Basic Science: Concise Communication
CD36 deficiency induced by antiretroviral therapy
Serghides, Lena; Nathoo, Salima; Walmsley, Sharon; Kain, Kevin C.
From the the Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada.
Requests for reprints to: Dr K. C. Kain, Toronto General Hospital, EN G-224, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4.
Sponsorship: This work was supported by the Ontario HIV Treatment Network (302479), the Medical Research Council of Canada/CIHR (MT-13721) and the Heart and Stroke Foundation of Canada (NA-3391). L. Serghides is the recipient of a Medical Research of Canada Studentship. K. C. Kain is supported by a Career Scientist Award from the Ontario Ministry of Health.
Note: L. Serghides and S. Nathoo have contributed equally to this work.
Received: 9 March 2001;
revised: 3 September 2001; accepted: 3 October 2001.
Background: The molecular basis of lipodystrophy, a syndrome associated with HIV antiretroviral (ARV) therapy, remains unknown.
Objectives: To examine whether ARV therapy might inhibit the expression of CD36, which is known to play an important role in fatty acid and glucose metabolism, and if this might contribute to the metabolic alterations associated with lipodystrophy.
Design: The effects of ARV therapy on CD36 levels was examined in vivo in a prospective cohort of individuals treated with ARV therapy and in vitro in assays of human cell lines exposed to ARV drugs.
Methods: Monocyte CD36 levels were assessed by flow cytometry at baseline and after 7 days of therapy in five healthy volunteers and 10 treatment-naive HIV-1-infected individuals. ARV therapy included protease inhibitors (ritonavir, nelfinavir or lopinavir/ritonavir). In addition, human cell lines (THP-1 and C32) were assessed for CD36 levels pre and post-ritonavir treatment.
Results: Three of four healthy controls (one withdrew because of adverse effects) and 6 of 10 HIV-1-infected individuals had a 50 to > 90% decrease in monocyte CD36 levels after 7 days of therapy. One of ten HIV-infected subjects had a 30% decrease, and the remaining individuals had no change or an increase in CD36 levels. CD36 levels decreased significantly in human cell lines treated with ritonavir but not in those treated with zidovudine.
Conclusions: ARV therapy resulted in a marked decrease in CD36 in approximately 70% of our participants. Sustained ARV therapy-induced CD36 deficiency may contribute to insulin resistance and other metabolic complications of lipodystrophy.
Combination antiretroviral (ARV) therapy that includes protease inhibitors (PI) represents a major advance in the management of HIV-1 disease and is now a ‘standard-of-care’ for HIV infection [1–5]. However ARV therapy, particularly that which includes a PI, is associated with adverse effects, including peripheral fat wasting, central adiposity, dyslipidaemia and insulin resistance; these form part of a syndrome known as lipodystrophy [4,6–8]. Lipodystrophy may be a significant cardiovascular risk factor and several reports of deaths from cardiac disease have been linked to PI therapy [4,6–13]. Concerns about this and about changes in body appearance are major obstacles to the successful long-term use of PI as components of combination therapy for HIV-1 infection [4,6–11]. However, not all patients on PI develop lipodystrophy and patients on non-PI regimens may also develop features of this syndrome, although metabolic abnormalities are more pronounced in those receiving PI . A method to predict those at risk of developing lipodystrophy or its metabolic complications would represent an important advance.
The molecular basis by which ARV therapy induces lipodystrophy is unknown. It has been reported that PI inhibit the differentiation of adipocytes in vitro, although the mechanism of action is unclear [14,15]. Carr and colleagues hypothesized that PI may induce lipodystrophy by impairing the production of 9-cis-retinoic acid, the sole natural ligand for the retinoid X receptor (RXR) . RXR functions as a heterodimer with PPARγ (peroxisome proliferator-activated receptor γ), a nuclear receptor that regulates adipocyte differentiation, insulin response and monocyte function [16,17].
PPARγ transcriptionally activates a number of genes essential to adipogenesis, lipid storage and metabolism, including the scavenger receptor CD36. CD36 mediates the uptake of modified lipoproteins by macrophages and also functions as a high-affinity transporter of long-chain fatty acids (FA) in adipose tissue and skeletal muscle [18,19]. CD36 deficiency has been linked to the phenotype observed in spontaneous hypertensive rats, which includes defects in FA metabolism, dyslipidaemia and insulin resistance [20–22]. Similarly, CD36 null mice exhibit increased serum FA, triglycerides and cholesterol, and abnormal insulin levels [23,24]. More recently, CD36 deficiency has been associated with insulin resistance and hyperlipidaemia in humans [25,26].
The putative link between ARV therapy and PPARγ signalling prompted us to examine the influence of ARV therapy on CD36 expression. We hypothesized that ARV therapy might induce CD36 deficiency and that this defect may contribute to the metabolic alterations associated with lipodystrophy.
Between February 1999 and July 1999, five healthy volunteers and 10 treatment-naive HIV-1-infected individuals were followed prior to and during ARV therapy. The healthy volunteers were consecutive enrollees in a pharmacokinetic study of ritonavir. Volunteers received 200 mg ritonavir by mouth, twice daily for 7 days. HIV-infected participants were consecutive treatment-naive individuals enrolled in a randomized clinical trial of combination ARV therapy. These patients received stavudine (40 mg twice daily) plus lamivudine (150 mg twice daily) and were randomized to receive either nelfinavir (750 mg three times daily) or lopinavir/ritonavir (400 mg/100 mg twice daily) in a blinded, placebo-controlled manner. Participants had CD4 cell counts of > 100 × 106 cells/l and none were receiving concurrent therapy with corticosteroids, anabolic steroids, or drugs known to modulate immune function. This study was approved by the Institutional Review Boards of the Toronto and Ottawa General Hospitals and all subjects gave informed consent.
Peripheral monocytes were isolated from controls and HIV-infected participants prior to commencing ARV therapy; the cells were fixed in 4% paraformaldehyde and then stained for surface-associated CD36 using the monoclonal anti-CD36 antibody FA6-152 (Immunotech, Westbrook, Maine, USA) as described . A secondary antibody only and an unstained control were also performed. Surface-associated CD36 was quantified by flow cytometry using the Epics Elite cytometer (Beckman-Coulter, Marseille, France). The flow cytometer was calibrated daily using calibration beads and control samples. All samples were analysed by an expert technician using the same Epics Elite Flow Cytometer. The voltage/FL1 detector as well as the acquisition gate settings remained constant throughout the study.
Following 7 days of ritonavir therapy for healthy volunteers and 7 and 30 days of ARV therapy for HIV-infected participants, CD36 surface levels were determined on isolated monocytes as above.
In vitro assays
THP-1 (human pre-monocytic cell line; ATCC, Manassas, Virginia, USA), and C32 (human melanoma cell line; ATCC) cells were plated (500 × 106 cells/l) and cultured for 3 days in the presence of 10 μmol/l ritonavir suspended in dimethyl sulfoxide (DMSO), 10 μmol/l zidovudine suspended in DMSO, or appropriate concentrations of DMSO as a control. DMSO concentrations were kept below 0.1%. Samples of 1 × 106 cells were incubated with FA6-152 and CD36 levels were measured as above.
Surface-associated CD36 in vivo
Four of the five volunteers completed 7 days of ritonavir therapy; one withdrew because of adverse effects. Adherence was confirmed by measurements of ritonavir levels (data not shown). All ten of the HIV-infected individuals continued ARV therapy and provided a blood sample after 7 and 30 days of treatment. HIV-infected participants showed a marked decrease in viral load on treatment (at 1 month), an indirect measure of adherence.
Ritonavir therapy induced a decrease in CD36 levels in three of the four volunteers after 7 days of therapy (Fig. 1a,b and Fig. 2a). In the fourth volunteer, there was no significant change in CD36 expression (Fig. 2a). Similarly, marked decreases in CD36 (> 75% decrease) were observed in 6 of 10 HIV-infected individuals, a moderate decrease in one participant (30% decrease), and in three individuals the levels were unchanged or increased (Fig. 1d–f and Fig. 2b). The decrease in monocyte CD36 was more marked in HIV-infected subjects taking combination ARV therapy than in healthy volunteers taking ritonavir alone (compare Fig. 1a,b with Fig. 1d,e and Fig. 2a,b). Similar changes were observed after 1 month of ARV therapy (data not shown).
The level of monocyte CD36 was also assessed in healthy controls (n = 10) receiving no ARV therapy followed over 4–12 weeks. No significant changes in CD36 levels were observed in controls followed over time (Fig. 1c and Fig. 2c).
Two HIV-infected individuals had elevated fasting triglyceride and cholesterol levels at the time of enrolment and before initiating antiretroviral therapy. Of the remaining eight patients, two developed elevated cholesterol (total cholesterol > 5.5 mmol/l) and/or triglyceride levels (> 2.2 mmol/l) by week 8 of therapy. Both of these individuals had a marked decrease in CD36 levels (> 75% decrease) by day 7 of therapy.
CD36 surface levels in vitro
THP-1 and C32 cells treated with 10 μmol/l ritonavir had significantly lower CD36 levels than appropriate controls, as determined by flow cytometry. The mean log fluorescence over background in THP-1 cells (n = 3) was 4.10 ± 0.87 in ritonavir-treated cells and 5.67 ± 1.09 in untreated cells; the average percentage decrease was 28 ± 2.58% (P < 0.05, paired Student's t-test). The mean log fluorescence over background in C32 cells (n = 5) was 15.68 ± 9.70 in ritonavir-treated cells and 25.35 ± 6.12 in untreated cells; the average percentage decrease was 40.26 ± 14.5% (P < 0.05, paired Student's t-test). Neither nevirapine (data not shown) nor zidovudine treatment of THP-1 cells had a significant effect on CD36 surface levels (mean log fluorescence over background 6.29 ± 0.58 for zidovudine-treated cells and 5.44 ± 1.01 for untreated cells (P = NS).
CD36 plays an important role in FA, lipid and glucose metabolism, and CD36 deficiency has been directly linked to defective fatty acid utilization, dyslipidaemia, and insulin resistance [19–26]. Our results demonstrate that ARV therapy that includes a PI is associated with an early and marked decrease in CD36 levels in healthy and HIV-infected individuals. These in vivo findings are supported by in vitro data showing that ritonavir, but not zidovudine, induces a decrease in CD36 levels in different human cell lines. If CD36 deficiency is sustained in vivo, these observations provide a putative mechanism by which ARV therapy may contribute to insulin resistance and other metabolic complications of lipodystrophy.
CD36 mediates the uptake of modified lipoproteins and has been implicated in both pro- and antiatherogenic processes [28–33]. CD36 is also a major fatty acid transporter in tissues with high metabolic capacity. Using CD36 knockout mice, CD36 was shown to be essential for normal rates of FA uptake and oxidation, mediating 50–80% of uptake in the myocardium, adipose tissue and skeletal muscle in vivo . The phenotype of spontaneous hypertensive rats, which includes dyslipidaemia and features of human insulin resistance syndromes, has been linked to a spontaneous deletion in CD36 . Transgenic rescue of defective CD36 in spontaneous hypertensive rats improved insulin responsiveness, reduced glucose intolerance and lowered levels of serum FA , providing direct evidence that CD36 deficiency contributes to insulin resistance and disordered FA metabolism. Similarly, CD36 null mice have increased serum levels of FA, triglyceride and cholesterol and abnormal glucose and insulin levels .
Based on the rodent models, CD36 deficiency in humans might be expected to result in dyslipidaemia, disrupted PPARγ activation , impaired fat cell differentiation and storage, and decreased insulin responsiveness [19,20]. Although studies are limited, human CD36 deficiency has been associated with elevated serum total cholesterol, low density lipoprotein cholesterol, decreased uptake of modified low density lipoprotein by monocyte-derived macrophages and, most recently, with impaired glucose tolerance, insulin resistance and hyperlipidaemia [25,26,35,36]. CD36 deficiency in humans has also been linked to cardiomyopathies associated with decreased myocardial FA utilization [37,38].
Features of lipodystrophy have been reported in individuals receiving nucleoside reverse transcriptase inhibitors alone, in particular stavudine [9,39]. Brinkman and colleagues have postulated that these changes may be secondary to drug-induced mitochondrial toxicity . In our study, individuals on combination ARV therapy that included a PI and stavudine had more marked decreases in CD36 levels than healthy individuals on PI alone. This may be attributable to HIV infection and/or combination ARV therapy, which may have additive or synergistic effects on CD36 expression and PPAR signalling. HIV infection and ARV therapy may ultimately induce lipodystrophy by a combination of effects on CD36 expression, mitochondrial function and other genes or gene products important in lipid and carbohydrate metabolism. Of note, CD36 deficiency might also contribute to mitochondrial dysfunction since CD36 mediates the uptake of FA essential to cell functions such as mitochondrial β-oxidation and activation of PPARγ [32,39–41].
The molecular mechanism by which ARV therapy induces CD36 deficiency is unknown. Whether decreased CD36 surface levels are the result of altered signalling, reduced activation of the PPARγ–RXR heterodimer  or another mechanism remains to be elucidated. It will be important to determine if PPARγ agonists, which upregulate CD36 , can prevent or reverse the suppression of CD36 and the metabolic alterations induced by ARV drugs and/or PI. Preliminary studies in our laboratory indicate that PPARγ agonists can rescue CD36 deficiency induced by ritonavir in vitro. Furthermore, troglitazone, which upregulates CD36, has recently been reported to improve insulin sensitivity, decrease visceral fat and triglycerides, and increase subcutaneous adipose tissue in a small cohort of HIV-infected patients with ARV therapy-associated lipodystrophy .
Of interest, not all individuals taking ARV drugs or PI in this study showed reduced levels of CD36. Similarly, many but not all HIV-positive patients receiving combination ARV therapy develop lipodystrophy and approximately 70% develop dyslipidaemia at levels associated with increased cardiovascular disease [6,8,9]. It remains to be determined whether the degree of CD36 deficiency we observed is sufficient to mediate the metabolic abnormalities observed in HIV-positive patients receiving combination ARV therapy and if CD36 levels are predictive of these treatment complications. A longitudinal analysis of CD36 expression in monocytes, adipocytes and peripheral muscle in controlled clinical trials will be required to answer these questions definitively.
In summary, ARV therapy including a PI in this study resulted in a marked and early decrease in CD36 in a proportion of recipients. If ARV therapy-induced CD36 deficiency is sustained in vivo, it may contribute to the induction of lipodystrophy and its associated metabolic complications including insulin resistance and dyslipidaemia.
We thank Drs Y. Khaliq and A. MacCarthy at the Ottawa General Hospital for allowing us to study a group of their patients. We thank Dr S. Read and Cheryl Smith for assistance with flow cytometry. We thank Drs J. Brunton and K. MacDonald for helpful suggestions and support and Mrs K. Raposa, study nurse, who was responsible for enrolling patients and collecting blood samples.
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