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Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013 Article ID 493413 13 pageshttpdxdoiorg1011552013493413

Review ArticleRole of Mitochondria in HIV Infection and AssociatedMetabolic Disorders Focus on Nonalcoholic Fatty LiverDisease and Lipodystrophy Syndrome

P Peacuterez-Matute1 L Peacuterez-Martiacutenez1 J R Blanco12 and J A Oteo12

1 HIV and AssociatedMetabolic Alterations Unit Infectious Diseases Department Center for Biomedical Research of La Rioja (CIBIR)Piqueras 98 La Rioja 26006 Logrono Spain

2 Infectious Diseases Department Hospital San Pedro La Rioja 26006 Logrono Spain

Correspondence should be addressed to P Perez-Matute cpperezriojasaludes

Received 28 June 2012 Revised 9 January 2013 Accepted 26 June 2013

Academic Editor Jose Magalhaes

Copyright copy 2013 P Perez-Matute et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients Howeverprolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associatedlipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD) There is consistent evidence for a central roleof mitochondrial dysfunction in these pathologies Nucleotide reverse transcriptase inhibitors (NRTIs) have been described tobe mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors(NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity which is a major concern for the selection and thelong-term adherence to a particular therapy Several mechanisms explain these deleterious effects of HAART on mitochondriaand evidence points to other mechanisms beyond the ldquoPol-120574 hypothesisrdquo HIV infection has also direct effects on mitochondria Inaddition to the negative effects described for HIV itself andor HAART on mitochondria HIV-infected patients are more proneto develop a premature aging and therefore to present an increased oxidative state that could lead to the development of thesemetabolic disturbances observed in HIV-infected patients

1 HIV Infection and Antiretroviral Therapy

Human immunodeficiency virus (HIV) infection is a seriouspublic health disorder that affects up to 34 million peoplein the world [1] Since this disease was firstly identifiedand described in the 80s it has infected at least 60 millionpeople and caused more than 25 million deaths [2] Theintroduction of highly active antiretroviral therapy (HAART)has considerably improved the prognosis of HIV-infectedpatients leading to a significant reduction of HIV-relatedmorbidity andmortality [3] For these reasons HIV infectionis nowadays considered ldquojustrdquo a chronic infection There aremore than 20 approved antiretroviral drugs classified into fivegroups according to the mechanisms by which they interruptthe HIV life cycle (Table 1) Current HAART guidelines rec-ommend as first line of treatment two nucleosidenucleotidereverse transcriptase inhibitors (NRTIs) combined with

either one protease inhibitor (PI) one nonnucleoside reversetranscriptase inhibitor (NNRTI) or an integrase inhibitor[4 5] Cohort studies and clinical trials have demonstratedthat an early initiation of antiretroviral therapy is neededto optimize individual and public health outcomes [6 7]However HAART does not completely eliminate HIV andtreatment must continue throughout patientrsquos life Prolongeduse of HAART has been related to long-term adverse eventsthat can compromise patient healthThese deleterious effectshave been reported for the majority of antiretroviral drugsand are themost common causes for therapy discontinuationSome of these disturbances are cardiovascular neurocog-nitive bone or renal diseases [8ndash10] One of the mostfrequent secondary adverse events caused by HAART isknown as HIV-associated lipodystrophy syndrome (HALS)Recent studies also suggest that since the widespread useof HAART liver diseases represent an important cause of

2 Oxidative Medicine and Cellular Longevity

Table 1 Current employed anti-HIV drug families and reported mitochondrial toxicity (modified from Apostolova et al 2011) [17]

Drug family (antiretroviral) Mechanism of action Mitochondrial dysfunction

Nucleosidenucleotide reversetranscriptase inhibitor (AbacavirDidanosine Emtricitabine LamivudineStavudine Tenofovir and Zidovudine)

Interferes with the HIV reversetranscriptase protein needed by the virusto make new copies of itself

Inhibition of Pol-120574Depletion of mtDNAReduction of mtDNA-encoded proteinsRespiratory chain dysfunctionDirect inhibition of ETC complexes (I IV)Reduction of ATP levelsROS productionDecrease in 119860120595

119898

Impairment of ADPATP translocaseImpairment of fatty acid oxidation

Nonnucleoside reverse transcriptaseinhibitor (Efavirenz Etravirine andNevirapine)

Stops HIV replication within cells byinhibiting the reverse transcriptaseprotein

Respiratory chain dysfunctionReduction of ATP levelsROS productionDecrease in 119860120595

119898

Apoptosis

Protease inhibitor (AtazanavirDarunavir Fosamprenavir LopinavirRitonavir and Saquinavir)

Inhibits the HIV protease activity aprotein required for HIV replication

Inhibition of MPP (mitochondrial proteaseprocessing)Fragmentation of mitochondrial networkIncrease in mitochondrial Ca2+ accumulationApoptosisROS production

Fusion inhibitor (Enfuvirtide) Prevents HIV from binding to or fromentering human immune cells Unknown

CCR5 inhibitor (Maraviroc) Prevents HIV from binding to or fromentering human immune cells Unknown

Integrase inhibitor (Raltegravir)Interferes with the integrase enzymewhich is needed to insert HIV geneticmaterial into human cells

Unknown

morbidity and mortality in HIV-infected patients Severalstudies have demonstrated mitochondrial impairment inHIV-infected patients and especially in those suffering fromHALS or fatty liver suggesting a pivotal role of mitochondriadysfunction in the pathophysiology of these alterationsThusthis review summarizes the main findings related to therole of mitochondria in HIV and these two alterationsassociated HALS and fatty liver Furthermore evidence hasaccumulated suggesting that HIV-infected patients are underchronic oxidative stress and mitochondria dysfunction couldcontribute to this increased oxidative stateTherefore we alsodescribe the role of oxidative stress in HIV infection and howdifferent compounds with antioxidant capacities have beenstudied in an attempt to decrease this oxidative state in a wayto ameliorate the deleterious effects of HIV-infection and itsmetabolic associated disorders

2 HIV and Mitochondria

Mitochondria are intracellular organelles present in all mam-malian cells (except red blood cells) They contain an outermembrane an intramembrane space an inner membraneand the matrix where the mitochondrial genome is found

Eachmammalian cell contains several hundreds tomore thana thousand mitochondria The size shape and abundanceof mitochondria vary dramatically in different cell typesand may change under different energy demands and dif-ferent physiological or environmental conditions The mainfunction of mitochondria is to synthesize ATP throughelectron transport andoxidative phosphorylation (OXPHOS)in conjunction with the oxidation of metabolites by tricar-boxylic acid cycle and catabolism of fatty acids by beta-oxidation In this sense the mitochondrion had been foryears considered to be simply the fuel provider for the mostbasic energy demands of the cells Howevermitochondria arenow recognised as being critical components in the controlof multiple key cellular processes being the main arbitratorin the initiation and execution of apoptosis and thereforeplaying a pivotal role in the determination of life and deathof the mammalian cells In addition mitochondria are themain intracellular source and immediate target of reactiveoxygen species (ROS) [14] During energy transduction in themitochondrial electron transport chain a small number ofelectrons ldquoleakrdquo to oxygen prematurely forming the oxygen-free radical superoxide [15] Under normal conditions thekey site of superoxide formation in the mitochondrial

Oxidative Medicine and Cellular Longevity 3

membrane is complex I and the ubiquinone-complex IIIinterface Given that ROS are highly reactive and short-livedspecies it is tempting to suggest that their effects should begreatest in immediate area surrounding their locus of produc-tion Thus mitochondrial membrane constituents includingthe complexes of the respiratory chain and phospholipidsconstituents are not only important sources of ROS but alsomajor targets of ROS attack [16]

Several factors can affect the functionality of mitochon-dria such as aging infections or certain antiretroviral drugsThese factors can damage the mitochondria affecting thenormal functioning of the cell Mitochondrial toxicity is ageneral term that refers to these changes it can cause differentsymptoms in the heart nerves muscles pancreas kidneysand liver and it is involved in several disorders

It is plausible that chronic infection and inflammationandor drugs with adverse effects on mitochondrial func-tion would contribute to long-term complications in HIV-infected persons A large list of clinical manifestations ofmitochondrial toxicity has been described within HAART-associated adverse events which is a major concern for theselection and the long-term adherence to a particular therapyFor example the increase in tumor necrosis factor (TNF120572)production which can directly affect the mitochondrialfunction has been observed in patients with HIV infectionand under antiretroviral treatment [18]

NRTIs have long been considered the main source ofHAART-related mitochondrial toxicity These toxicities canbe difficult to reverse and can be life-threatening The exactpathogenesis underlying NRTI-induced mitochondrial toxi-city remains unclear and likely differs for specific NRTI drugs[19] NRTIs ability to inhibit Pol-120574 the DNA polymeraseresponsible for the synthesis of mitochondrial DNA hasbeen described Nevertheless accumulating evidence pointsto a more complex relationship between these organelles andNRTIs and other mechanisms beyond the ldquoPol-120574 hypothesisrdquohave been raised in the last years suggesting that there areothermechanisms ofmitochondrial interference both relatedand unrelated to mtDNA (reviewed by Apostolova et al2011) [17]Thus inhibition of mitochondrial RNA expressionhas been observed in several cell lines exposed to NRTIs[20] which may occur through mtRNA polymerase inhibi-tion or by limitation of the cofactors essential for mtDNAtranscription Some NRTIs also exert a direct inhibitoryeffect on specific mitochondrial targets unrelated to mtDNAThus AZT inhibits the mitochondrial adenylate kinase andadenosine nucleotide translocator in isolated mitochondria[19] AZT also promotes oxidative stress (OS) and exertsa direct inhibitory effect on the electron transport chainthereby diminishing OXPHOS [21 22] NRTIs also inducea significant reduction in complex IV activity and a specificinhibition of complex I [21 23 24] In vivo studies with AZTdemonstrated a disrupted cardiac mitochondrial ultrastruc-ture diminished expression of mitochondrial cytochromeb mRNA and the presence of OS in mtDNA Mitochon-drial ROS generation has also been suggested to accom-pany or even constitute a separate mechanism of NRTI-induced mitochondrial toxicity It is also important to statethat tissue and compound-specific patterns of drug import

compartmentalization and activation may account at leastin part for variation in mitochondrial toxicity according tospecific NRTIs andor tissue Furthermore not all the drugsof this group exert their deleterious effects on mitochondriawith the same intensity In fact what became apparentfrom several in vitro studies is that the order of ranking oftoxicity differs depending on the cell line and the methodused for measuring mitochondrial dysfunction (reviewed byMallon 2007) [25] Thus AZT and D4T are more toxicto adipocytes while ddC is more toxic to other cell typessuch as hepatocytes and peripheral blood mononuclear cells(PBMCs) Some observations in vivo state that ddC compo-nent of antiretrovirals (and possibly ddI) rather than d4T orAZT mediates mtDNA depletion in PBMCs in HIV-infectedpatients [25] Other anti-HIV drugs apart from NRTIs seemto also interfere with mitochondria such as PIs and NNRTIs(reviewed by Apostolova et al 2011) [26] Interestingly PIsand NNRTIs do not inhibit Pol-120574 or reduce mtDNA contentIn vitro studies revealed an increase in mtDNA in murineadipocytes treated with indinavir (IDV) [27] or treated withnevirapine (NVP) [28] Recent evidence suggests an inter-action of these groups of drugs with mitochondrial targetsimplicated in the regulation of bioenergetics and apoptosis(deeply reviewed by Apostolova et al 2011) [29] Althoughthe clinical repercussion of this interaction is undeterminedit may be relevant in the context of diseases present in long-termHAARTpatientsHowevermost findings point to drug-rather than class-specific effects [29]

It is also important to take into account that the pro-gressive aging of the HAART-treated population and thesubsequent appearance of age-related diseases are relevantIn fact it has been demonstrated that antiretroviral therapythrough the clonal expansion of mtDNA mutations acceler-ates mitochondrial aging and therefore induces mitochon-drial dysfunction [30]

Not only antiretrovirals but also HIV itself contributes tomitochondrial dysfunction HIV per se seems to underminemtDNA and provoke other mtDNA-independent mitochon-drial alterations [31] Thus HIV and HIV polypeptides(in the absence of ART) have been shown to contributeto mitochondrial dysfunction and apoptosis in CD4+ andCD8+ T cells [32ndash34] The study from Morse et al (2012)also corroborated that HIV infection has direct effects onmitochondria and that immune cell activation and inflam-mation are involved in this process In fact mitochondrialgenes were downregulated in PBMCs and adipose tissue fromHIV-infected-untreated persons relative toHIV-seronegativeand treated patients using a huMITOchip microarray [35] Astudy has demonstrated increased plasma mtDNA in acuteHIV seroconverters and ART-naive subjects compared withHIV-seronegative controls and long-term nonprogressorsand a positive correlation between plasma HIV RNA andplasma mtDNA was also observed [36] However it is worthmentioning that both increases and decreases in mtDNAhave been reported in pathogenic conditions as there isnot a standard tool for defining what constitutes an abnor-mal mtDNA quantity and therefore data from heteroge-neous HIV-infected populations were inconsistent [37ndash41]


In this sense there are also other methods to quantify thefunctionality of mitochondria such as measures of OXPHOSgenes and enzymes activities genes involved in Krebs cyclelipogenesis measurement of mitochondrial DNA damage byPCR and so forth [42]Thus depending on themeasurementused the results could be contradictory

In summary it seems quite clear that HAART andHIV itself contribute to mitochondrial dysfunction althoughthe underlying mechanisms remain partially understood Inthis context we cannot forget the importance of patientgenetics the presence of mitochondrial pathologies andorpathological settings with compromisedmitochondrial func-tion as they can all magnify the adverse effects related tomitochondria

3 Role of Mitochondria inHIV-Associated Fatty Liver Disease

Liver diseases constitute a major health problem nowadaysAmong distinct diseases nonalcoholic fatty liver disease(NAFLD) is a multifactorial condition which affects bothyoung and adult patients and which is associated with severalrisk factors (reviewed by Pettinelli et al 2011) [43] NAFLDis defined as a chronic inflammatory liver disease that occursin the absence of alcohol abuse (less than 20 g per day) andalso without infection with hepatitis B or C viruses NAFLDincludes a wide spectrum of liver diseases whose naturalhistory has not yet been fully clarified and ranging from thesimple accumulation of fat or fatty liver (process usually mildand reversible) to other phases that are not reversible suchas steatohepatitis fibrosis cirrhosis and even hepatocellularcarcinoma (HCC)

Nowadays NAFLD is one of the most prevalent chronicliver diseases in industrialized countries This is mainly dueto its association with obesity so it is prevalent in thesecountries [44] In fact NAFLD is the hepatic manifestationof themetabolic syndrome It is estimated that the prevalenceof NAFLD in the general population ranges from 25 to46 increasing to 70 in diabetics and 90 among obese[45] At present the prevalence of NAFLD continues torise worldwide and it is estimated that by 2025 more than25 million Americans may suffer from NAFLD It is alsosuggested that 20 of these patients suffering from NAFLDwill develop cirrhosis or HCC if not diagnosed or treated intime [46 47]

Prevalence of NAFLD is higher in individuals with HIVinfection (30ndash40) than in the general population (14ndash31) [48 49] In fact in HIV-infected patients since thewidespread use of HAART liver diseases represent an impor-tant cause of morbidity and mortality [50 51] Prospectivedata from the Data collection on Adverse events of Anti-HIVDrugs (DAD) showed that liver-related death was the mostfrequent cause of non-AIDS-related death and a strong asso-ciation between immunodeficiency and risk of liver-relateddeath was demonstrated [51] In a study analysing 13 cohortsof HIV-infected patients hepatic mortality accounted for71 of deaths of which 56 were associated with hepatitisindicating a significant proportion of nonhepatitis-related

deaths unrelated to the severity of HIV infection (reviewedby Lemoine et al 2012) [11 52] Recent studies also corrob-orate these results and suggest a high prevalence of hepaticsteatosis and fatty liver in HIV patients especially thoseco-infected with HCV or under antiretroviral therapy withNRTIs Although most of these studies have been carriedout in coinfected patients a recent study found that sixty-seven of 216 (31) HIV patients without HCV coinfectionhad NAFLD based on ultrasound evaluation [53] A veryrecent study also observed steatosis in 30ndash40 of HIV-infected patients associated with increased adiposity andmetabolic disorders This study also demonstrated that thedevelopment of fibrosis in these patients was related to ageinsulin resistance and the use of stavudinedidanosine [54]

The pathogenesis of NAFLD was previously based onthe ldquotwo-hit hypothesisrdquo considering steatosis as the resultof the first step in the development of NASH [55] The newldquomultiple parallel hit modelrdquo recently replaced this theoryThis new model suggests that insulin resistance and cellulardysfunction play a central role in the development of liverinjuries In fact insulin resistance is probably the ldquotruefirst hitrdquo leading to increased hepatic free fatty acid fluxfrom adipose tissue and to hepatocyte oxidativeendoplasmicreticulum stress inducing both steatosis and inflammation[56] Cellular dysfunction is the consequence of numeroushepatic and extrahepaticmechanisms andmediators Amongthem are cytokines derived from the liver but also from gutmicroflora and adipose tissue (revised by Lemoine et al 2012)[11] (Figure 1)

In the context of aging and increased prevalence ofage-related comorbidities in HIV-infected patients NAFLDNASH might represent a facet of this global aging processIn addition there is consistent evidence for a central roleof mitochondrial dysfunction in the pathophysiology ofNAFLD Mitochondria can be directly involved in the firststeps of NAFLD either when their function is affected bydrugs or by harbouring a primary defect (eg resultingfrom a DNA depletion syndrome)The loss of mitochondrialfunction will affect fatty acid beta-oxidation which willlead to the accumulation of nonmetabolized fatty acids inthe cytosol This is further complicated in the presence ofobesity and higher circulating levels of fatty acids whichmay determine per se an increased demand of mitochondrialoxidation On the other hand an increase in fatty acid beta-oxidation as a response to increase hepatocyte influx candamage normally functional mitochondria through severalmechanisms including uncoupling induction of the mito-chondrial permeability transition (MPT) and OS (Figure 1)(reviewed by Grattagliano et al 2012) [12] However impair-ment of mitochondrial function also participates in otherlevels of NAFLD pathogenesis as increasing OS and cytokineproduction triggering cell death inflammation and fibrosis(reviewed byGrattagliano et al 2012 andRolo et al 2012) [1257] In fact accumulation of lipids in the hepatocyte impairsthe oxidative capacity of the mitochondria increasing thereduced state of the electron transport chain complexes andstimulating peroxisomal and microsomal pathways of fatoxidation The consequent increased generation of ROS andreactive aldehydic derivates causes OS and cell death via ATP


Fatty

ROSROS

Increased fatty acid influx in the hepatocyte

Obesity Dyslipemia

Fatty

ROS

tissue

Insulinresistance

Obesity

Normal Fatty liver (NASH)

Dislipidemia

ROSOxidative stress(increased ROS

production)Mitochondrial

dysfunction

Drug toxicity

Healthy patient Primary defect in the liver

Loss of mitochondrial function

Increased accumulation of lipids in the cytosol


Visceral adipose

HCV HIV

HIV

NRTIs

HCV

Life style (high fat diet

InflammationCirrhosis

Increased mitochondrial fatty acid 120573-oxidationDecreased mitochondrial fatty acid120573-oxidation

intake sedentary life ect)

Figure 1 Role ofmitochondria inNAFLD initiation and progression (modified fromLemoine et al 2012 andGrattagliano et al 2012) [11 12]

NAD and glutathione depletion and it finally leads to DNAlipid and protein damage [57]Throughmitochondrial toxic-ity NRTIs such as stavudine and didanosine have been iden-tified as factors of NAFLD and fibrosis [58ndash60] In this sensethe study of Guaraldi et al (2008) suggested that NAFLD iscommon in HIV patients who have traditional risk factorsbut this study also highlights that treatment with NRTIs isalso an important independent risk factor increasing up to11 the risk of developing hepatic impairment for each yearof use [60] Some protease inhibitors are also hepatotoxic inparticular full-dose ritonavir and tipranavir [61] Howeverthe generalized use of only boosting concentrations of riton-avir prevents the liver toxicity Other protease inhibitors wereproposed to induce abdominal lipohypertrophy and to dis-turb glucose and lipid homeostasis the underlying conditionsof NAFLDNASH In addition some HIV-infected patientseven receiving recently marketed antiretroviral drugs con-sidered as nondeleterious on metabolism and adipose tissuedevelop striking abdominal hypertrophy Efforts have beenrecently made to assess the clinical relevance of noninvasivetests including the evaluation of mtDNA or mitochondrialfunctions in peripheral blood mononuclear cells for thediagnosis of antiretroviral-associated toxicity (reviewed by

Duong et al 2005) [62] In addition COX subunit I labelinghas been suggested to be a valuable tool for the diagnosis ofmitochondrial liver disease in HIV patients [63] Efavirenz(EFV) is the most widely used NNRTIs applied in HAARTIts use has been associated with the development of severaladverse events including hepatotoxicity Recent reports havehighlighted features of mitochondrial dysfunction in hepaticcells exposed to clinically relevant concentrations of EFV inhuman hepatic cells in vitro [64] Clinical concentrations ofEFV also induce bioenergetic stress in hepatic cells by acutelyinhibiting mitochondrial function This new mechanism ofmitochondrial interference leads to an accumulation of lipidsin the cytoplasm that is mediated by activation of AMPK[65] A recent study has also suggested that autophagy couldbe involved in the EFV-associated hepatotoxicity and itmay constitute a new mechanism implicated in the genesisof pharmacological liver damage and in the recovery ofhepatic homeostasis upon a drug-induced cellular insult [66]However and despite the fact thatmitochondrial dysfunctionseems to be associated with the development of NAFLD inHIV-infected patients there are other studies carried out inliver biopsies where no association has been found betweenthe presence of NASH and liver mitochondrial function or


mitochondrial DNA content [67 68] These discrepanciescould be due to the fact that it is very difficult to comparein vitro versus in vivo studies or that these two studies relateNASH and not NAFLD with mitochondrial dysfunction Sofar more studies are needed in this regard to confirm theinvolvement of mitochondrial dysfunctiondamage in thedevelopment of NAFLD in HIV-infected patients

A novel mechanism by which HIV not only enhancesHCV replication but also contributes to progression ofhepatic fibrosis has been demonstrated [69] In fact it hasbeen found that inactivated HIV or its envelope glucoproteingp120 were capable of upregulating TGB-1205731 expressionFurthermore HIV and HCV may independently regulatehepatic fibrosis progression through the generation of ROSand this regulation occurs in an NF-120581B-dependent manner[70]

To date there is no specific treatment against NAFLDboth in general and HIV-infected populations Since insulinresistance is the pathophysiological hallmark of NAFLDNASH interventions to improve insulin sensitivity representone of the main strategies for the therapeutic managementof these patients Thus one therapeutic option is the use ofmolecules that sensitize to insulin and although histologicalimprovements have been observed the fact is that they do notoffer additional long-termbenefitsMetformin and glitazones(thiazolidinediones) have been the main insulin-sensitizingmolecules tested for the treatment of NASH but the poorbenefit of metformin has been confirmed in a recent meta-analysis [71] However metformin treatment was recentlyfound to decrease HCC occurrence and liver-related deathin HCV-related compensated cirrhosis [72] Indeed the poorsafety of glitazones has recently led to their removal from themarket Hepatoprotective agents have been also evaluatedand some of them may be proposed in the case of severeliver disease defined by the presence of NASH and significantfibrosis (F2) The correction of metabolic risk factors loss ofweight and physical activity seem to be the cornerstones forthat [73] Another treatment option is the use of statins toimprove several biological markers of this disease (ASTALTlipid profile) although their effects on liver histology areunknown In most cases liver transplantation is requiredIn fact NAFLD is the third most frequent cause of livertransplant and some researchers suggest that in the next 10ndash20 years NAFLDwill be the leading cause of transplants withthe high cost that it implies in health services

4 Role of Mitochondria in HIV-AssociatedLipodystrophy Syndrome

HIV-associated lipodystrophy syndrome is characterised byalterations in adipose tissue distribution in association withsystemic metabolic complications The alterations of adiposetissue consist of loss of subcutaneous fat in face limbsand buttocks [74] accumulation of visceral adipose tissuein abdomen breast and dorsocervical regions [75] andlipomatosis especially in the dorsocervical area (ldquobuffalohumprdquo) These alterations do not necessarily occur togetherin the same patient or with the same frequency Subcutaneous

loss of adipose tissue occurs frequently although more thanhalf patients present a mixed form loss of subcutaneoustogether with marked increase in visceral adipose tissue[76]Themetabolic abnormalities comprise hyperlipidaemiainsulin resistance and lactic acidaemia HIV-linked lipodys-trophy is also associated with atherosclerosis hypertension[77 78] and hepatic steatosis [79] Increased central fatand decreased limb fat are both involved in these metaboliccomplications as the increased release of cytokines and freefatty acids together with decreased adiponectin productionby adipose tissue leads to insulin resistance and triglyc-eride depots in tissues such as liver skeletal muscle andheart Moreover aging is also physiologically associated withfat redistribution OS and low-grade inflammation so itmay be a relationship between HALS and aging Thereforelipodystrophy togetherwithmetabolic alterations contributesto the phenotypes of premature aging observed in thesepatients leading to early cardiovascular and hepatic diseaserisk (deeply reviewed by Caron-Debarle et al 2010) [80]

The prevalence of HALS is about 50 although reportedpercentages vary in different studies (20ndash80) [76 81 82]Lipodystrophy and especially facial lipoatrophy can erodeself-esteem cause psychological distress affect quality oflife and lead to depression It also affects adherence totreatments However and up to date there is no effectivetreatment for lipodystrophy and only cosmetic surgery seemsto be clinically recommended Because of that the knowledgeof the mechanisms involved in this syndrome will helpto develop different strategies to prevent it or at least tominimize its metabolic complications Unfortunately themolecular basis of this syndrome is not fully understoodalthough intensive research in recent years has suggested thatadipocyte dysfunction is a key point

HAARTmight play an important role in the developmentof HALS In this sense NRTIs favour lipoatrophy whereasviral PIs tend to promote visceral lipohypertrophy andsystemic metabolic disturbances However recent studiessuggest that drugs of the three main classes (NRTIs IPs andNNRTIs) act in synergy Duration of HIV infection age andgender may also contribute to the risk of development ofHALS A role for genetics is also probable but has been onlypartly evaluatedThe toxicity of antiretroviral also depends onpatients metabolism which is partly genetically determined[83]

The importance of mitochondria in most cells is knownIn adipocytes mitochondria play an important role in theirdifferentiation and function Preadipocytes mature in twosteps differentiation and then hypertrophy During the earlymaturation stage an increased number of mitochondriaare required [84 85] resulting in small adipocytes whichare highly sensitive to insulin and that secrete high levelsof adiponectin [85] By contrast older adipocytes increasein size (hypertrophy) lose their functional activities andbecome resistant to insulin They exhibit decreased numbersof mitochondria with impaired functions and secrete lessadiponectin [85] Furthermore the respiratory chain gener-ates mitochondrial ROS which could have dual effects onadipocyte differentiation At physiologically low levels ROScould act as secondary messengers to activate adipogenesis


HIV

Pisr

HIV

PIsr

HIV

Pisr

NRTIsInhibition of mtRNA

Increased adipogenesis(hyperplasia)

Increased lipogenesis(hypertrophy)HIV

Mitochondrial mutations in mtDNA accelerate mitochondria aging

PIsr

Inhibition of targets unrelated to mtDNA (krebs cycle lipogenesis ect)

Mild mitochondrial dysfunction

If not treated

Severe mitochondrial dysfunction

uarr ROS

uarruarr ROS

darr mtDNA

darrdarr mtDNA

Decreased adipogenesisDecreased cell sizeIncreased apoptosis

Lipoatrophy

Inhibition of DNA polymerase 120574

Figure 2 Proposed deleterious impact of mitochondrial dysfunction on adipose tissue (modified from Caron-Debarle et al 2010) [13]

and lipogenesis resulting in increased adipocyte number andsize but at higher levels ROS could inhibit differentiationHigh ROS concentrations which are associated with severemitochondrial dysfunction inhibit the expression of theadipogenic factor PPAR120574 [86] and induce cell apoptosis [8487] which could result in lipoatrophy [84]

Longitudinal studies comparing subcutaneous fat inHIV-infected patients before and after HAART initiation haveprovided important clues Thus six to eight months oftreatment with NRTIs alter the expression of several keymitochondrial electron transport genes in subcutaneous fatwhich leads to increased OS [88] A reduction in mitochon-drial activity and mtDNA has also been observed [89] Inaddition several in vitro studies have shown that NRTIs suchas zidovudine stavudine and didanosine result in mtDNAdepletion [90] Thus NRTIs exert severe adverse effects onmitochondria leading to increased ROS production that isprobably directly involved in lipoatrophy This early drug-induced mitochondrial dysfunction could lead to an initialincrease in subcutaneous fat before fat loss associated withmore advanced and severe mitochondria dysfunction Mildmitochondrial toxicity leads to an increased production ofROS which probably activates mitochondrial biogenesisadipogenesis and adipocyte hypertrophy If mitochondrialfunction is more severely affected several disturbances inmitochondrial bioenergetics including increased ROS pro-duction are produced which makes the tissue not ableto supply the necessary energy requirements A decreasein adipocyte size and an increase in adipocyte death isinduced and this could lead to clinical lipoatrophy [13](Figure 2) Switching patients from stavudine to tenofovir

improves fat mitochondrial function and decreases OS [91]The replacement of these drugs with other NRTIs or NNRTIsor new drugs allows for the partial recovery of lipoatrophy oreven causes fat hypertrophy

As lipodystrophy has been observed in HIV-infectedantiretroviral-naive patients a possible role for the virus inthe development of this syndrome has been suggested Infact the HIV infection of macrophages itself could resultin low-grade fat inflammation and leads to the releaseof viral proteins that affect neighboring adipocytes anddecreases their differentiation Even when HIV infection iscontrolled by HAART the persistent infection of reservoirfat macrophages which is probably related to the severityof the initial infection could help maintain the lipodys-trophic phenotype Furthermore initial HIV infection asso-ciates with increased bacterial translocation through the gutleading to increased circulating levels of lipopolysaccharide(LPS) [92] which activates macrophages through the TLF-4 receptor and increases cytokine production (reviewed byCaron-Debarle et al 2010) [80] In this context whethermitochondrial function is altered in fat from naive patientsremains a matter of debate either no or mild alterations havebeen reported in most studies [88 89 93] whereas moresevere defects were observed by Giralt and colleagues [94]In this context a very recent study has demonstrated thatHIV infection and antiretroviral therapy could have divergenteffects on mtDNA in adipose tissue [35] Thus mtDNAcontent in adipose tissue is decreased in HIV-infected adultsreceivingHAART with themost profound reductions seen inpatients with lipodystrophy whereas an increase in mtDNAcontent in adipose tissue was also observed in HIV-infected


patients not receiving HAART Therefore more work isneeded in this regard in order to better elucidate the physi-ological significance of such duality

5 HIV and Oxidative Stress

As stated before mitochondria are the main intracellularsource and immediate target of ROSThese reactive species ifnot counterbalanced by antioxidant defenses could damageDNA proteins carbohydrates and lipid constituents andcompromise cell function leading to the development ofa number of diseases such as AIDS [95] Oxidative stresscan result from diminished levels of antioxidants but canalso result from increased production of ROS [96] It istempting to suggest thatmitochondria dysfunction andmorespecifically the abnormal mitochondrial ROS generationcould contribute to the increased oxidative state observedin HIV-infected patients In fact evidence has accumulatedsuggesting that HIV-infected patients are under chronicOS Indications of OS are observed in asymptomatic HIV-infected patients early in the course of the disease A widevariety of research supports the theory that OS is involved inthe progression of HIV disease (reviewed by Pace and Leaf1995) [97] In fact the role of oxidative stress in HIV diseaseappears to be quite broad and may involve viral replicationbut also immune response apoptosis disease progressionweight loss and so forth [97ndash99] Tat protein (a proteinthat plays a pivotal role in both HIV-1 replication cycle andthe pathogenesis of HIV-1 infection) induces a progressiveelevation of cytoplasmic-free calcium levels which is fol-lowed by mitochondrial calcium uptake and generation ofmitochondrial ROS [100] These mechanisms also contributeto increase HIV transcription Apart from increased ROSproduction observed inHIV-infected patients HIV infectionis also able to inhibit glutathione synthesis [101] which isthe main endogen antioxidant HIV-infected persons at allstages of the disease have decreased intracellular glutathionelevels In this sense perturbations to the antioxidant defencesystem including changes in levels of ascorbic acid toco-pherols carotenoids selenium superoxide dismutase andglutathione have been observed in various tissues of thesepatients in comparison with a control population In addi-tion plasma zinc and selenium concentrations are very lowin HIV-infected patients [102] In fact selenium deficiencyis common in HIV-positive patients as documented by lowplasma and red blood cell levels of selenium diminishedactivity of glutathione peroxidase and low cardiac seleniumlevels in AIDS hearts Poor dietary intake and malabsorptioncould lead to this condition which has important impli-cations for both cardiac and immune functions in HIV-positive patients [103] Not only HIV monoinfection but alsoHIVHCV-coinfection is associated with decreased plasmaantioxidants when compared to HIV monoinfection [104]Furthermore a decrease of serum total antioxidant statushas also been observed in HIV-infected patients on HAART[95] In this context it is suggested that HIV infectionincreases the OS process and antiretroviral combinationtherapy increases protein oxidation and preexistent OS [99]Thus those patients who had an optimal HAART adherence

have significantly higherOS than thosewith a poor adherence[95] In general terms the increase in OS observed afterHAART exposure could be due to different biochemicalmechanisms but mainly mitochondrial interference causedby NRTIs or by NNRTIs as previously described It could alsobe caused by the activation of the P450 hepatic cytochromeby PIs (reviewed by Apostolova et al 2011) [29] ThereforeHAART seems to increaseOS by increasing the production ofROS which in turn could contribute to the development ofseveralmetabolic disturbances associatedwithHIV-infectionsuch as insulin resistance or cardiovascular events [95 105ndash108]

Aging is also associated with a chronic low level inflam-mation [109] and makes the organism more vulnerableto many diseases (ie diabetes obesity or cardiovasculardisease) By 2015 it is expected thatmore that 50of theHIV-infected patients in the United States will be ge50 years [110]The age of 50 has been considered as a cut-off to discrim-inate older subjects within HIV-infected patients [111] Theappearance and maintenance of the low-grade inflammationobserved in aging is mainly due to the increased OS [109]Thus if immune activation and long-term chronic inflamma-tion aremajor players in the aging process and these processesare more prevalent in HIV-infected patients even when theinfection is well controlled HIV-infected patients will bemore prone to develop a premature aging and therefore topresent an increased oxidative state that could lead to thedevelopment of several metabolic disturbances

6 Compounds with Antioxidant Capacity asPotential Tools against HIV-Infection andAssociated Disorders Fact or Artifact

If an increased oxidative stress is observed in HIV-infectedpatients actions that could decrease it should be therapeu-tically beneficial [70 104] In fact attenuation or completesuppression of OS as a way to improve several diseases hasflourished as one of themain challenges of research in the lastyearsThus several approaches have been carried out in orderto either decrease the high levels of ROS generated or boostthe endogenous levels of antioxidants It is proposed thatin the clinical management of HIV-infection withwithouthepatitis C (HCV) co-infection and especially in their earlystages considerable benefit should accrue from antioxidantrepletion In this context the study ofChandra and colleaguesshowed that thymoquinone (TQ) an active ingredient ofblack seed oil from the plant Nigella sativa with potentantioxidant properties is able to inhibit the effect of nelfinaviron augmented ROS production and suppressed SOD levelsin pancreatic 120573-cells [112] A recent study has demonstratedthat resveratrol a SIRT1 activator attenuates the transactiveeffects of Tat in HeLa-CD4-long terminal repeat-120573-gal cells(MAGI) via NAD(+)-dependent SIRT1 activity suggestingthat this antioxidant could be a novel therapeutic approachin anti-HIV-1 therapy [113] Similarly the study of Touzetand Philips demonstrated a protective effect of resveratrolagainst protease inhibitor-induced sarcoendoplasmic retic-ulum stress in human myotubes [114] Plasma glutathione


of HIV-infected patients responded positively and differentlyto dietary supplementation with cysteine and glutamine Infact an increase in total glutathione may be attained by N-acetyl-cysteine (NAC) or glutamine (Gln) supplementationwith NAC acting by increasing cysteine levels and Gln likelyacting by replenishing the glycine pool [115] Other studiesdemonstrated that gp120 glycoprotein (released during activeHIV infection of brain macrophages thereby generatinginflammation and OS which contribute to the developmentof the AIDS-dementia complex) is toxic to astroglial cellsby lipid peroxidation and by altering glutamine releaseAll the effects of gp120 on astroglial cells were counter-acted by NAC suggesting a novel and potentially usefulapproach in the treatment of glutamatergic disorders foundin these HIV-infected patients [116] Because plasma zincand selenium concentrations are very low in HIV-infectedpatients as previously reported their replenishment by highdosages seems to be urgent and mandatory particularly inadvanced HIV infections Also recommended is their long-term continuance at high normal levels [102] However it isimportant to note that only selenium-deficient individualsmay benefit from selenium supplementation because suchsupplementation in selenium-replete individuals may evencause higher risk of diseases such as cancer [117] Further-more seleniumhas a narrow therapeuticwindow and there isconsiderable interindividual variability in terms of metabolicsensitivity and optimal selenium intake Optimal intake forany individual is likely to depend on polymorphisms inselenoprotein genes that may also affect the risk of diseaseMoreover the baseline levels of each subject could determinethe beneficial effect of the selenium intake (reviewed byPerez-Matute et al 2012) [118] Several clinical trials withantioxidant supplements like vitamin E andor C have alsofailed to show any significant improvement in markersof OS in other diseases such as type 2 diabetic patients[119] which corroborates that despite the initial positiveand beneficial effects observed in many studies not all thatglitters is gold In this context a recent study showed thatantioxidant supplementation may have a protective role inmitochondrial function with limited effects on the reversalof clinical lipodystrophic abnormalities in HIV-1-infectedpatients [120] Thus whether supplementation with antiox-idants will reduce OS in HIV infection is still unknown andcontroversial results have been found [99]

Other potential strategy to ameliorate OS caused byHAART is switching to a new drug with a better profileThusatazanavir increases bilirubin plasma levels This increasehas been associated with improved endothelial functionin patients with type 2 diabetes mellitus [121] Howevercontroversial results have also been observed in this regardIn virologically suppressed HIV-infected adults on stableHAART neither total bilirubin nor atazanavir use was asso-ciated with improved endothelial function inflammationor OS as measured using several biomarkers [122] So farthere is no available information about the possible relationbetweenOS and other new antiretroviral such as the integraseinhibitors or CCR5 antagonists which limits the chance ofusing these drugs in an attempt to minimize the impact onOS described for some drugs

7 Concluding Remarks

In the last years several studies highlighted the central rolefor mitochondrial impairment in HIV infection and associ-ated disturbances such as NAFLD and HALS Mitochondrialdysfunction seems to be associated with premature aging inthese patients which could contribute to the development ofseveral metabolic pathologies such as cardiovascular eventsdiabetes and so forthThe underlyingmechanisms that couldexplain the relationship between mitochondrial dysfunctionand HIV NASH or HALS are not fully understood despiteaccumulating evidence points to other mechanisms beyondthe Pol-120574 hypothesis NRTIs have long been consideredthe main source of mitochondrial toxicity In this contextin many parts of the world persons have been or arecurrently treated with older NRTIs and remain at riskfor overt mitochondrial toxicities Therefore mitochondrialtoxicity management during HIV therapy has become animportant challenge with growing interest in developingnew compounds and identifying combinations of availableantiretroviral drugs that are clinically effective while elicitingminimal mitochondrial interference in these patients [17]Therefore and given that HIV treatment is for life and thatantiretroviral drugs have been in use for only 25 years thefruit of such work could induce invaluable improvementin the quality of life of present and future patients Otherdrugs different from NRTIs could also negatively affectthe mitochondria In this regard evidence points to drug-rather than the class-specific effects on mitochondria HIVvirus itself is also able to induce mitochondrial impairmentMitochondrial toxicity differs depending on the tissue andthe method used for measuring mitochondrial dysfunctionThere are also some limitations in this field since thereare not yet adequately validated markers of mitochondrialdysfunctionThere is therefore an urgent need to investigatein this direction Finally it is tempting to suggest thatstimulation of mitochondrial function may prevent NAFLDand lipodystrophy development in HIV-infected patientsalthough more studies are also needed in this regard

Acknowledgments

Thiswork was supported by Fundacion Rioja Salud (La RiojaSpain) The authors thank Javier Aguilera-Lizarraga for hishelp in the paper preparation

References

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[2] M H Merson J OrsquoMalley D Serwadda and C Apisuk ldquoThehistory and challenge of HIV preventionrdquoThe Lancet vol 372no 9637 pp 475ndash488 2008

[3] N Lohse and N Obel ldquoStable long-term effect of HIV therapyTheDanish Society for Infectious DiseasesrdquoUgeskrift for Laeliggervol 169 no 12 article 1109 2007

[4] M A Thompson J A Aberg P Cahn et al ldquoAntiretroviraltreatment of adult HIV infection 2010 recommendations of the


International AIDS Society-USA panelrdquo Journal of the Ameri-can Medical Association vol 304 no 3 pp 321ndash333 2010

[5] Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents April 20 AihwangGGaG

[6] M S Cohen Y Q Chen M McCauley et al ldquoPreventionof HIV-1 infection with early antiretroviral therapyrdquo The NewEngland Journal of Medicine vol 365 no 6 pp 493ndash505 2011

[7] J A Sterne M May D Costagliola et al ldquoTiming of initiationof antiretroviral therapy in AIDS-free HIV-1-infected patientsa collaborative analysis of 18 HIV cohort studiesrdquo The Lancetvol 373 no 9672 pp 1352ndash1363 2009

[8] F Fedele N Bruno and M Mancone ldquoCardiovascular riskfactors and HIV diseaserdquo AIDS Reviews vol 13 no 2 pp 119ndash129 2011

[9] N Z Mothobi and B J Brew ldquoNeurocognitive dysfunction inthe highly active antiretroviral therapy erardquo Current Opinion inInfectious Diseases vol 25 no 1 pp 4ndash9 2012

[10] J Stebbing N Wong L Tan et al ldquoThe relationship betweenprolonged antiretroviral therapy and cryptogenic liver diseaserdquoJournal of Acquired Immune Deficiency Syndromes vol 50 no5 pp 554ndash556 2009

[11] M Lemoine L Serfaty and J Capeau ldquoFrom nonalcoholicfatty liver to nonalcoholic steatohepatitis and cirrhosis in HIV-infected patients diagnosis andmanagementrdquo Current Opinionin Infectious Diseases vol 25 no 1 pp 10ndash16 2012

[12] I Grattagliano O de Bari T C Bernardo P J OliveiraD Q-H Wang and P Portincasa ldquoRole of mitochondria innonalcoholic fatty liver disease-from origin to propagationrdquoClinical Biochemistry vol 45 no 9 pp 610ndash618 2012

[13] M Caron-Debarle F Boccara C Lagathu et al ldquoAdipose tissueas a target of hIV-1 antiretroviral drugs potential consequenceson metabolic regulationsrdquo Current Pharmaceutical Design vol16 no 30 pp 3352ndash3360 2010

[14] D C Wallace ldquoA mitochondrial paradigm of metabolic anddegenerative diseases aging and cancer a dawn for evolution-ary medicinerdquo Annual Review of Genetics vol 39 pp 359ndash4072005

[15] P Kovacic ldquoRole of oxidative metabolites of cocaine in toxicityand addiction oxidative stress and electron transferrdquo MedicalHypotheses vol 64 no 2 pp 350ndash356 2005

[16] A A Starkov ldquoThe role of mitochondria in reactive oxygenspecies metabolism and signalingrdquo Annals of the New YorkAcademy of Sciences vol 1147 pp 37ndash52 2008

[17] N Apostolova A Blas-Garcıa and J V Esplugues ldquoMitochon-drial interference by anti-HIV drugs mechanisms beyond Pol-120574 inhibitionrdquo Trends in Pharmacological Sciences vol 32 no 12pp 715ndash725 2011

[18] A Cossarizza C Mussini N Mongiardo et al ldquoMitochondriaalterations and dramatic tendency to undergo apoptosis inperipheral blood lymphocytes during acute HIV syndromerdquoAIDS vol 11 no 1 pp 19ndash26 1997

[19] E R Feeney and P W G Mallon ldquoImpact of mitochondrialtoxicity of HIV-1 antiretroviral drugs on lipodystrophy andmetabolic dysregulationrdquo Current Pharmaceutical Design vol16 no 30 pp 3339ndash3351 2010

[20] L Galluzzi M Pinti L Troiano et al ldquoChanges in mitochon-drial RNA production in cells treated with nucleoside ana-loguesrdquo Antiviral Therapy vol 10 no 1 pp 191ndash195 2005

[21] H C F Cote ldquoPossible ways nucleoside analogues can affectmitochondrial DNA content and gene expression during HIVtherapyrdquo Antiviral Therapy vol 10 supplement 2 pp M3ndashM112005

[22] B Jiang A R Khandelwal L K Rogers et al ldquoAntiretrovi-rals induce endothelial dysfunction via an oxidant-dependentpathway and promote neointimal hyperplasiardquo ToxicologicalSciences vol 117 no 2 pp 524ndash536 2010

[23] K C Lund and K B Wallace ldquoAdenosine 3101584051015840-cyclicmonophosphate (cAMP)-dependent phosphoregulation ofmitochondrial complex I is inhibited by nucleoside reversetranscriptase inhibitorsrdquo Toxicology and Applied Pharmacologyvol 226 no 1 pp 94ndash106 2008

[24] A Maagaard and D Kvale ldquoMitochondrial toxicity in HIV-infected patients both off and on antiretroviral treatment acontinuum or distinct underlying mechanismsrdquo Journal ofAntimicrobial Chemotherapy vol 64 no 5 pp 901ndash909 2009

[25] P W G Mallon ldquoAntiretroviral therapy-induced lipid alter-ations in-vitro animal and human studiesrdquo Current Opinion inHIV and AIDS vol 2 no 4 pp 282ndash292 2007

[26] N Apostolova A Blas-Garcia and J V Esplugues ldquoMitochon-dria sentencing about cellular life and death a matter ofoxidative stressrdquo Current Pharmaceutical Design vol 17 no 36pp 4047ndash4060 2011

[27] S Viengchareun M Caron M Auclair et al ldquoMitochondrialtoxicity of indinavir stavudine and zidovudine involves mul-tiple cellular targets in white and brown adipocytesrdquo AntiviralTherapy vol 12 no 6 pp 919ndash929 2007

[28] M L R de la Concepcion P Yubero J C Domingo et alldquoReverse transcriptase inhibitors alter uncoupling protein-1and mitochondrial biogenesis in brown adipocytesrdquo AntiviralTherapy vol 10 no 4 pp 515ndash526 2005

[29] N Apostolova A Blas-Garcıa and J V Esplugues ldquoMitochon-drial toxicity in haart an overview of in vitro evidencerdquoCurrentPharmaceutical Design vol 17 no 20 pp 2130ndash2144 2011

[30] B A I Payne I J Wilson C A Hateley et al ldquoMitochondrialaging is accelerated by anti-retroviral therapy through the clonalexpansion ofmtDNAmutationsrdquoNature Genetics vol 43 no 8pp 806ndash810 2011

[31] A Maagaard M Holberg-Petersen G Loslashvgarden M HolmF O Pettersen and D Kvale ldquoDistinct mechanisms for mito-chondrial DNA loss in T and B lymphocytes fromHIV-infectedpatients exposed to nucleoside reverse-transcriptase inhibitorsand those naive to antiretroviral treatmentrdquo Journal of InfectiousDiseases vol 198 no 10 pp 1474ndash1481 2008

[32] D Arnoult F Petit J Lelievre and J Estaquier ldquoMitochon-dria in HIV-1-induced apoptosisrdquo Biochemical and BiophysicalResearch Communications vol 304 no 3 pp 561ndash574 2003

[33] K Muthumani A Y Choo D S Hwang et al ldquoMechanismof HIV-1 viral protein R-induced apoptosisrdquo Biochemical andBiophysical Research Communications vol 304 no 3 pp 583ndash592 2003

[34] T Roumier M Castedo J Perfettini et al ldquoMitochondrion-dependent caspase activation by the HIV-1 enveloperdquo Biochem-ical Pharmacology vol 66 no 8 pp 1321ndash1329 2003

[35] C G Morse J G Voss G Rakocevic et al ldquoHIV infection andantiretroviral therapy have divergent effects onmitochondria inadipose tissuerdquo The Journal of Infectious Diseases vol 205 no12 pp 1778ndash1787 2012

[36] A Cossarizza M Pinti M Nasi et al ldquoIncreased plasma levelsof extracellular mitochondrial DNA during HIV infectiona new role for mitochondrial damage-associated molecularpatterns during inflammationrdquoMitochondrion vol 11 no 5 pp750ndash755 2011


[37] H C F Cote Z L Brumme K J P Craib et al ldquoChanges inmitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patientsrdquo The New England Journal of Medicine vol346 no 11 pp 811ndash820 2002

[38] H C F Cote J Raboud A Bitnun et al ldquoPerinatal exposureto antiretroviral therapy is associated with increased bloodmitochondrial DNA levels and decreased mitochondrial geneexpression in infantsrdquo Journal of Infectious Diseases vol 198 no6 pp 851ndash859 2008

[39] J K Min C Jardel C Barthelemy et al ldquoMitochondrialDNA content an inaccurate biomarker of mitochondrial alter-ation in human immunodeficiency virus-related lipodystro-phyrdquo Antimicrobial Agents and Chemotherapy vol 52 no 5 pp1670ndash1676 2008

[40] C Petit D Mathez C Barthelemy et al ldquoQuantitation ofblood lymphocyte mitochondrial DNA for the monitoring ofantiretroviral drug-induced mitochondrial DNA depletionrdquoJournal of Acquired Immune Deficiency Syndromes vol 33 no4 pp 461ndash469 2003

[41] P W G Mallon P Unemori R Sedwell et al ldquoIn vivo nucle-oside reverse-transcriptase inhibitors alter expression of bothmitochondrial and lipid metabolism genes in the absence ofdepletion ofmitochondrial DNArdquo Journal of Infectious Diseasesvol 191 no 10 pp 1686ndash1696 2005

[42] M P Valdecantos P Perez-Matute P Gonzalez-Muniesa PL Prieto-Hontoria M J Moreno-Aliaga and J A MartınezldquoLipoic acid administration prevents nonalcoholic steatosislinked to long-term high-fat feeding by modulating mitochon-drial functionrdquo Journal of Nutritional Biochemistry vol 23 no12 pp 1676ndash1684 2012

[43] P Pettinelli A M Obregon and L A Videla ldquoMolecularmechanisms of steatosis in nonalcoholic fatty liver diseaserdquoNutricion Hospitalaria vol 26 no 3 pp 441ndash450 2011

[44] B A Swinburn G Sacks K D Hall et al ldquoThe global obesitypandemic shaped by global drivers and local environmentsrdquoThe Lancet vol 378 no 9793 pp 804ndash814 2011

[45] V Ratziu V de Ledinghen F Oberti et al ldquoA randomizedcontrolled trial of high-dose ursodesoxycholic acid for nonal-coholic steatohepatitisrdquo Journal of Hepatology vol 54 no 5 pp1011ndash1019 2011

[46] E Bugianesi N Leone E Vanni et al ldquoExpanding the naturalhistory of nonalcoholic steatohepatitis from cryptogenic cir-rhosis to hepatocellular carcinomardquo Gastroenterology vol 123no 1 pp 134ndash140 2002

[47] E E Powell W G E Cooksley R Hanson J Searle J WHalliday and LW Powell ldquoThe natural history of nonalcoholicsteatohepatitis a follow-up study of forty-two patients for up to21 yearsrdquo Hepatology vol 11 no 1 pp 74ndash80 1990

[48] P Angulo J M Hui G Marchesini et al ldquoThe NAFLD fibrosisscore a noninvasive system that identifies liver fibrosis inpatients with NAFLDrdquo Hepatology vol 45 no 4 pp 846ndash8542007

[49] G Moyle and A Carr ldquoHIV-associated lipodystropy metaboliccomplications and antiretroviral toxicitiesrdquoHIVClinical Trialsvol 3 no 1 pp 89ndash98 2002

[50] C Lewden T May E Rosenthal et al ldquoChanges in causesof death among adults infected by HIV between 2000 and2005 the ldquomortality 2000 and 2005rdquo surveys (ANRS EN19 andmortavic)rdquo Journal of Acquired Immune Deficiency Syndromesvol 48 no 5 pp 590ndash598 2008

[51] R Weber C A Sabin N Friis-Moller et al ldquoLiver-relateddeaths in persons infected with the human immunodeficiency

virus the DAD studyrdquo Archives of Internal Medicine vol 166no 15 pp 1632ndash1641 2006

[52] Antiretroviral Therapy Cohort Collaboration ldquoCauses of deathin HIV-1-infected patients treated with antiretroviral therapy-caoHcsrdquoClinical InfectiousDiseases vol 50 pp 1387ndash1396 2010

[53] N Crum-Cianflone A Dilay G Collins et al ldquoNonalcoholicfatty liver disease among HIV-infected personsrdquo Journal ofAcquired Immune Deficiency Syndromes vol 50 no 5 pp 464ndash473 2009

[54] M Lemoine and L Serfaty ldquoNonalcoholic fatty liver diseaserdquoPresse Medicale vol 41 no 2 pp 169ndash189 2012

[55] C P Day and O F W James ldquoSteatohepatitis a tale of twoldquohitsrdquordquo Gastroenterology vol 114 no 4 I pp 842ndash845 1998

[56] E Bugianesi A J McCullough and G Marchesini ldquoInsulinresistance a metabolic pathway to chronic liver diseaserdquo Hep-atology vol 42 no 5 pp 987ndash1000 2005

[57] A P Rolo J S Teodoro and C M Palmeira ldquoRole of oxidativestress in the pathogenesis of nonalcoholic steatohepatitisrdquo FreeRadical Biology and Medicine vol 52 no 1 pp 59ndash69 2012

[58] MAAkhtar KMathieson B Arey et al ldquoHepatic histopathol-ogy and clinical characteristics associated with antiretroviraltherapy in HIV patients without viral hepatitisrdquo EuropeanJournal of Gastroenterology and Hepatology vol 20 no 12 pp1194ndash1204 2008

[59] F Blanco P Barreiro P Ryan et al ldquoRisk factors for advancedliver fibrosis in HIV-infected individuals role of antiretroviraldrugs and insulin resistancerdquo Journal of Viral Hepatitis vol 18no 1 pp 11ndash16 2011

[60] G Guaraldi N Squillace C Stentarelli et al ldquoNonalcoholicfatty liver disease in HIV-infected patients referred to ametabolic clinic prevalence characteristics and predictorsrdquoClinical Infectious Diseases vol 47 no 2 pp 250ndash257 2008

[61] M Nunez ldquoClinical syndromes and consequences of antire-troviral-related hepatotoxicityrdquo Hepatology vol 52 no 3 pp1143ndash1155 2010

[62] M Duong M Buisson G Peytavin et al ldquoLow trough plasmaconcentrations of nevirapine associated with virologic re-bounds in HIV-infected patients who switched from proteaseinhibitorsrdquo Annals of Pharmacotherapy vol 39 no 4 pp 603ndash609 2005

[63] C A Duong C A Sepulveda J B Graham and K ADickson ldquoMitochondrial proton leak rates in the slow oxidativemyotomal muscle and liver of the endothermic shortfin makoshark (Isurus oxyrinchus) and the ectothermic blue shark(Prionace glauca) and leopard shark (Triakis semifasciata)rdquoJournal of Experimental Biology vol 209 part 14 pp 2678ndash26852006

[64] N Apostolova L J Gomez-Sucerquia AMoran A Alvarez ABlas-Garcia and J V Esplugues ldquoEnhanced oxidative stress andincreased mitochondrial mass during Efavirenz-induced apop-tosis in human hepatic cellsrdquo British Journal of Pharmacologyvol 160 no 8 pp 2069ndash2084 2010

[65] A Blas-Garcıa N Apostolova D Ballesteros et al ldquoInhibitionof mitochondrial function by efavirenz increases lipid contentin hepatic cellsrdquoHepatology vol 52 no 1 pp 115ndash125 2010

[66] N Apostolova L J Gomez-Sucerquia A Gortat A Blas-Garcia and J V Esplugues ldquoAutophagy as a rescue mechanismin Efavirenz-induced mitochondrial dysfunction a lesson fromhepatic cellsrdquo Autophagy vol 7 no 11 pp 1402ndash1404 2011


[67] P Ingiliz M Valantin C Duvivier et al ldquoLiver damage under-lying unexplained transaminase elevation in human immun-odeficiency virus-1 mono-infected patients on antiretroviraltherapyrdquo Hepatology vol 49 no 2 pp 436ndash442 2009

[68] M Lemoine V Barbu P M Girard et al ldquoAltered hep-atic expression of SREBP-1 and PPAR120574 is associated withliver injury in insulin-resistant lipodystrophic HIV-infectedpatientsrdquo AIDS vol 20 no 3 pp 387ndash395 2006

[69] W Lin E M Weinberg A W Tai et al ldquoHIV increases HCVreplication in a TGF-1205731-dependent mannerrdquo Gastroenterologyvol 134 no 3 pp 803ndash811 2008

[70] W LinGWu S Li et al ldquoHIV andHCVcooperatively promotehepatic fibrogenesis via induction of reactive oxygen speciesand NF 120581Brdquo The Journal of Biological Chemistry vol 286 no4 pp 2665ndash2674 2011

[71] G Musso R Gambino M Cassader and G Pagano ldquoA meta-analysis of randomized trials for the treatment of nonalcoholicfatty liver diseaserdquo Hepatology vol 52 no 1 pp 79ndash104 2010

[72] G Nkontchou E Cosson M Aout et al ldquoImpact of metforminon the prognosis of cirrhosis induced by viral hepatitis Cin diabetic patientsrdquo Journal of Clinical Endocrinology andMetabolism vol 96 no 8 pp 2601ndash2608 2011

[73] G Musso R Gambino and M Cassader ldquoNon-alcoholic fattyliver disease from pathogenesis to management an updaterdquoObesity Reviews vol 11 no 6 pp 430ndash445 2010

[74] A Carr K Samaras S Burton et al ldquoA syndrome of periph-eral lipodystrophy hyperlipidaemia and insulin resistance inpatients receiving HIV protease inhibitorsrdquo AIDS vol 12 no7 pp F51ndashF58 1998

[75] K D Miller E Jones J A Yanovski R Shankar I Feuersteinand J Falloon ldquoVisceral abdominal-fat accumulation associatedwith use of indinavirrdquoTheLancet vol 351 no 9106 pp 871ndash8751998

[76] J Miller A Carr S Emery et al ldquoHIV lipodystrophy preva-lence severity and correlates of risk inAustraliardquoHIVMedicinevol 4 no 3 pp 293ndash301 2003

[77] H M Crane C Grunfeld R D Harrington and M MKitahata ldquoLipoatrophy and lipohypertrophy are independentlyassociated with hypertensionrdquo HIV Medicine vol 10 no 8 pp496ndash503 2009

[78] S Grinspoon and A Carr ldquoCardiovascular risk and body-fatabnormalities inHIV-infected adultsrdquoTheNewEngland Journalof Medicine vol 352 no 1 pp 48ndash62 2005

[79] F Villarroya P Domingo and M Giralt ldquoDrug-induced lipo-toxicity Lipodystrophy associated with HIV-1 infection andantiretroviral treatmentrdquo Biochimica et Biophysica Acta vol1801 no 3 pp 392ndash399 2010

[80] M Caron-Debarle C Lagathu F Boccara C Vigouroux andJ Capeau ldquoHIV-associated lipodystrophy from fat injury topremature agingrdquo Trends in Molecular Medicine vol 16 no 5pp 218ndash229 2010

[81] E Bernasconi K Boubaker C Junghans et al ldquoAbnormalitiesof body fat distribution in HIV-infected persons treated withantiretroviral drugs the Swiss HIV cohort studyrdquo Journal ofAcquired Immune Deficiency Syndromes vol 31 no 1 pp 50ndash55 2002

[82] D Chen A Misra and A Garg ldquoLipodystrophy in humanimmunodeficiency virus-infected patientsrdquo Journal of ClinicalEndocrinology and Metabolism vol 87 no 11 pp 4845ndash48562002

[83] S Rodrıguez-Novoa P Barreiro I Jimenez-Nacher and VSoriano ldquoOverview of the pharmacogenetics of HIV therapyrdquoPharmacogenomics Journal vol 6 no 4 pp 234ndash245 2006

[84] A De Pauw S Tejerina M Raes J Keijer and T ArnouldldquoMitochondrial (dys)function in adipocyte (de)differentiationand systemicmetabolic alterationsrdquoAmerican Journal of Pathol-ogy vol 175 no 3 pp 927ndash939 2009

[85] H K Eun J ParkH Park et al ldquoEssential role ofmitochondrialfunction in adiponectin synthesis in adipocytesrdquo Diabetes vol56 no 12 pp 2973ndash2981 2007

[86] S Furukawa T FujitaM Shimabukuro et al ldquoIncreased oxida-tive stress in obesity and its impact onmetabolic syndromerdquoTheJournal of Clinical Investigation vol 114 no 12 pp 1752ndash17612004

[87] J Villarroya M Giralt and F Villarroya ldquoMitochondrial DNAan up-and-coming actor in white adipose tissue pathophysiol-ogyrdquo Obesity vol 17 no 10 pp 1814ndash1820 2009

[88] M Boothby K C McGee J W Tomlinson et al ldquoAdipocytedifferentiation mitochondrial gene expression and fat distri-bution differences between zidovudine and tenofovir after 6monthsrdquo Antiviral Therapy vol 14 no 8 pp 1089ndash1100 2009

[89] D Nolan E Hammond A Martin et al ldquoMitochondrial DNAdepletion and morphologic changes in adipocytes associatedwith nucleoside reverse transcriptase inhibitor therapyrdquo AIDSvol 17 no 9 pp 1329ndash1338 2003

[90] C-H Chen M Vazquez-Padua and Y-C Cheng ldquoEffect ofanti-human immunodeficiency virus nucleoside analogs onmitochondrial DNA and its implication for delayed toxicityrdquoMolecular Pharmacology vol 39 no 5 pp 625ndash628 1991

[91] M Gerschenson C Kim B Berzins et al ldquoMitochondrialfunction morphology and metabolic parameters improve afterswitching from stavudine to a tenofovir-containing regimenrdquoJournal of Antimicrobial Chemotherapy vol 63 no 6 pp 1244ndash1250 2009

[92] D Douek ldquoHIV disease progression immune activationmicrobes and a leaky gutrdquo Topics in HIV Medicine vol 15 no4 pp 114ndash117 2007

[93] G A McComsey D E Libutti M OrsquoRiordan et al ldquoMitochon-drial RNA and DNA alterations in HIV lipoatrophy are linkedto antiretroviral therapy and not to HIV infectionrdquo AntiviralTherapy vol 13 no 5 pp 715ndash722 2008

[94] M Giralt P Domingo J P Guallar et al ldquoHIV-1 infection altersgene expression in adipose tissue which contributes to HIV-1HAART-associated lipodystrophyrdquo Antiviral Therapy vol 11no 6 pp 729ndash740 2006

[95] AMandas E L IorioMGCongiu et al ldquoOxidative imbalancein HIV-1 infected patients treated with antiretroviral therapyrdquoJournal of Biomedicine and Biotechnology vol 2009 Article ID749575 7 pages 2009

[96] P Perez-Matute M A Zulet and J A Martınez ldquoReactivespecies and diabetes counteracting oxidative stress to improvehealthrdquo Current Opinion in Pharmacology vol 9 no 6 pp 771ndash779 2009

[97] G W Pace and C D Leaf ldquoThe role of oxidative stress in HIVdiseaserdquo Free Radical Biology and Medicine vol 19 no 4 pp523ndash528 1995

[98] D R Suresh V Annam K Pratibha and B V M PrasadldquoTotal antioxidant capacity a novel early bio-chemical markerof oxidative stress in HIV infected individualsrdquo Journal ofBiomedical Science vol 16 no 1 article 61 2009


[99] AWanchu S V Rana S Pallikkuth and R K Sachdeva ldquoShortcommunication oxidative stress in HIV-infected individuals across-sectional studyrdquo AIDS Research and Human Retrovirusesvol 25 no 12 pp 1307ndash1311 2009

[100] I I Kruman A Nath and M P Mattson ldquoHIV-1 protein tatinduces apoptosis of hippocampal neurons by a mechanisminvolving caspase activation calcium overload and oxidativestressrdquo Experimental Neurology vol 154 no 2 pp 276ndash2881998

[101] J A Martin J Sastre J Garcia de la Asuncion F V Pallardoand J Vina ldquoHepatic 120574-cystathionase deficiency in patients withAIDSrdquo Journal of the AmericanMedical Association vol 285 no11 pp 1444ndash1445 2001

[102] W E Stehbens ldquoOxidative stress in viral hepatitis and AIDSrdquoExperimental and Molecular Pathology vol 77 no 2 pp 121ndash132 2004

[103] B M Dworkin ldquoSelenium deficiency in HIV infection andthe acquired immunodeficiency syndrome (AIDS)rdquo Chemico-Biological Interactions vol 91 no 2-3 pp 181ndash186 1994

[104] M K Baum S Sales D T Jayaweera et al ldquoCoinfection withhepatitis C virus oxidative stress and antioxidant status inHIV-positive drug users in Miamirdquo HIV Medicine vol 12 no 2 pp78ndash86 2011

[105] B J Day and W Lewis ldquoOxidative stress in NRTI-inducedtoxicity evidence from clinical experience and experiments invitro and in vivordquo Cardiovascular Toxicology vol 4 no 3 pp207ndash216 2004

[106] G N Kumar J Dykstra E M Roberts et al ldquoPotent inhibitionof the cytochrome P-450 3A-mediated human liver microsomalmetabolism of a novel HIV protease inhibitor by ritonavir apositive drug-drug interactionrdquo Drug Metabolism and Disposi-tion vol 27 no 8 pp 902ndash908 1999

[107] W Lewis ldquoUse of the transgenic mouse in models of AIDScardiomyopathyrdquo AIDS vol 17 supplement 1 pp S36ndashS452003

[108] T Hulgan J Morrow R T DrsquoAquila et al ldquoOxidant stress isincreased during treatment of human immunodeficiency virusinfectionrdquo Clinical Infectious Diseases vol 37 no 12 pp 1711ndash1717 2003

[109] M De la Fuente and J Miquel ldquoAn update of the oxidation-inflammation theory of aging the involvement of the immunesystem inOxi-Inflamm-AgingrdquoCurrent Pharmaceutical Designvol 15 no 26 pp 3003ndash3026 2009

[110] R B Effros C V Fletcher K Gebo et al ldquoWorkshop onHIV infection and aging what is known and future researchdirectionsrdquo Clinical Infectious Diseases vol 47 no 4 pp 542ndash553 2008

[111] J R Blanco I Jarrin M Vallejo et al ldquoDefinition of advancedage in HIV infection looking for an age cut-offrdquoAIDS Researchand Human Retroviruses vol 28 no 9 pp 1000ndash1006 2012

[112] S Chandra D Mondal and K C Agrawal ldquoHIV-1 proteaseinhibitor induced oxidative stress suppresses glucose stimulatedinsulin release protection with thymoquinonerdquo ExperimentalBiology and Medicine vol 234 no 4 pp 442ndash453 2009

[113] H Zhang Y Zhou M Wu H Zhou and F Xu ldquoResveratrolinhibited Tat-induced HIV-1 LTR transactivation via NAD+-dependent SIRT1 activityrdquo Life Sciences vol 85 no 13-14 pp484ndash489 2009

[114] O Touzet and A Philips ldquoResveratrol protects against proteaseinhibitor-induced reactive oxygen species production reticu-lum stress and lipid raft perturbationrdquo AIDS vol 24 no 10 pp1437ndash1447 2010

[115] M D Borges-Santos F Moreto P C M Pereira Y Ming-Yu and R C Burini ldquoPlasma glutathione of HIV+ patientsresponded positively and differently to dietary supplementationwith cysteine or glutaminerdquo Nutrition vol 28 no 7-8 pp 753ndash756 2012

[116] V Visalli C Muscoli I Sacco et al ldquoN-acetylcysteine preventsHIV gp 120-related damage of human cultured astrocytescorrelation with glutamine synthase dysfunctionrdquo BMC Neuro-science vol 8 article 106 2007

[117] J Brozmanova D Manikova V Vlckova and M ChovanecldquoSelenium a double-edged sword for defense and offence incancerrdquoArchives of Toxicology vol 84 no 12 pp 919ndash938 2010

[118] P Perez-Matute A B Crujeiras M Fernandez-Galilea and PL Prieto-Hontoria ldquoCompounds with antioxidant capacity aspotential tools against several oxidative stress related disordersfact or artifactrdquo in Oxidative Stress and Diseases InTechVienna Austria 2012

[119] D Darko A Dornhorst F J Kelly J M Ritter and P JChowienczyk ldquoLack of effect of oral vitamin C on bloodpressure oxidative stress and endothelial function in Type IIdiabetesrdquo Clinical Science vol 103 no 4 pp 339ndash344 2002

[120] L Milazzo B Menzaghi I Caramma et al ldquoEffect of antioxi-dants on mitochondrial function in HIV-1-related lipoatrophya pilot studyrdquo AIDS Research and Human Retroviruses vol 26no 11 pp 1207ndash1214 2010

[121] D Dekker M J Dorresteijn M Pijnenburg et al ldquoThebilirubin-increasing drug atazanavir improves endothelialfunction in patients with type 2 diabetesmellitusrdquoArteriosclero-sisThrombosis and Vascular Biology vol 31 no 2 pp 458ndash4632011

[122] C Hileman C Longenecker T Carman et al ldquoRelationshipbetween total bilirubin and endothelial function inflammationand oxidative stress in HIV-infected adults on stable antiretro-viral therapyrdquo HIV Medicine vol 13 no 10 pp 609ndash616 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Current employed anti-HIV drug families and reported mitochondrial toxicity (modified from Apostolova et al 2011) [17]

Drug family (antiretroviral) Mechanism of action Mitochondrial dysfunction

Nucleosidenucleotide reversetranscriptase inhibitor (AbacavirDidanosine Emtricitabine LamivudineStavudine Tenofovir and Zidovudine)

Interferes with the HIV reversetranscriptase protein needed by the virusto make new copies of itself

Inhibition of Pol-120574Depletion of mtDNAReduction of mtDNA-encoded proteinsRespiratory chain dysfunctionDirect inhibition of ETC complexes (I IV)Reduction of ATP levelsROS productionDecrease in 119860120595

119898

Impairment of ADPATP translocaseImpairment of fatty acid oxidation

Nonnucleoside reverse transcriptaseinhibitor (Efavirenz Etravirine andNevirapine)

Stops HIV replication within cells byinhibiting the reverse transcriptaseprotein

Respiratory chain dysfunctionReduction of ATP levelsROS productionDecrease in 119860120595

119898

Apoptosis

Protease inhibitor (AtazanavirDarunavir Fosamprenavir LopinavirRitonavir and Saquinavir)

Inhibits the HIV protease activity aprotein required for HIV replication

Inhibition of MPP (mitochondrial proteaseprocessing)Fragmentation of mitochondrial networkIncrease in mitochondrial Ca2+ accumulationApoptosisROS production

Fusion inhibitor (Enfuvirtide) Prevents HIV from binding to or fromentering human immune cells Unknown

CCR5 inhibitor (Maraviroc) Prevents HIV from binding to or fromentering human immune cells Unknown

Integrase inhibitor (Raltegravir)Interferes with the integrase enzymewhich is needed to insert HIV geneticmaterial into human cells

Unknown

morbidity and mortality in HIV-infected patients Severalstudies have demonstrated mitochondrial impairment inHIV-infected patients and especially in those suffering fromHALS or fatty liver suggesting a pivotal role of mitochondriadysfunction in the pathophysiology of these alterationsThusthis review summarizes the main findings related to therole of mitochondria in HIV and these two alterationsassociated HALS and fatty liver Furthermore evidence hasaccumulated suggesting that HIV-infected patients are underchronic oxidative stress and mitochondria dysfunction couldcontribute to this increased oxidative stateTherefore we alsodescribe the role of oxidative stress in HIV infection and howdifferent compounds with antioxidant capacities have beenstudied in an attempt to decrease this oxidative state in a wayto ameliorate the deleterious effects of HIV-infection and itsmetabolic associated disorders

2 HIV and Mitochondria

Mitochondria are intracellular organelles present in all mam-malian cells (except red blood cells) They contain an outermembrane an intramembrane space an inner membraneand the matrix where the mitochondrial genome is found

Eachmammalian cell contains several hundreds tomore thana thousand mitochondria The size shape and abundanceof mitochondria vary dramatically in different cell typesand may change under different energy demands and dif-ferent physiological or environmental conditions The mainfunction of mitochondria is to synthesize ATP throughelectron transport andoxidative phosphorylation (OXPHOS)in conjunction with the oxidation of metabolites by tricar-boxylic acid cycle and catabolism of fatty acids by beta-oxidation In this sense the mitochondrion had been foryears considered to be simply the fuel provider for the mostbasic energy demands of the cells Howevermitochondria arenow recognised as being critical components in the controlof multiple key cellular processes being the main arbitratorin the initiation and execution of apoptosis and thereforeplaying a pivotal role in the determination of life and deathof the mammalian cells In addition mitochondria are themain intracellular source and immediate target of reactiveoxygen species (ROS) [14] During energy transduction in themitochondrial electron transport chain a small number ofelectrons ldquoleakrdquo to oxygen prematurely forming the oxygen-free radical superoxide [15] Under normal conditions thekey site of superoxide formation in the mitochondrial




















Fatty

ROSROS


Obesity Dyslipemia

Fatty

ROS

tissue

Insulinresistance

Obesity


Dislipidemia



dysfunction

Drug toxicity





Visceral adipose

HCV HIV

HIV

NRTIs

HCV



















HIV

Pisr

HIV

PIsr

HIV

Pisr





PIsr



If not treated


uarr ROS

uarruarr ROS

darr mtDNA

darrdarr mtDNA


Lipoatrophy




















Acknowledgments


References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































Fatty

ROSROS


Obesity Dyslipemia

Fatty

ROS

tissue

Insulinresistance

Obesity


Dislipidemia



dysfunction

Drug toxicity





Visceral adipose

HCV HIV

HIV

NRTIs

HCV



















HIV

Pisr

HIV

PIsr

HIV

Pisr





PIsr



If not treated


uarr ROS

uarruarr ROS

darr mtDNA

darrdarr mtDNA


Lipoatrophy




















Acknowledgments


References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























HIV

Pisr

HIV

PIsr

HIV

Pisr





PIsr



If not treated


uarr ROS

uarruarr ROS

darr mtDNA

darrdarr mtDNA


Lipoatrophy




















Acknowledgments


References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Acknowledgments


References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article role of mitochondria in hiv infection and ... · hiv infection and antiretroviral...

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