Skip Navigation LinksHome > June 13, 2003 - Volume 17 - Issue 9 > Mitochondrial DNA depletion and morphologic changes in adipo...
Clinical Science

Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy

Nolan, David; Hammond, Emma; Martin, Annalise; Taylor, Louise; Herrmann, Susan; McKinnon, Elizabeth; Metcalf, Cecilya; Latham, Brucea; Mallal, Simon

Free Access
Article Outline
Collapse Box

Author Information

From the Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, and aDepartment of Pathology, Royal Perth Hospital, Western Australia.

Correspondence to S. Mallal, Centre for Clinical Immunology and Biomedical Statistics, Level 2, North Block, Royal Perth Hospital, Wellington Street, Western Australia, 6000 Australia. Tel: +61 89 224 2899; fax: +61 89 224 2920; e-mail:

Received: 8 May 2002; revised: 27 July 2002; accepted: 28 August 2002.

Collapse Box


Background: Nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy provides sufficient conditions for progressive subcutaneous fat wasting in HIV-infected patients. As NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion, determinants of cellular mtDNA copy number and mitochondrial mass in adipocyte samples from NRTI-treated HIV-infected patients and antiretroviral-naive controls were investigated. Adipose tissue morphology was also assessed.

Methods: Subcutaneous fat samples were obtained from NRTI-treated, HIV-infected patients (n = 21), antiretroviral therapy-naive HIV-infected controls (n = 11), and HIV-seronegative controls (n = 6). Non-adipocytes were removed by collagenase digestion. Adipocyte mtDNA copies/cell was measured using a real time PCR-based assay, and adipocyte mitochondrial protein content was also measured. Light and electron microscopy were performed on tissue samples.

Findings: Adipocyte mtDNA copies/cell values were similar (P = 0.56) in HIV seronegative and HIV-infected control groups. NRTI treatment was associated with reduced adipocyte mtDNA copies/cell, representing mean mtDNA depletion in NRTI-treated individuals of 77.7% compared with the mean value for the HIV-infected control group (P < 0001). Additionally, significant differences were found in adipocyte mtDNA copies/cell between patients receiving stavudine (n = 12, mean mtDNA depletion 87.1%) and zidovudine (n = 9, mean mtDNA depletion 52.1%) (P < 0.001). Adipocyte mitochondrial mass was increased in the stavudine group only (mean increase 289%, P < 0.01).

Interpretation: NRTI therapy is associated with mtDNA depletion and mitochondrial proliferation in adipocytes, consistent with the hypothesis that NRTI-induced mtDNA depletion contributes to the pathogenesis of subcutaneous fat wasting. Morphologic assessment also supports a role for NRTI therapy in inducing adipocyte metabolic dysfunction and cell death.

Back to Top | Article Outline


Nucleoside analogue reverse transcriptase inhibitors (NRTI) were the first therapeutic agents to demonstrate clinical efficacy as antiretroviral therapy for HIV infection, and continue to be utilized in contemporary highly active antiretroviral therapy (HAART) regimens that may combine three NRTI, or two NRTI drugs with either HIV protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). The use of drugs from this class appears to be an important determinant of the durability and effectiveness of these HAART regimens, so it is likely that NRTI therapy will continue to be used for the foreseeable future [1]. In this context, it is recognized that while the use of HAART has substantially reduced the risk of progressive immune deficiency induced by uncontrolled HIV infection, these benefits may be offset by an increased burden of long-term antiretroviral drug toxicity, including those mediated specifically by NRTI therapy [1–4].

The antiretroviral activity of NRTI drugs is determined by their ability to inhibit the RNA-dependent DNA polymerase activity of HIV reverse transcriptase. Hence, NRTI drugs compete with endogenous nucleic acids for incorporation by DNA polymerase, and cause premature termination of viral DNA chain elongation when incorporated [2]. Adverse effects of NRTI drugs also appear to be mediated by their effects on host DNA polymerase activity [1–4]. Mitochondrial DNA (mtDNA) polymerase gamma appears particularly susceptible to inhibition, as this unique polymerase – indispensable for mtDNA synthesis – lacks the ability shared by nuclear DNA (nDNA) polymerases to effectively discriminate against NRTI in favour of endogenous nucleic acids [5]. NRTI-induced inhibition of mtDNA synthesis is proposed to induce depletion of cellular mtDNA copy number, ultimately leading to cellular toxicity when mitochondrial function is compromised to the extent that bioenergetic needs cannot be met. Within the NRTI class, the capacity of a select drug to induce mtDNA depletion is determined by a number of factors, including the efficiency with which the relevant nucleoside (or nucleotide) analogue is converted to its active form, and its ability to gain entry to the mitochondrial compartment within the cell. The principal determinant, however, is its affinity for DNA polymerase gamma [6]. It is notable that the relative antiretroviral activity of specific drugs within this class do not predict their effects on mtDNA synthesis, indicating that inhibition of viral and host DNA polymerases act as independent processes [3,4].

It has been proposed that this model of NRTI toxicity – commonly referred to as the ‘pol-γ’ hypothesis – is relevant to the pathogenesis of the ‘lipodystrophy syndrome', a highly prevalent clinical entity among HAART recipients in which progressive loss of subcutaneous fat in the peripheries and face is a prominent feature [6]. NRTI therapy alone provides sufficient conditions for the development of subcutaneous fat wasting [7,8], and is an independent risk factor for the development of fat wasting in individuals treated with HAART regimens [9–11]. Moreover, data from observational studies [9,10] and clinical trials [12–14] indicate differences in relative risk of lipodystrophy onset associated with select drugs within the NRTI class. Hence, a comprehensive model of lipodystrophy pathogenesis must be able to account for the contribution of NRTI therapy, and provide for the minimal conditions under which fat wasting can develop; that is, in the setting of NRTI therapy alone.

We sought to address the hypothesis that adipocyte-specific mtDNA depletion contributes to the pathogenesis of NRTI-associated subcutaneous fat wasting, as proposed by Brinkman and colleagues [6]. In this study, subcutaneous fat biopsies have been performed using an excisional technique to avoid contamination with non-adipose tissue, and adipocytes were subsequently purified from subcutaneous fat samples through the use of collagenase digestion. Adipocyte mtDNA quantity was measured using a precise real-time PCR quantification assay. Additionally, histological and ultrastructural features of adipose tissue samples were assessed, as well as mitochondrial protein content as a marker of mitochondrial organelle mass. Results of this cross-sectional study indicate an association between NRTI therapy and mtDNA depletion as well as mitochondrial organellar proliferation in vivo, of sufficient severity to provide a plausible mechanism for adipose tissue toxicity in the context of antiretroviral therapy-associated lipodystrophy.

Back to Top | Article Outline

Materials and methods

Patient characteristics

Subcutaneous fat biopsies were obtained from participants in the Western Australian (WA) HIV Cohort Study [15]. Subjects were aged > 18 years, and had no recent history or current evidence of opportunistic infection or systemic illness. Comprehensive demographic, clinical and laboratory data are routinely collected on all participants of the WA HIV Cohort Study, including variables relevant to this study such as age, HIV and non-HIV related illnesses, history of antiretroviral drugs including reason for therapy revision, history of prophylactic and non-HIV related medications, and serial CD4 T-cell counts. Clinical assessment for the presence of subcutaneous fat wasting was performed routinely at 3-monthly clinic visits, with all patients completing a follow-up period of 12 months from the time of biopsy. All procedures, as well as storage and analysis of genetic material, were performed with informed consent from participants, and the study was approved by the Royal Perth Hospital ethics committee.

Back to Top | Article Outline
Subcutaneous fat biopsies

Biopsies involving HIV-infected individuals were performed by a single operator. Excisional fat biopsies from the supra-iliac region were obtained by direct dissection of the adipose layer following a surgical incision. Adipose tissue samples were immediately dissected by a second operator. Aliquots were placed in fixative (10% w/v formalin or 2.5% glutaraldehyde) for light and electron microscopy studies, while aliquots destined for genetic studies were immediately frozen in liquid nitrogen prior to storage at −70°C to avoid risk of artefactual mtDNA depletion [16]. Six biopsies obtained from HIV-seronegative individuals attending the Royal Perth Hospital dermatology department were also obtained by an excisional technique, and tissue processing procedures were identical in these cases.

Back to Top | Article Outline
Genetic studies

Collagenase digestion was adapted from methods described by Crisp et al. [17] and McIntosh et al. [18]. Total DNA was extracted from samples using QIAamp DNA MIDI Kit (Qiagen Inc., Chatsworth, California, USA) according to the manufacturer's recommended protocol for tissue DNA extraction. mtDNA and nDNA copy numbers were determined by a quantitative PCR assay developed in our laboratory, using the ABI 7700 sequence detection system (ABI 7700 Sequence Detection System; Perkin-Elmer Applied Biosystems, Foster City, California, USA). Mitochondrial protein extraction was adapted from the method described by Slinde et al. [19], and protein content estimated using the Bradford dye-binding procedure (microtitre plate protein assay, Bio-Rad Laboratories Inc., Hercules, California, USA).

Back to Top | Article Outline
Quantitative real-time PCR

mtDNA and nDNA copy numbers were determined by quantitative PCR using the ABI 7700 sequence detection system. Primer sets and probes were designed using Primer Express software (Perkin-Elmer Applied Biosystems) according to primer design guidelines. Forward primer, 5′-TTGGACGAACCAGAGTGTA GCTT-3′ and reverse primer, 5′-TTAGCTCAGAG CGGTCAAGTTAAG-3′ were used to amplify the mtDNA region between nucleotide positions 1592 and 1675. The fluorophore labelled probe, 5′-6FAM-CAC AAAGCACCCAACTTACACTTAGGAGATTTC-A-quencher TAMRA-3′ (nucleotides 1617–1650), was included in the reaction as a detector for the amplified product. The amount of DNA amplified from a highly conserved region of the nuclear-encoded human growth hormone gene was also measured. The reaction used forward primer 5′-TATCCCAAAGGACAGAAG TATTCATT-3′ and reverse primer 5′-TTGTGTTT CCCTCCCTGTTGGA-3′ to amplify a 141-nucleotide product. The fluorophore labelled probe used was 5′-VIC-ACCTCCCTCTGTTTCTCAGAGTCTATT CCGACA-quencher TAMRA-3′.

Each 50-μl reaction contained 50 ng total genomic DNA in a final concentration of 2.5 μM probe, 15 μM forward primer, 15 μM reverse primer, and 2 × Taqman Universal Master mix [containing heat-activated AmpliTaq Gold DNA polymerase, AmpErase UNG for carryover prevention, dNTPs with dUTP, Passive Reference dye (Rox), and buffer components].

Amplifications were performed in specifically designed optical 96-well plates using a spectrofluorometric thermal cycler (ABI 7700 Sequence Detection System; Perkin-Elmer Applied Biosystems). Mitochondrial and nuclear products were amplified separately, using identical cycling conditions. An initial cycle at 50°C for 2 min incubation was performed for activation of AmpErase UNG, followed by a 10 min incubation at 95°C for activation of AmpliTaq Gold, then 45 cycles of one step at 95°C (15 sec) for denaturing, and one step at 60°C (1 min) for annealing/extension. Reactions were kept on hold at 4°C. All samples were run in duplicate.

The detection system used in this study measures the increase in fluorescent reporter dye emission from baseline during PCR amplification. The PCR cycle number that yields an assigned level of fluorescence intensity in the exponential phase of PCR is designated as the threshold cycle (CT). The CT is directly proportional to the log10 of the copy number of the input DNA target sequence. (That is, the CT is directly proportional to x where 10x = input DNA copy number).

Measurements of mtDNA or nDNA copy number were determined using serial dilutions of plasmid standard of known copy number. The stock standards used were created by ligating nuclear and mitochondrial PCR products into plasmid vector systems (pGEM-T, Promega, USA) according to the manufacturer's protocol. The amount of plasmid DNA was determined by spectrophotometric analyses of the insert-containing plasmid DNA at A260 (1 OD = 50 μg/ml of plasmid DNA), and the copy number per ml was determined based on molecular weight.

A measure of mtDNA copy number per cell was obtained by normalizing mtDNA content to nDNA content. This derived ratio assumes that two copies of nDNA are present per cell, so that mtDNA copies/cell = mtDNA copies/ml divided by 0.5 nDNA copies/ml. As the number of PCR cycles taken to generate an assigned level of normalized fluorescence is directly proportional to the log10 of the input DNA quantity in the sample, results were expressed and analysed in logarithmic form. Hence, calculations of mtDNA copies/cell from the mitochondrial and nuclear quantitative PCR assay results utilize the formula: log10 mtDNA/cell = log10 mtDNA−log10 nDNA− log10 0.5.

Within each assay, duplicate amplifications of each dilution were performed and data was collected over five PCR runs. Dilutions of standard (log10 of copies/reaction) ranged from 2.01 to 5.12 nDNA copies/reaction, and from 3.78 to 7.96 mtDNA copies/reaction. The within-assay variation, determined by calculating the average coefficient of variation between all duplicate samples in an assay, was 0.81% for measures of nDNA and 0.20% for mtDNA (all values log10 of copies/reaction). Concordance of results between assays was assessed separately for mtDNA and nDNA quantification using three controls, ranging from low to high copies/reaction, run in each assay. mtDNA and nDNA values for controls varied by an average of 0.82% and 1.4%, respectively. Shewhart plots were used to monitor the performance of each assay.

Back to Top | Article Outline
Adipose tissue histology: light and electron microscopy

Light microscopy was performed by a histopathologist in a routine manner on 10% formalin-fixed, paraffin-embedded tissue sections. Electron microscopy was performed on all biopsy samples. One-millimetre diameter samples were fixed in cacodylate-buffered 2.5% glutaraldehyde, post-fixed in 1% Veronal-buffered osmium tetroxide, and embedded in araldite resin. Ultrathin sections were obtained on LKB Ultratome 3. Grids were then stained with saturated uranyl acetate, then lead citrate, and were viewed with a Phillips 410 electron microscope. Electron microscopy was performed to identify and describe possible ultrastructural features associated with antiretroviral therapy and/or fat wasting, and did not incorporate a quantitative assessment tool.

Back to Top | Article Outline
Statistical methods

Data analysis was performed using SPSS version 10.0 (SPSS Inc., Chicago, Illinois, USA). Normality of data distribution was assessed using the Shapiro-Wilk test. Group comparisons of demographic data, immunological status, adipocyte mtDNA and mitochondrial protein were carried out using analysis of variance (ANOVA), using the Tukey HSD method for adjustment for multiple comparisons. Comparisons of antiretroviral therapy exposure and immunological status in the treated patients used non-parametric Mann–Whitney tests because data was skewed. Values for adipocyte mtDNA copies/cell and adipocyte mitochondrial protein content (ng/mg tissue) were measured on a log10 scale. Absolute values are derived directly from these values. Adipocyte mtDNA copies/cell and mitochondrial protein content is expressed as mean and 95% confidence intervals of the mean. Percentage depletion of mtDNA, and percentage increase in mitochondrial mass from mean values of the control group is shown in Tables 2 and 3.

Table 2
Table 2
Image Tools
Table 3
Table 3
Image Tools
Back to Top | Article Outline


Patient characteristics

Thirty-seven individuals participated in the study. Biopsy samples were classified according to NRTI exposure into the following groups: group 1 HIV-seronegative controls (n = 6); group 2, antiretroviral therapy-naive, HIV-infected controls (n = 11); group 3, current zidovudine therapy (n = 9). This included two biopsies in patients who had a biopsy while on stavudine therapy and then had a second biopsy performed after switching therapy to zidovudine. Duration of zidovudine therapy in this group ranged from 4 to 61 months; group 4, current stavudine therapy (n = 12). Duration of stavudine therapy in this group ranges from 5 to 55 months. Demographic data, immunological status and history of antiretroviral drug exposure among the HIV-infected individuals are presented in Table 1.

Table 1
Table 1
Image Tools
Back to Top | Article Outline
mtDNA depletion in adipocytes

mtDNA copies/cell in adipocytes is expressed as mean and 95% confidence intervals of the mean (95% CI) for the groups. Table 2 and Fig. 1 present these results in logarithmic form, in which all values were measured and analysed (see Methods).

Fig. 1
Fig. 1
Image Tools

mtDNA copies/cell was similar in the HIV-infected control group (mean 708; 95% CI, 447–1122) and the HIV-negative controls (mean 851; 95% CI, 513–1412) (P = 0.56). NRTI treatment was associated with reduced adipocyte mtDNA copies/cell (mean 158 copies/cell; 95% CI, 107–234), representing average mtDNA depletion in NRTI-treated individuals of 77.7% (95% CI, 66.9–84.9%) compared with the mean value for the HIV-infected control group (P < 0001). Comparing HIV-infected controls with the zidovudine- (n = 10) and stavudine- (n = 12) treated groups, mtDNA copies/cell was significantly reduced in the zidovudine group (mean, 339 copies/cell; 95% CI, 200–526) compared with controls (P = 0.03). Stavudine treatment was associated with significant mtDNA depletion (mean, 91 copies/cell; 95% CI, 66–123), compared with HIV-infected controls (P < 0.001) and zidovudine-treated individuals (P < 0.001). Demographic and immunological variables were similar between these treatment groups, as well as duration of exposure to NRTI and PI antiretroviral therapy (Table 2, Fig. 1). Expressing mtDNA depletion as a reduction from the mean value for the HIV-infected control group, mean mtDNA depletion was 52.1% (95% CI, 25.7–71.8%) in the zidovudine group, and 87.1% (95% CI, 82.6–90.7%) in the stavudine group.

To exclude possible confounding effects attributable to previous NRTI therapy, and/or of concurrent NRTI therapy with lamivudine or didanosine in comparisons of stavudine and zidovudine treatment, analyses were repeated on data sets restricted to individuals who had received only zidovudine/lamivudine (n = 8) or stavudine/lamivudine (n = 7) NRTI therapy. The effect of choice of NRTI therapy on adipocyte mtDNA copies/cell was similar in these groups as in the previous analyses (zidovudine/lamivudine versus stavudine/lamivudine, P = 0.012), as presented in Table 3. Compared with HIV-infected controls, mtDNA copies/cell was reduced in both the zidovudine/lamivudine-treated (P = 0.008) and the stavudine/lamivudine-treated group (P < 0.001).

Back to Top | Article Outline
Mitochondrial mass

Mitochondrial protein content was measured as a marker of mitochondrial organelle mass (Table 2). Similar results were obtained in the HIV-infected control group and the zidovudine-treated group (P = 0.85). Mitochondrial protein content was significantly increased in the stavudine-treated group (389% of mean control value; 95% CI, 219–692%) compared with controls (P < 0.001) and in the zidovudine-treated group (P = 0.004). Mitochondrial mass showed a significant negative correlation with adipocyte mtDNA copies/cell in NRTI-treated patients (r = −0.53; P = 0.01).

Back to Top | Article Outline
Adipose tissue histology

Samples from both HIV-seronegative and HIV-infected control subjects demonstrated typical adipose tissue histologic features (Fig. 2a). Adipocytes were regular in size and appearance, with moderate numbers of vascular and stromal cells within a delicate reticular architecture. Among NRTI-treated individuals, a consistent pattern of abnormalities was observed in adipose tissue from individuals affected by fat wasting, irrespective of choice of NRTI therapy or concurrent use of PI therapy (Fig. 2b). Increased variation in adipocyte size was noted, with an increased number of small adipocytes. Lipogranulomata were also seen, characterized by the presence of lipid-laden macrophages (confirmed by MAC 385 staining) that encircled adipocytes in some instances (Fig. 2c). Adipocyte cell loss was evident, with preservation of stromal tissue architecture in regions where adipocytes were absent. Tissue vascularity was also increased, although a lack of evidence of proliferation within the vascular fraction suggested that this may be more apparent than real (i.e., reflecting decreased volume and/or number of the intervening adipocytes). Moderate to marked abnormalities of this kind were present in all cases of clinically apparent fat wasting (four out of nine zidovudine-treated, nine out of 12 stavudine-treated), while normal histology (four out of nine zidovudine-treated, one out of 12 stavudine-treated) or mild changes (one out of nine zidovudine-treated, two out of 12 stavudine-treated) were noted in samples obtained from individuals without evidence of fat wasting at the time of biopsy.

Fig. 2
Fig. 2
Image Tools
Back to Top | Article Outline
Adipose tissue ultrastructure

Assessment of adipocyte ultrastructure revealed several pathologic features observed exclusively in NRTI-treated individuals. Mitochondrial proliferation was most notable, occurring in densely packed and expanded cytoplasmic extrusions (Fig. 3a) and in intimate association with frequent intracytoplasmic lipid droplets (Fig. 3b). This feature was observed in none of 11 HIV-infected controls, seven out of 12 in the stavudine-treated group, and three out of nine in the zidovudine-treated group. Abnormal cristal architecture was also present, with whorled forms and disorganized crystal orientation (Fig. 3b). Redundant folds of basal lamina were noted, indicating loss of cellular volume despite cytoplasmic expansion (Fig. 3a), suggestive of decreased volume of the central triglyceride-rich lipid pool within the adipocyte.

Fig. 3
Fig. 3
Image Tools
Back to Top | Article Outline
Subcutaneous fat wasting

Measures of adipocyte mtDNA copies/cell and mitochondrial protein content were not significantly different between antiretroviral-treated patients with clinically apparent fat wasting at the time of biopsy, and those without (P = 0.44 and P = 0.88 respectively; post-switch cases excluded from analysis). Given the highly significant differences in these variables between stavudine- and zidovudine-treated patients, informative cases in these analyses may be those treated with stavudine who had no evidence of subcutaneous fat wasting at the time of biopsy, and zidovudine-treated patients with clinical fat wasting at the time of biopsy. In the stavudine-treated group, results from the three patients without fat wasting were: 49 copies/cell (5 months stavudine/didanosine/efavirenz), 98 copies/ cell (20 months stavudine/lamivudine/nelfinavir) and 50 copies/cell (22 months stavudine/lamivudine/nelfinavir). Over a 12-month follow-up period, the first two of these patients developed clinically apparent fat wasting. In the zidovudine group, results from patients with fat wasting at the time of biopsy were: 156 copies/cell (30 months zidovudine/lamivudine/nevirapine), and 427 copies/cell (49 months zidovudine/lamivudine/indinavir). No zidovudine-treated patient developed fat wasting subsequent to the biopsy, over 12 months of follow-up.

Back to Top | Article Outline


The major finding of this study is that NRTI therapy is associated with adipocyte mtDNA depletion and mitochondrial proliferation. Additionally, morphologic assessment of adipose tissue indicates that subcutaneous fat wasting is associated with adipose cell loss associated with lipogranuloma formation, and characteristic mitochondrial proliferation in the remaining adipocytes. None of these outcomes were dependent on the presence of HIV PI in antiretroviral therapy regimens. Highly significant differences in adipocyte mtDNA depletion were also noted between the zidovudine- and stavudine-treated groups, which were not abrogated after excluding the possible confounding effects of previous NRTI therapy, and of choice of concurrent NRTI within the HAART regimen. This does not exclude the possibility that differences between didanosine and lamivudine may exist – rather, that in this study the observed stavudine effect could not be attributed to an effect of the second NRTI in the regimen.

The severity of mtDNA depletion in adipocytes in the presence of NRTI therapy provides a plausible basis for the development of mitochondrial dysfunction and cellular pathology. mtDNA depletion attributable to stavudine- as compared with zidovudine therapy is consistent with the results of clinical studies demonstrating increased relative risk of developing subcutaneous fat wasting associated with stavudine therapy [7–10,12–14], and is also supported by in vitro studies of mtDNA polymerase gamma inhibition associated with these drugs [3,4]. Hence, these data support the hypothesis that mtDNA depletion contributes to the pathogenesis of subcutaneous fat wasting associated with NRTI therapy, and that select drugs within the NRTI class are associated with increased relative risk of inducing adipocyte mtDNA depletion. However, establishing a causal relationship between NRTI therapy, mtDNA depletion, and clinically relevant adipose tissue toxicity requires longitudinal studies in which these parameters can be measured prior to, as well as following, the introduction of antiretroviral therapy in each individual. Additionally, further research is needed to establish the degree of correlation between NRTI-induced mtDNA depletion and mitochondrial organelle dysfunction. It is well established that the mitochondrial genome exhibits a degree of redundancy, so that a significant loss of mtDNA through mutation or depletion may be required before tissue pathology develops. In vitro, it is estimated that this ‘threshold’ is attained when mtDNA is reduced by approximately 80% [20]—a value that is consistent with the results of this study. This requires clarification in adipose tissue.

Similar studies published by Walker [21] and Shikuma [22] have noted significant mtDNA depletion in adipose tissue samples from patients with subcutaneous fat wasting. In this study, these observations are extended by the demonstration of NRTI-associated mtDNA depletion in adipocytes – thereby excluding confounding effects that may be attributed to the presence of stromal-vascular cell populations within adipose tissue samples. Additionally, the use of a real-time PCR quantitation assay in this study allows for precision of measurement that has not been available previously.

These findings complement a recently published study demonstrating specific effects of HIV PI therapy on adipose tissue differentiation markers and insulin sensitivity in vivo [23], establishing the relevance of adipose tissue as a target for the contributions of both NRTI and PI drug classes to the pathogenesis of lipodystrophy. This is consistent with an aetiopathogenic model in which PI and NRTI drugs make independent, as well as synergistic, contributions to lipodystrophy pathogenesis [24,25]. In this study, we were unable to identify an independent association between PI therapy and mtDNA depletion or mitochondrial proliferation, suggesting that these effects were determined primarily by NRTI use. Additionally, use of PI therapy was not required for the development of abnormal adipose tissue morphology.

The pathologic consequences of mtDNA depletion and associated mitochondrial dysfunction have generally been considered in terms of their effects on oxidative phosphorylation—the creation of cellular energy (adenosine triphosphate, ATP) within mitochondria from aerobic metabolism [6]. In adipose tissue, however, mitochondrial energy production is predominantly harnessed to biosynthetic pathways, so that energy may be stored as triglyceride rather than expended by the adipocyte itself [26]. Mitochondrial dysfunction in adipocytes and other lipogenic tissues appears to activate a complex regulatory response [27–30] that attempts to restore bioenergetic equilibrium by increasing oxidative metabolism and mitochondrial proliferation [31] at the expense of energy-dependent biosynthetic reactions. Hence, while profound mitochondrial toxicity may induce cell death, as proposed by Brinkman [7], chronic sublethal mitochondrial dysfunction in adipose tissue may induce adipocyte metabolic dysfunction characterized by decreased capacity for triglyceride synthesis and storage, and a reciprocal increase in substrate oxidation and mitochondrial proliferation.

This phenotype is consistent with adipose tissue morphologic assessment presented in this study, and in a recent report by Lloreta and colleagues [32]. Cellular loss was associated with the recruitment of macrophages, but the absence of other inflammatory changes suggests that apoptotic, rather than necrotic, mechanisms are involved in cell death [33]. This is supported by studies demonstrating increased apoptosis in adipose tissue in individuals with HAART-associated lipodystrophy (assessed with TdT-mediated dUTP nick-end labelling staining) that was not ameliorated after switching from an HIV PI to NNRTI therapy while maintaining NRTI therapy [34,35]. In surviving adipocytes (that is, those available for ultrastructural assessment), increased mitochondrial biogenesis may represent a compensatory response to sublethal mitochondrial dysfunction.

This cross-sectional study provides evidence that in vivo adipocyte mtDNA depletion induced by NRTI therapy may be relevant to the pathogenesis of subcutaneous fat wasting, as previously hypothesized by Brinkman and colleagues [6], although the establishment of causality will require longitudinal studies. It is anticipated that further elucidation of the relationships between NRTI therapy-induced mtDNA depletion and adipose tissue pathophysiology will provide an increased understanding of the cellular basis for this clinical syndrome. This may in turn provide for a directed approach to the monitoring of NRTI effects in the development and maintenance of fat wasting, based on the assessment of cellular pathology in the target tissue.

Back to Top | Article Outline


1.Squires KE. An introduction to nucleoside and nucleotide analogues. Antivir Ther 2001, 6(Suppl 3):1–14.

2.Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000, 22:685–708.

3.Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS, et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001, 276: 40847–40857.

4.Martin JL, Brown CE, Matthews-Davis N, Reardon JE. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994, 38:2743–2749.

5.Longley MJ, Ropp PA, Lim SE, Copeland WC. Characterization of the native and recombinant catalytic subunit of human DNA polymerase γ: Identification of residues critical for exonuclease activity and dideoxynucleotide sensitivity. Biochemistry 1998, 37:10529–10539.

6.Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999, 354: 1112–1115.

7.Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999, 13:1659–1667.

8.Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 2000, 14(3):F25–F32.

9.Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000, 14:1309–1316.

10.Saint-Marc T, Partisani M, Poizot-Martin, Rouviere O, Bruno F, Lang JM, et al. Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 2000, 14(1):37–49.

11.van der Valk M, Gisolf EH, Reiss P, Wit FW, Japour A, Weverling GJ, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS 2001, 15:847–855.

12.Chene G, Angelini E, Cotte L, Lang JM, Morlat P, Rancinan C, et al. Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis 2002, 34:649–657.

13.Law M, Emery S, French M, Carr A, Chuah J and Cooper D. Lipodystrophy and metabolic abnormalities in a cross-sectional study of participants in randomised controlled studies of combination antiretroviral therapy. Second International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 2000. Toronto, September 2000 [abstract 028].

14.Joly V, Flandre P, Meiffredy V, Hazebrouck S, Harel M, Aboulker JP, Yeni P. Assessment of lipodystrophy in patients previously exposed to AZT, ddI or ddC, but naïve for d4T and protease inhibitors (PI), and randomised between d4T/3TC/Indinavir and AZT/3TC/Indinavir (NOVAVIR trial). Eighth Conference on Retroviruses and Opportunistic Infections. Chicago, February 2001 [abstract 539].

15.Mallal SA. The Western Australian HIV Cohort Study, Perth, Australia. J Acquir Immune Defic Syndr Hum Retrovirol 1998, 17:(Suppl 1):S23–S27.

16.Berger A, Bruschek M, Grethen C, Sperl W, Kofler B. Poor storage and handling of tissue mimics mitochondrial DNA depletion. Diagn Mol Pathol 2001, 10:55–59.

17.Crisp M, Starkey KJ, Lane L, Ham J, Ludgate M. Adipogenesis in thyroid eye disease. Invest Ophthalmol Visual Sci 2001, 41:3249–3255.

18.McIntosh M, Hausman D, Martin R, Hausman G. Dehydroepiandrosterone attentuates preadipocyte growth in primary cultures of stromal vascular cells. 1998, 275:E285–E293.

19.Slinde E, Morild E, Flatmark T. A general and rational approach to the optimal recovery of mitochondria by differential centrifugation in homogenous media. Anal Biochem 1975, 66:151–158.

20.Rossignol R, Malgat M, Mazat J-P, Letellier T. Threshold effect and tissue specificity. Implications for mitochondrial cytopathies. J Biol Chem 1999, 274:33426–33432.

21.Walker UA, Bickel M, Lutke Volksbeck SI, Ketelsen UP, Scofer UP, Setzer B, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002, 29:117–121.

22.Shikuma CM, Hu N, Milne C, Yost F, Waslien C, Shimizu S, Shiramizu B. Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy. AIDS 2001, 15:1801–1809.

23.Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1- infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002, 359:1026–1031.

24.John M, Nolan D, Mallal S. Antiretroviral therapy and the lipodystrophy syndrome. Antiviral Ther 2001, 6:9–20.

25.Nolan D, John M, Mallal S. Antiretroviral therapy and the lipodystrophy syndrome. Part 2: Concepts in aetiopatrhogenesis. Antiviral Ther 2001, 6:145–160.

26.Frayn KN. Metabolism Regulation. A Human Perspective. London: Portland Press Ltd.; 1996.

27.Rossmeisl M, Syrovy I, Baumurk F, Flachs P, Janovska P, Kopecky J. Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue. FASEB J 2000, 14:1793–17800.

28.Hardie DG, Carling D, Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Ann Rev Biochem 1998, 67:821–855.

29.Muoio DM, Seefeld K, Witters LA, Coleman RA. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem J 1999, 338:783–791.

30.Sullivan JE, Brocklehurst KJ, Marley AE, Carey F, Carling D, Beri RK. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett 1994, 353:33–36.

31.Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 2001, 281:E1340–E1346.

32.Lloreta J, Domingo P, Pujol R, Arroyo J, Sambeat M, Serrano S. An ultrastructural insight into the pathogenesis study of HAART-associated partial lipodystrophy. First International AIDS Society Conference on HIV Pathogenesis and Treatment. Buenos Aires, July 2001 [abstract 494].

33.Saraste A. Morphologic criteria and detection of apoptosis. Herz 1999, 24:189–195.

34.Domingo P, Matias-Guiu X, Pujol RM, Francia E, Lagarda E, Sambeat MA, Vazquez G. Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS 1999, 13:2261–2267.

35.Domingo P, Matias-Guiu X, Pujol RM, Domingo JC, Arroyo JA, Sambeat MA, et al. Switching to nevirapine decreases insulin levels but does not improve subcutaneous adipocyte apoptosis in patients with highly active antiretroviral therapy-associated lipodystrophy. J Infect Dis 2001, 184:1197–1201.

Cited By:

This article has been cited 131 time(s).

Mechanisms of Ageing and Development
Mitochondrial CSA and CSB: Protein interactions and protection from ageing associated DNA mutations
Kamenisch, Y; Berneburg, M
Mechanisms of Ageing and Development, 134(): 270-274.
Future Lipidology
Genetic and acquired lipodystrophies: from fat redistribution to insulin resistance and aging
Capeau, J; Magre, J; Caron, M; Lagathu, C; Bastard, JP; Vigouroux, C
Future Lipidology, 1(5): 593-604.
Antiviral Therapy
Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes
Viengchareun, S; Caron, M; Auclair, M; Kim, MJ; Frachon, P; Capeau, J; Lombes, M; Lombes, A
Antiviral Therapy, 12(6): 919-929.

Pharmacogenetics of antiretroviral therapy: genetic variation of response and toxicity
Martin, AM; Nolan, D; Gaudieri, S; Phillips, E; Mallal, S
Pharmacogenomics, 5(6): 643-655.

Cumulative insults to mitochondrial function may promote the emergence of 'syndrome X' and diabetes mellitus in HIV/HCV co-infected patients
Revuelta, MP
Mitochondrion, 4(): 175-184.
Antiviral Therapy
Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients
Jan, V; Cervera, P; Maachi, M; Boudrimont, M; Kim, M; Vidal, H; Girard, PM; Levan, P; Rozenbaum, W; Lombes, A; Copeau, J; Bastard, JP
Antiviral Therapy, 9(4): 555-564.

Antiviral Therapy
Effects of zidovudine, stavudine and beta-aminoisobutyric acid on lipid homeostasis in mice: possible role in human fat wasting
Maisonneuve, C; Igoudjil, A; Begriche, K; Letteron, P; Guimont, MC; Bastin, J; Laigneau, JP; Pessayre, D; Fromenty, B
Antiviral Therapy, 9(5): 801-810.

Lipids in Health and Disease
Is oxygen a key factor in the lipodystrophy phenotype?
Gentil, C; Le Jan, S; Philippe, J; Leibowitch, J; Sonigo, P; Germain, S; Pietri-Rouxel, F
Lipids in Health and Disease, 5(): -.
Clinical Infectious Diseases
Improvement of Mitochondrial Toxicity in Patients Receiving a Nucleoside Reverse-Transcriptase Inhibitor-Sparing Strategy: Results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA)
Negredo, E; Miro, O; Rodriguez-Santiago, B; Garrabou, G; Estany, C; Masabeu, A; Force, L; Barrufet, P; Cucurull, J; Domingo, P; Alonso-Villaverde, C; Bonjoch, A; Moren, C; Perez-Alvarez, N; Clotet, B
Clinical Infectious Diseases, 49(6): 892-900.
Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies
McComsey, GA; Walker, UA
Mitochondrion, 4(): 111-118.
Journal of Infectious Diseases
In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA
Mallon, PWG; Unemori, P; Sedwell, R; Morey, A; Rafferty, M; Williams, K; Chisholm, D; Samaras, K; Emery, S; Kelleher, A; Cooper, DA; Carr, A
Journal of Infectious Diseases, 191(): 1686-1696.

Antiviral Therapy
Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level
Nolan, D; Hammond, E; James, I; McKinnon, E; Mollal, S
Antiviral Therapy, 8(6): 617-626.

Antiviral Therapy
Possible ways nucleoside analogues can affect mitochondrial DNA content and gene expression during HIV therapy
Cote, HCF
Antiviral Therapy, 10(): M3-M11.

Annales De Pathologie
Antiretroviral treatments-related lipodystrophy syndrome: clinico-pathological findings
Lassalle, S; Cervera, P; Hofman, V; Mari, M; Dellamonica, P; Hofman, P
Annales De Pathologie, 25(4): 309-317.

HIV Clinical Trials
Once-daily abacavir/lamivudine/zidovudine plus tenofovir for the treatment of HIV-1 infection in antiretroviral-naive subjects: A 48-week pilot study
Elion, R; Cohen, C; deJesus, E; Redfield, R; Gathe, J; Hsu, R; Yau, L; Ross, L; Ha, B; Lanier, ER; Scott, T
HIV Clinical Trials, 7(6): 324-333.
Clinical Infectious Diseases
Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: A randomized, controlled study
McComsey, GA; Lo Re, V; O'Riordan, M; Walker, UA; Lebrecht, D; Baron, E; Mounzer, K; Frank, I
Clinical Infectious Diseases, 46(8): 1290-1296.
Brazilian Journal of Infectious Diseases
Lipodystrophic Syndrome in Children and Adolescents Infected With the Human Immunodeficiency Virus
Alves, C; Oliveira, AC; Brites, C
Brazilian Journal of Infectious Diseases, 12(4): 342-348.

Expert Review of Anti-Infective Therapy
Trends in the European HIV/AIDS epidemic: a perspective from Italy
Madeddu, G; Rezza, G; Mura, MS
Expert Review of Anti-Infective Therapy, 7(1): 25-36.
Journal of Antimicrobial Chemotherapy
Mitochondrial toxicity in HIV-infected patients both off and on antiretroviral treatment: a continuum or distinct underlying mechanisms?
Maagaard, A; Kvale, D
Journal of Antimicrobial Chemotherapy, 64(5): 901-909.
Expert Opinion on Therapeutic Patents
Cardiovascular risk associated with antiretroviral therapy in IV-infected patients
Calza, L; Manfredi, R; Chiodo, F
Expert Opinion on Therapeutic Patents, 16(): 1497-1516.

Antiviral Therapy
Effect of pioglitazone on HIV-1-related lipodystrophy: a randomized double-blind placebo-controlled trial (ANRS 113)
Slama, L; Lanoy, E; Valantin, MA; Bastard, JP; Chermak, A; Boutekatjirt, A; William-Faltaos, D; Billaud, E; Molina, JM; Capeau, J; Costagliola, D; Rozenbaum, W
Antiviral Therapy, 13(1): 67-76.

Journal of Clinical Virology
Mitochondrial DNA depletion in adipose tissue of HIV-infected patients with peripheral lipoatrophy
Buffet, M; Schwarzinger, M; Amellal, B; Gourlain, K; Bui, P; Prevot, M; Deleuze, J; Morini, JP; Gorin, I; Calvez, V; Dupin, N
Journal of Clinical Virology, 33(1): 60-64.
Antiviral Therapy
Nucleoside analogue-sparing strategy for the treatment of chronic HIV infection: potential interest and clinical experience
Joly, V; Yeni, P
Antiviral Therapy, 10(1): 29-40.

HIV Clinical Trials
Mild to moderate symptoms do not correlate with lactate levels in HIV-positive patients on nucleoside reverse transcriptase inhibitors
Tan, D; Walmsley, S; Shen, S; Raboud, J
HIV Clinical Trials, 7(3): 107-115.

AIDS Research and Human Retroviruses
Changes in the peripheral blood mtDNA levels in naive patients treated by different nucleoside reverse transcriptase inhibitor combinations and their association with subsequent lipodystrophy
Chene, G; Amellal, B; Pedrono, G; Gourlain, K; Rancinan, C; Journot, V; Cotte, L; Palmer, P; De Castro, N; Calvez, V; Molina, JM
AIDS Research and Human Retroviruses, 23(1): 54-61.
Expert Opinion on Pharmacotherapy
Strategies in the treatment of HIV-1-associated adipose redistribution syndromes
Gutierrez, MDM; Mateo, G; Domingo, P
Expert Opinion on Pharmacotherapy, 8(): 1871-1884.
Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids
Drug-induced lipotoxicity: Lipodystrophy associated with HIV-1 infection and antiretroviral treatment
Villarroya, F; Domingo, P; Giralt, M
Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids, 1801(3): 392-399.
Netherlands Journal of Medicine
Antiretroviral therapy in HIV patients: aspects of metabolic complications and mitochondrial toxicity
ter Hofstede, HJM; Burger, DM; Koopmans, PP
Netherlands Journal of Medicine, 61(): 393-403.

Oxygen consumption by cultured human cells is impaired by a nucleoside analogue cocktail that inhibits mitochondrial DNA synthesis
Petit, C; Pietri-Rouxel, F; Lesne, A; Leste-Laserre, T; Mathez, D; Naviaux, RK; Sonigo, P; Bouillaud, F; Leibowitch, J
Mitochondrion, 5(3): 154-161.
Antiviral Therapy
Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations
Gougeon, ML; Penicaud, L; Fromenty, B; Leclercq, P; Viard, JP; Capeau, J
Antiviral Therapy, 9(2): 161-177.

Comptes Rendus Biologies
Lipodystrophic syndromes: congenital or acquired diseases of adipose tissue
Capeau, J; Vigouroux, C; Magre, J; Lascols, O; Caron, M; Bastard, JP
Comptes Rendus Biologies, 329(8): 639-652.
Journal of Infectious Diseases
Effects of ddanosine-related depletion of mtDNA in human T lymphocytes
Setzer, B; Schlesier, M; Walker, UA
Journal of Infectious Diseases, 191(6): 848-855.

Jaids-Journal of Acquired Immune Deficiency Syndromes
Chronic loss of subcutaneous adipose tissue in HIV-associated lipodystrophy may not be associated with accelerated apoptosis (vol 38, pg 53, 2005)
Mynarcik, D; Wei, LX; Komaroff, E; Ferris, R; McNurlan, M; Gelato, M
Jaids-Journal of Acquired Immune Deficiency Syndromes, 38(3): 366-371.

Biochemical Pharmacology
Activity profiles of deoxynucleoside kinases and 5'-nucleotidases in cultured adipocytes and myoblastic cells: insights into mitochondrial toxicity of nucleoside analogs
Rylova, SN; Albertioni, F; Flygh, G; Eriksson, S
Biochemical Pharmacology, 69(6): 951-960.
Antiviral Therapy
Complications associated with NRTI therapy: update on clinical features, and possible pathogenic mechanisms
Nolan, D; Mallal, S
Antiviral Therapy, 9(6): 849-863.

New Microbiologica
Sequencing antiretroviral drugs for long-lasting suppression of HIV replication
Gianotti, N; Lazzarin, A
New Microbiologica, 28(4): 281-297.

Antiviral Therapy
Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients
Maagaard, A; Holberg-Petersen, M; Kollberg, G; Oldfors, A; Sandvik, L; Bruun, JN
Antiviral Therapy, 11(5): 601-608.

Antiviral Therapy
Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection
McComsey, GA; Libutti, DE; O'Riordan, M; Shelton, JM; Storer, N; Ganz, J; Jasper, J; Harrill, D; Gerschenson, M
Antiviral Therapy, 13(5): 715-722.

AIDS Research and Human Retroviruses
Mitochondrial Oxidative Phosphorylation Protein Levels in Peripheral Blood Mononuclear Cells Correlate with Levels in Subcutaneous Adipose Tissue within Samples Differing by HIV and Lipoatrophy Status
Shikuma, CM; Gerschenson, M; Chow, D; Libutti, DE; Willis, JH; Murray, J; Capaldi, RA; Marusich, M
AIDS Research and Human Retroviruses, 24(): 1255-1262.
Human & Experimental Toxicology
Ex vivo zidovudine (AZT) treatment of CD34+bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production
Lewis, LD; Amin, S; Civin, CI; Lietman, PS
Human & Experimental Toxicology, 23(4): 173-185.
HIV Medicine
Depletion of mitochondrial DNA copies/cell in peripheral blood mononuclear cells in HIV-1-infected treatment-naive patients
Maagaard, A; Holberg-Petersen, M; Kvittingen, EA; Sandvik, L; Bruun, JN
HIV Medicine, 7(1): 53-58.

Antiviral Therapy
Arterial stiffness in HIV-infected patients receiving highly active antiretroviral therapy
Sevastianova, K; Sutinen, J; Westerbacka, J; Ristola, M; Yki-Jarvinen, H
Antiviral Therapy, 10(8): 925-935.

American Journal of Physiology-Endocrinology and Metabolism
Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults
Fleischman, A; Johnsen, S; Systrom, DM; Hrovat, M; Farrar, CT; Frontera, W; Fitch, K; Thomas, BJ; Torriani, M; Cote, HCF; Grinspoon, SK
American Journal of Physiology-Endocrinology and Metabolism, 292(6): E1666-E1673.
HIV Clinical Trials
Improvements in Subcutaneous Fat, Lipid Profile, and Parameters of Mitochondrial Toxicity in Patients with Peripheral Lipoatrophy When Stavudine is Switched to Tenofovir (LIPOTEST Study)
Ribera, E; Paradineiro, JC; Curran, A; Sauleda, S; Garcia-Arumi, E; Castella, E; Puiggros, C; Crespo, M; Feijoo, M; Diaz, M; del Saz, SV; Planas, M; Sureda, D; Falco, V; Ocana, I; Pahissa, A
HIV Clinical Trials, 9(6): 407-417.
Journal of Antimicrobial Chemotherapy
Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen
Gerschenson, M; Kim, C; Berzins, B; Taiwo, B; Libutti, DE; Choi, J; Chen, D; Weinstein, J; Shore, J; da Silva, B; Belsey, E; McComsey, GA; Murphy, RL
Journal of Antimicrobial Chemotherapy, 63(6): 1244-1250.
Clinical Infectious Diseases
Mitochondrial DNA levels in fat and blood cells from patients with lipodystrophy or peripheral neuropathy and the effect of 90 days of high-dose coenzyme Q treatment: A randomized, double-blind, placebo-controlled pilot study
Christensen, ER; Stegger, M; Jensen-Fangel, S; Laursen, AL; Ostergaard, L
Clinical Infectious Diseases, 39(9): 1371-1379.

Clinical Endocrinology
Thyroid function in human immunodeficiency virus patients treated with highly active antiretroviral therapy (HAART): a longitudinal study
Madeddu, G; Spanu, A; Chessa, F; Calia, GM; Lovigu, C; Solinas, P; Mannazzu, M; Falchi, A; Mura, MS; Madeddu, G
Clinical Endocrinology, 64(4): 375-383.
M S-Medecine Sciences
Lipodystrophies related to antiretroviral treatment of HIV infection
Capeau, J; Caron, M; Vigouroux, C; Cervera, P; Kim, M; Maachi, M; Lagathu, C; Bastard, JP
M S-Medecine Sciences, 22(5): 531-536.

American Journal of Physiology-Endocrinology and Metabolism
Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy
Sevastianova, K; Sutinen, J; Kannisto, K; Hamsten, A; Ristola, M; Yki-Jarvinen, H
American Journal of Physiology-Endocrinology and Metabolism, 295(1): E85-E91.
Antimicrobial Agents and Chemotherapy
Zidovudine impairs adipogenic differentiation through inhibition of clonal expansion
Stankov, MV; Schmidt, RE; Behrens, GMN
Antimicrobial Agents and Chemotherapy, 52(8): 2882-2889.
Journal of Infectious Diseases
Effect of Rosiglitazone on Peroxisome Proliferator-Activated Receptor gamma Gene Expression in Human Adipose Tissue Is Limited by Antiretroviral Drug-Induced Mitochondrial Dysfunction
Mallon, PWG; Sedwell, R; Rogers, G; Nolan, D; Unemori, P; Hoy, J; Samaras, K; Kelleher, A; Emery, S; Cooper, DA; Carr, A
Journal of Infectious Diseases, 198(): 1794-1803.
Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy
Kallianpur, AR; Hulgan, T
Pharmacogenomics, 10(4): 623-637.
HIV Medicine
Recovery of fat following a switch to nucleoside reverse transcriptase inhibitor-sparing therapy in patients with lipoatrophy: results from the 96-week randomized ANRS 108 NoNuke Trial
Valantin, MA; Lanoy, E; Bentata, M; Kalmykova, O; Boutekadjirt, A; Allavena, C; Rozenbaum, W; Peytavin, G; Amellal, B; Calvez, V; Costagliola, D; Katlama, C
HIV Medicine, 9(8): 625-635.
Mitochondrial DNA: An Up-and-coming Actor in White Adipose Tissue Pathophysiology
Villarroya, J; Giralt, M; Villarroya, F
Obesity, 17(): 1814-1820.
Antimicrobial Agents and Chemotherapy
Mitochondrial DNA Depletion and Respiratory Chain Activity in Primary Human Subcutaneous Adipocytes Treated with Nucleoside Analogue Reverse Transcriptase Inhibitors
Stankov, MV; Lucke, T; Das, AM; Schmidt, RE; Behrens, GMN
Antimicrobial Agents and Chemotherapy, 54(1): 280-287.
Journal of Antimicrobial Chemotherapy
The LOPSAQ study: 48 week analysis of a boosted double protease inhibitor regimen containing lopinavir/ritonavir plus saquinavir without additional antiretroviral therapy
Staszewski, S; Babacan, E; Stephan, C; Haberl, A; Carlebach, A; Gute, P; Klauke, S; Hermschulte, Y; Stuermer, M; Dauer, B
Journal of Antimicrobial Chemotherapy, 58(5): 1024-1030.
Antiviral Therapy
The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients
Milinkovic, A; Martinez, E; Lopez, S; de Lazzari, E; Miro, O; Vidal, S; Blanco, JL; Garrabou, G; Laguno, M; Arnaiz, JA; Leon, A; Larrousse, M; Lonca, M; Mallolas, J; Gatell, JM
Antiviral Therapy, 12(3): 407-415.

The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro
Caron, M; Auclair, M; Lagathu, C; Lombes, A; Walker, UA; Kornprobst, M; Capeau, J
AIDS, 18(): 2127-2136.

Antiviral Therapy
Altered mitochondrial RNA production in adipocytes from HIV-infected individuals with lipodystrophy
Galluzzi, L; Pinti, M; Guaraldi, G; Mussini, C; Troigno, L; Roat, E; Giovenzana, C; Nemes, E; Nasi, M; Orlando, G; Solomoni, P; Cossarizza, A
Antiviral Therapy, 10(): M91-M99.

Antiviral Therapy
HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy
Giralt, M; Domingo, P; Guallar, JP; de la Concepcion, MLR; Alegre, M; Domingo, JC; Villarroya, F
Antiviral Therapy, 11(6): 729-740.

Antimicrobial Agents and Chemotherapy
Site-specific reduction of oxidative and lipid metabolism in adipose tissue of 3 '-azido-3 '-deoxythymidine-treated rats
Deveaud, C; Beauvoit, B; Reynaud, A; Bonnet, J
Antimicrobial Agents and Chemotherapy, 51(2): 583-590.
Antimicrobial Agents and Chemotherapy
Mitochondrial DNA content, an inaccurate biomarker of mitochondrial alteration in human immunodeficiency virus-related lipodystrophy
Kim, MJ; Jardel, C; Barthelemy, C; Jan, W; Bastard, JP; Fillaut-Chapin, S; Houry, S; Capeau, J; Lombes, A
Antimicrobial Agents and Chemotherapy, 52(5): 1670-1676.
Journal of Infection
Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy
Calza, L; Manfredi, R; Pocaterra, D; Chiodo, F
Journal of Infection, 57(1): 16-32.
Journal of Infectious Diseases
Mitochondrial DNA and RNA increase in peripheral blood mononuclear cells from HIV-1-infected patients randomized to receive stavudine-containing or stavudine-sparing combination therapy
Casula, M; Weverling, GJ; Wit, FW; Timmermans, EC; Stek, M; Lange, JM; Reiss, P
Journal of Infectious Diseases, 192(): 1794-1800.

European Journal of Clinical Nutrition
Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices
McComsey, GA; O'Riordan, M; Setzer, B; Lebrecht, D; Baron, E; Walker, UA
European Journal of Clinical Nutrition, 62(8): 1031-1037.
International Journal of Biochemistry & Cell Biology
Novel antibody-based strategies for the rapid diagnosis of mitochondrial disease and dysfunction
Marusich, MF; Murray, J; Xie, J; Capaldi, RA
International Journal of Biochemistry & Cell Biology, 41(): 2081-2088.
Expert Opinion on Drug Metabolism & Toxicology
Apoptosis: a clinically useful measure of antiretroviral drug toxicity?
Hooker, DJ; Cherry, CL
Expert Opinion on Drug Metabolism & Toxicology, 5(): 1543-1553.
Differences in cytosolic and mitochondrial 5 '-nucleotidase and deoxynucleoside kinase activities in Sprague-Dawley rat and CD-1 mouse tissues: Implication for the toxicity of nucleoside analogs in animal models
Mirzaee, S; Eriksson, S; Albertioni, F
Toxicology, 267(): 159-164.
Metabolic complications of HIV therapy in children
McComsey, GA; Leonard, E
AIDS, 18(): 1753-1768.

Jaids-Journal of Acquired Immune Deficiency Syndromes
Management of morphologic changes associated with antiretroviral use in HIV-infected patients
Wohl, DA; Brown, TT
Jaids-Journal of Acquired Immune Deficiency Syndromes, 49(): S93-S100.

AIDS Reviews
Pharmacogenetics of Adverse Effects Due To Antiretroviral Drugs
Vidal, F; Gutierrez, F; Gutierrez, M; Olona, M; Sanchez, V; Mateo, G; Peraire, J; Vilades, C; Veloso, S; Lopez-Dupla, M; Domingo, P
AIDS Reviews, 12(1): 15-30.

Antiviral Therapy
Mitochondrial changes during D-drug-containing once-daily therapy in HIV-positive treatment-naive patients
Maggiolo, F; Roat, E; Pinti, M; Nasi, M; Gibellini, L; De Biasi, S; Airoldi, M; Ravasio, V; Mussini, C; Suter, F; Cossarizza, A
Antiviral Therapy, 15(1): 51-59.
New England Journal of Medicine
Medical progress - Cardiovascular risk and body-fat abnormalities in HIV-infected adults
Grinspoon, S; Carr, A
New England Journal of Medicine, 352(1): 48-62.

AIDS Reviews
Could mitochondrial DNA quantitation be a surrogate marker for drug mitochondrial toxicity?
de Mendoza, C; Sanchez-Conde, M; Ribera, E; Domingo, P; Soriano, V
AIDS Reviews, 6(3): 169-180.

Expert Opinion on Drug Safety
Mitochondrial disease in the offspring as a result of antiretroviral therapy
Venhoff, N; Walker, UA
Expert Opinion on Drug Safety, 5(3): 373-381.
Journal of Infection
Glucose production, oxidation and disposal correlate with plasma lactate levels in HIV-infected patients on HAART
Haugaard, SB; Andersen, O; Madsbad, S; Iversen, J; Dela, F
Journal of Infection, 54(1): 89-97.
AIDS Reviews
Pathogenesis of lipodystrophy and lipid abnormalities in patients taking antiretroviral therapy
Mallon, PWG
AIDS Reviews, 9(1): 3-15.

Antiviral Therapy
The influence of HIV infection and antiretroviral therapy on the mitochondrial membrane potential of peripheral mononuclear cells
Sternfeld, T; Schmid, M; Tischleder, A; Mudra, S; Schlamp, A; Kost, BP; Gruber, R; Youle, M; Bogner, JR; Goebel, FD
Antiviral Therapy, 12(5): 769-778.

Antiviral Therapy
High doses of stavuldine induce fat wasting and mild liver damage without impairing mitochondrial respiration in mice
Igoudjil, A; Abbey-Toby, A; Begriche, K; Grodet, A; Chataigner, K; Peytavin, G; Maachi, M; Colin, M; Robin, MA; Letteron, P; Feldmann, G; Pessayre, D; Fromenty, B
Antiviral Therapy, 12(3): 389-400.

Nature Clinical Practice Endocrinology & Metabolism
Therapy Insight: body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy
Falutz, J
Nature Clinical Practice Endocrinology & Metabolism, 3(9): 651-661.
Antiviral Therapy
Antiretroviral drugs with adverse effects on adipocyte lipid metabolism and survival alter the expression and secretion of proinflammatory cytokines and adiponectin in vitro
Lagathu, C; Bastard, JP; Auclair, M; Maachi, M; Kornprobst, M; Capeau, J; Caron, M
Antiviral Therapy, 9(6): 911-920.

Antiviral Therapy
Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes
de la Concepcion, MLR; Yubero, P; Domingo, JC; Iglesias, R; Domingo, P; Villarroya, F; Giralt, M
Antiviral Therapy, 10(4): 515-526.

American Journal of Clinical Dermatology
Dermatologic adverse effects of Antiretroviral therapy
Luther, J; Glesby, MJ
American Journal of Clinical Dermatology, 8(4): 221-233.

AIDS Care-Psychological and Socio-Medical Aspects of AIDS/HIV
Impact of lipoatrophy on quality of life in HIV patients receiving anti-retroviral therapy
Rajagopalan, R; Laitinen, D; Dietz, B
AIDS Care-Psychological and Socio-Medical Aspects of AIDS/HIV, 20(): 1197-1201.
Aesthetic Plastic Surgery
A Comparison of Lipoatrophy and Aging: Volume Deficits in the Face
Coleman, S; Saboeiro, A; Sengelmann, R
Aesthetic Plastic Surgery, 33(1): 14-21.
Antiviral Therapy
Mitochondrial DNA levels of peripheral blood mononuclear cells and subcutaneous adipose tissue from thigh, fat and abdomen of HIV-1 seropositive and negative individuals
Gerschenson, M; Shiramizu, B; LiButti, DE; Shikuma, CM
Antiviral Therapy, 10(): M83-M89.

HIV Clinical Trials
Update on HIV lipodystrophy
Kravcik, S
HIV Clinical Trials, 5(3): 152-167.

Journal of Medical Virology
Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy
Haugaard, SB; Andersen, O; Pedersen, SB; Dela, F; Richelsen, B; Nielsen, JO; Madsbad, S; Iversen, J
Journal of Medical Virology, 77(1): 29-38.
Antiviral Therapy
Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive FLAART recipients
Pace, CS; Martin, AM; Hammond, EL; Mamotte, CD; Nolan, DA; Mallal, SA
Antiviral Therapy, 8(4): 323-331.

Journal of the American Dietetic Association
Position of the American Dietetic Association and Dietitians of Canada: Nutrition intervention in the care of persons with human immunodeficiency virus infection
Fields-Gardner, C; Fergusson, P; Hayes, CR; Sanders, M; Kelley, C; Brison, CM; Knoll, LL; Rothpletz-Puglia, P; Badenhorst, AM; Kasten, G; De Maio, S; McDermid, JM; Marchand, MJ; McKinney, S; Bloch, A; Fenton, M
Journal of the American Dietetic Association, 104(9): 1425-1441.
Jama-Journal of the American Medical Association
Metabolic and skeletal complications of HIV infection - The price of success
Morse, CG; Kovacs, JA
Jama-Journal of the American Medical Association, 296(7): 844-854.

Antiviral Therapy
Relationship of mitochondrial DNA depletion and respiratory chain activity in preadipocytes treated with nucleoside reverse transcriptase inhibitors
Stankov, MV; Lucke, T; Das, AM; Schmidt, RE; Behrens, GMN
Antiviral Therapy, 12(2): 205-216.

British Journal of Dermatology
Human immunodeficiency virus atrophy induces modification of subcutaneous adipose tissue architecture: in vivo visualization by high-resolution magnetic resonance imaging
Josse, G; Gensanne, D; Aquilina, C; Bernard, J; Saint-Martory, C; Lagarde, JM; Schmitt, AM
British Journal of Dermatology, 160(4): 741-746.
Antiviral Therapy
Combined effect of C-reactive protein and stavudine on adipogenesis
Stankov, MV; Schmidt, RE; Behrens, GMN
Antiviral Therapy, 14(6): 819-829.
Current HIV Research
Nucleoside Analog Stavudine Depletes Mitochondrial DNA with No Organelle Loss in Mouse Oocytes
Bostan, A; Demeestere, I; Vanderwinden, JM; Devreker, F; Englert, Y
Current HIV Research, 8(2): 127-133.

Jaids-Journal of Acquired Immune Deficiency Syndromes
Mitochondrial dysfunction: Patient monitoring and toxicity management
McComsey, G; Lonergan, JT
Jaids-Journal of Acquired Immune Deficiency Syndromes, 37(): S30-S35.

HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo
Lagathu, C; Kim, MJ; Maachi, M; Vigouroux, C; Cervera, P; Capeau, J; Caron, M; Bastard, JP
Biochimie, 87(1): 65-71.
Antiviral Therapy
Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS therapy
Lewis, W
Antiviral Therapy, 10(): M13-M27.

HIV Medicine
Mitochondrial DNA assessment in adipocytes and peripheral blood mononuclear cells of HIV-infected patients with lipodystrophy according to a validated case definition
Casula, M; van der Valk, M; Wit, FW; Nievaard, MA; Reiss, P
HIV Medicine, 8(1): 32-37.

Eruptive haemangioma associated with HIV therapy and mitochondrial pathology
Hammond, E; Martin, A; Nolan, D; Metcalf, C; Mallal, S
Pathology, 40(4): 425-429.
Antiviral Therapy
Methodological considerations in human studies of gene expression in HIV-associated lipodystrophy
Mallon, PWG; Sedwell, R; Unemori, P; Kelleher, A; Cooper, DA; Carr, A
Antiviral Therapy, 10(): M101-M108.

Presse Medicale
Adverse effects of antiretroviral treatments
Lagrange-Xelot, M; Molina, JM
Presse Medicale, 34(): 1571-1578.

Antiviral Therapy
In combination, nucleoside reverse transcriptase inhibitors have significant effects on 3T3-L1 adipocyte lipid accumulation and survival
Kosmiski, LA; Miller, HL; Klemm, DJ
Antiviral Therapy, 11(2): 187-195.

Infection and Immunity
Adipocyte, adipose tissue, and infectious disease
Desruisseaux, MS; Nagajyothi; Trujillo, ME; Tanowitz, HB; Scherer, PE
Infection and Immunity, 75(3): 1066-1078.
International Journal of Obesity
Lipodystrophy in HIV 1-infected patients: lessons for obesity research
Villarroya, F; Domingo, P; Giralt, M
International Journal of Obesity, 31(): 1763-1776.
Scandinavian Journal of Infectious Diseases
Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity
Maagaard, A; Kvale, D
Scandinavian Journal of Infectious Diseases, 41(): 808-817.
Biological Research for Nursing
Fatigue-Related Gene Networks Identified in CD14(+) Cells Isolated From HIV-Infected Patients-Part I: Research Findings
Voss, JG; Dobra, A; Morse, C; Kovacs, JA; Danner, RL; Munson, PJ; Logan, C; Rangel, Z; Adelsberger, JW; McLaughlin, M; Adams, LD; Raju, R; Dalakas, MC
Biological Research for Nursing, 15(2): 137-151.
Oxidative Medicine and Cellular Longevity
Role of Mitochondria in HIV Infection and Associated Metabolic Disorders: Focus on Nonalcoholic Fatty Liver Disease and Lipodystrophy Syndrome
Perez-Matute, P; Perez-Martinez, L; Blanco, JR; Oteo, JA
Oxidative Medicine and Cellular Longevity, (): -.
HIV Medicine
The early effects of stavudine compared with tenofovir on adipocyte gene expression, mitochondrial DNA copy number and metabolic parameters in South African HIV-infected patients: a randomized trial
Menezes, CN; Duarte, R; Dickens, C; Dix-Peek, T; Van Amsterdam, D; John, MA; Ive, P; Maskew, M; MacPhail, P; Fox, MP; Raal, F; Sanne, I; Crowther, NJ
HIV Medicine, 14(4): 217-225.
Journal of Infectious Diseases
Adipose Tissue and Immune Function: A Review of Evidence Relevant to HIV Infection
Koethe, JR; Hulgan, T; Niswender, K
Journal of Infectious Diseases, 208(8): 1194-1201.
Antimicrobial Agents and Chemotherapy
Thymidine Analogues Suppress Autophagy and Adipogenesis in Cultured Adipocytes
Stankov, MV; Panayotova-Dimitrova, D; Leverkus, M; Schmidt, RE; Behrens, GMN
Antimicrobial Agents and Chemotherapy, 57(1): 543-551.
Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine
McComsey, GA; Paulsen, DM; Lonergan, JT; Hessenthaler, SM; Hoppel, CL; Williams, VC; Fisher, RL; Cherry, CL; White-Owen, C; Thompson, KA; Ross, ST; Hernandez, JE; Ross, LL
AIDS, 19(1): 15-23.

PDF (162)
Lipoatrophy and mitochondrial DNA assays: see all, know all?
Brinkman, K
AIDS, 19(1): 91-92.

PDF (59)
Antiretroviral nucleoside and nucleotide analogues and mitochondria
Cossarizza, A; Moyle, G
AIDS, 18(2): 137-151.

PDF (283)
Induction therapy with trizivir plus efavirenz or lopinavir/ritonavir followed by trizivir alone in naive HIV-1-infected adults
Mallolas, J; Pich, J; Peñaranda, M; Domingo, P; Knobel, H; Pedrol, E; Gutiérrez, F; Barrufet, P; Peraire, J; Asenjo, MA; Vidal, F; Gatell, JM
AIDS, 22(3): 377-384.
PDF (209) | CrossRef
Differential gene expression indicates that ‘buffalo hump’ is a distinct adipose tissue disturbance in HIV-1-associated lipodystrophy
Guallar, JP; Gallego-Escuredo, JM; Domingo, JC; Alegre, M; Fontdevila, J; Martínez, E; Hammond, EL; Domingo, P; Giralt, M; Villarroya, F
AIDS, 22(5): 575-584.
PDF (477) | CrossRef
The longer the better? Four years of durable, initially boosted protease treatment
Katzenstein, D
AIDS, 18(5): 811-813.

PDF (59)
Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6–12 months of commencing nucleoside reverse transcriptase inhibitor therapy
Hammond, E; Nolan, D; James, I; Metcalf, C; Mallal, S
AIDS, 18(5): 815-817.

PDF (170)
Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment
Haubrich, RH; Riddler, SA; DiRienzo, AG; Komarow, L; Powderly, WG; Klingman, K; Garren, KW; Butcher, DL; Rooney, JF; Haas, DW; Mellors, JW; Havlir, DV; for the AIDS Clinical Trials Group (ACTG) A5142 Study Team,
AIDS, 23(9): 1109-1118.
PDF (384) | CrossRef
HIV therapy, hepatitis C virus infection, antibiotics and obesity, a mitochondria killer mix?
Côté, HC; Brumme, ZL; Chan, JW; Guillemi, S; Montaner, JS; Harrigan, PR
AIDS, 20(9): 1343-1345.
PDF (2353) | CrossRef
Stavudine in antiretroviral therapy: is this the end?
Brinkman, K
AIDS, 23(13): 1727-1729.
PDF (240) | CrossRef
Genetics in Medicine
IL-1[beta] (+3954C/T) polymorphism could protect human immunodeficiency virus (HIV)-infected patients on highly active antiretroviral treatment (HAART) against lipodystrophic syndrome
Asensi, V; Rego, C; Montes, AH; Collazos, J; Carton, JA; Castro, MG; Álvarez, V; Fernández, C; Maradona, JA; Valle-Garay, E
Genetics in Medicine, 10(3): 215-223.
PDF (303) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Loss of Subcutaneous Adipose Tissue in HIV-Associated Lipodystrophy Is Not Due to Accelerated Apoptosis
Mynarcik, D; Wei, L; Komaroff, E; Ferris, R; McNurlan, M; Gelato, M
JAIDS Journal of Acquired Immune Deficiency Syndromes, 38(1): 53-56.

PDF (1376)
JAIDS Journal of Acquired Immune Deficiency Syndromes
Less Lipoatrophy and Better Lipid Profile With Abacavir as Compared to Stavudine: 96-Week Results of a Randomized Study
Podzamczer, D; Ferrer, E; Sanchez, P; Gatell, JM; Crespo, M; Fisac, C; Lonca, M; Sanz, J; Niubo, J; Veloso, S; Llibre, JM; Barrufet, P; Ribas, MA; Merino, E; Ribera, E; Martínez-Lacasa, J; Alonso, C; Aranda, M; Pulido, F; Berenguer, J; Delegido, A; Pedreira, JD; Lérida, A; Rubio, R; Río, L; for the ABCDE (Abacavir vs. d4T (stavudine) plus efavirenz) Study Team,
JAIDS Journal of Acquired Immune Deficiency Syndromes, 44(2): 139-147.
PDF (258) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Increased Adipocyte Apoptosis in Lipoatrophy Improves Within 48 Weeks of Switching Patient Therapy From Stavudine to Abacavir or Zidovudine
Cherry, CL; Lal, L; Thompson, KA; McLean, CA; Ross, LL; Hernandez, J; Wesselingh, SL; McComsey, G
JAIDS Journal of Acquired Immune Deficiency Syndromes, 38(3): 263-267.

PDF (135)
JAIDS Journal of Acquired Immune Deficiency Syndromes
Adverse Effects of Antiretroviral Drugs on HIV-1-Infected and -Uninfected Human Monocyte-Derived Macrophages
Azzam, R; Lal, L; Goh, S; Kedzierska, K; Jaworowski, A; Naim, E; Cherry, CL; Wesselingh, SL; Mills, J; Crowe, SM
JAIDS Journal of Acquired Immune Deficiency Syndromes, 42(1): 19-28.
PDF (264) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Extensive Investigations of Mitochondrial DNA Genome in Treated HIV-Infected Subjects: Beyond Mitochondrial DNA Depletion
McComsey, G; Bai, R; Maa, J; Seekins, D; Wong, L
JAIDS Journal of Acquired Immune Deficiency Syndromes, 39(2): 181-188.

PDF (157)
JAIDS Journal of Acquired Immune Deficiency Syndromes
Induction With Abacavir/Lamivudine/Zidovudine Plus Efavirenz for 48 Weeks Followed by 48-Week Maintenance With Abacavir/Lamivudine/Zidovudine Alone in Antiretroviral-Naive HIV-1-Infected Patients
Markowitz, M; Hill-Zabala, C; Lang, J; DeJesus, E; Liao, Q; Lanier, ER; Davis, EA; Shaefer, M; for the ESS40013 Study Team,
JAIDS Journal of Acquired Immune Deficiency Syndromes, 39(3): 257-264.

PDF (399)
JAIDS Journal of Acquired Immune Deficiency Syndromes
Tissue-Specific Associations Between Mitochondrial DNA Levels and Current Treatment Status in HIV-Infected Individuals
Cherry, CL; Nolan, D; James, IR; McKinnon, EJ; Mallal, SA; Gahan, ME; Lal, L; McArthur, JC; Wesselingh, SL
JAIDS Journal of Acquired Immune Deficiency Syndromes, 42(4): 435-440.
PDF (146) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Metabolic Function and the Prevalence of Lipodystrophy in a Population of HIV-Infected African Subjects Receiving Highly Active Antiretroviral Therapy
Mutimura, E; Stewart, A; Rheeder, P; Crowther, NJ
JAIDS Journal of Acquired Immune Deficiency Syndromes, 46(4): 451-455.
PDF (91) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Upregulatory Mechanisms Compensate for Mitochondrial DNA Depletion in Asymptomatic Individuals Receiving Stavudine Plus Didanosine
Casademont, J; Miró, Ò; López, S; Rodríguez de la Concepción, M; Martínez, E; Pedrol, E; Garrabou, G; Giralt, M; Cardellach, F; Gatell, JM; Vilarroya, F
JAIDS Journal of Acquired Immune Deficiency Syndromes, 37(5): 1550-1555.

PDF (306)
Back to Top | Article Outline

HIV; nucleoside analogue reverse transcriptase inhibitor; mitochondrial DNA; adipocyte; lipodystrophy; lipoatrophy

© 2003 Lippincott Williams & Wilkins, Inc.


Article Level Metrics

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.