondrial dysfunction in naive and treated patients suggests that such upregulatory mechanism designed to preserve mitochondrial function may be weaker in adipocytes. This would explain adipocyte susceptibility to become damaged by mitotoxic agents and physiologic vulner- ability of individuals to lipodystrophy. Additionally, the idea of a complex scenario involving other modulating factors (inflammation, oxidative stress, apoptosis, alteration of adipogenesis and adipocyte differentiation or adipokine and cytokine levels) is gaining in strength and may help to explain lipodystrophy and different regional fat behavior (visceral versus subcutaneous) [1 - 4,10 - 12]. Probably, all these factors condition lipodystrophy. Nonetheless, without HIV or ART mitotoxic activity, lipodystrophy would not probably be developed.
In summary, we have demonstrated that uncontrolled HIV infection is associated with mitochondrial abnorm- alities in SAT. These effects are partially compensated by ART, even when such treatment contains tNRTIs.
Clinical implications of these findings in the context of currently administered ART are unknown and would deserve prospective evaluation in longitudinal studies to assess mitochondrial effects of ART introduction in adipose tissue of HIV individuals.
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