INVITED REVIEW
Adverse metabolic consequences of HIV protease inhibitor therapy: the search for a central mechanism

Paul W. Hruz1,2, Haruhiko Murata1, and Mike Mueckler1

Department of 1 Cell Biology and Physiology and 2 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
LIPOATROPHY
VISCERAL ADIPOSITY
HYPERLIPIDEMIA
INSULIN RESISTANCE
SUMMARY
REFERENCES

Although the clinical introduction of human immunodeficiency virus (HIV) protease inhibitors (PIs) has resulted in a dramatic decline in HIV-related morbidity and mortality, it is now recognized that PI therapy is associated with serious adverse metabolic effects, including peripheral lipoatrophy, increased visceral fat, hyperlipidemia, and insulin resistance. Despite increasing awareness of this metabolic syndrome, the etiology of these side effects remains obscure. This review critically examines current mechanistic hypotheses in the context of the available experimental data. To date, a single unifying explanation for this syndrome has not been confirmed. As data accumulate, it is becoming clear that PIs lack precision in their cellular targets and it is likely that many of the side effects of these drugs are due to inhibition of a number of unrelated molecules.

human immunodeficiency virus; lipodystrophy; metabolic complications; adipogenesis; glucose transport


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
LIPOATROPHY
VISCERAL ADIPOSITY
HYPERLIPIDEMIA
INSULIN RESISTANCE
SUMMARY
REFERENCES

THE DEVELOPMENT of human immunodeficiency virus (HIV) protease inhibitors (PIs) has been one of the most significant advances of the past decade in controlling HIV infection. Since the clinical introduction of PI therapy as part of highly active antiretroviral therapy, there has been a dramatic decline in AIDS-related morbidity and mortality (24, 32). These remarkable drugs were developed on the basis of detailed knowledge of the HIV protease tertiary and quarternary structure (reviewed in Ref. 37). The HIV protease is an aspartyl endopeptidase that catalyzes the cleavage of the HIV gag and gag-pol polyproteins, allowing maturation and budding of the developing virion. Because mammalian proteases rarely recognize the Phe-Pro and Tyr-Pro sequences cleaved by the HIV protease, it was hoped that the targeting of this molecule by active site inhibition would have minimal effects on mammalian cellular processes. However, there is growing evidence that this is not the case. Despite the clinical successes of PIs, these drugs are associated with a number of metabolic side effects. These include peripheral lipoatrophy, visceral adiposity, hyperlipidemia, and insulin resistance. Several recent reviews have described the incidence and features of this metabolic syndrome in great detail (25, 29).

Despite increasing awareness of the prevalence of the metabolic syndrome in patients treated with PIs, the underlying mechanism behind these metabolic effects remains obscure. As with any syndrome, the features observed in individual patients vary considerably. In addition, features of the metabolic syndrome have been observed in HIV-infected patients not receiving PI therapy (5, 13, 30). Recent cohort studies have shown conflicting results regarding the contribution of PIs to the development of abnormalities in fat distribution (31, 38). The cohort studies, however, have clearly established the primary contribution of PIs to the development of hyperlipidemia and insulin resistance (2, 36, 38). Several authors have attempted to provide a central mechanism by which PIs contribute to many or all of the features of the metabolic syndrome. Because this area of research is still in its infancy, only limited experimental data are currently available to address the hypotheses that have been proposed. This review will discuss and critically examine each of these hypotheses, focusing individually on each of the recognized features of the metabolic syndrome.


    LIPOATROPHY
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INTRODUCTION
LIPOATROPHY
VISCERAL ADIPOSITY
HYPERLIPIDEMIA
INSULIN RESISTANCE
SUMMARY
REFERENCES

Many of the adverse metabolic effects associated with PI therapy, including hypertriglyceridemia and insulin resistance, resemble those seen in patients with the rare congenital and acquired lipodystrophy syndromes (33). The central importance of adipose tissue in the control of normal energy homeostasis has been clearly established with the generation of mouse models of generalized lipodystrophy (4, 18, 34). Thus it has been proposed that peripheral lipoatrophy may be the primary effect caused by PI therapy, which subsequently leads to other adverse effects such as insulin resistance. A decrease in adipose tissue could result from decreased synthesis and/or accelerated destruction of adipocytes.

Several investigators have provided evidence that PIs inhibit preadipocyte differentiation. For instance, Zhang et al. (43) demonstrated that PIs inhibit triglyceride accumulation and expression of the fatty acid binding protein 422/aP2 in cultured 3T3-L1 preadipocytes. Wentworth et al. (40) reported that saquinavir and indinavir inhibit glycerol-3-phosphate dehydrogenase activity, a marker for adipocyte differentiation, in primary cultured human adipocytes. Lenhard et al. (11) observed decreased triglyceride accumulation, lipogenesis, and expression of aP2 and lipoprotein lipase in cultured C3H10T1/2 stem cells. Finally, in a more detailed study, Dowell et al. (8) observed that nelfinavir inhibited the expression of the adipogenic transcription factors CAAT box enhancer binding protein-alpha (C/EBPalpha ), peroxisome proliferator-activated receptor-gamma (PPARgamma ), sterol regulatory element binding protein-1 (SREBP-1)/adipocyte determination and differentiation factor 1 (ADD1), as well as 422/aP2, but had no effect on C/EBPbeta expression and preadipocyte clonal expansion. In addition to these effects, Dowell et al. also showed increased apoptosis in fully differentiated 3T3-L1 cells. Apoptotic changes have also been found in biopsies of subcutaneous adipocytes in PI-treated patients with peripheral lipoatrophy (7).

The mechanism by which adipocyte differentiation is affected by PIs remains unknown. On the basis of protein sequence similarity in 6 of 12 amino acid residues within a region of the HIV protease active site and the cis-9-retinoic acid binding protein (CRABP-1), Carr et al. (6) have proposed that PIs may inhibit CRABP-1. CRABP is involved in binding and presenting retinoic acid to cytochrome P-450 3A, which in turn catalyzes the formation of cis-9-retinoic acid. Decreased synthesis of cis-9-retinoic acid as a result of CRABP inhibition by PIs could then impair normal signaling through the retinoid X receptor (RXR). The heterodimeric nuclear receptor complex composed of RXR and PPARgamma is a known regulator of peripheral adipocyte differentiation and apoptosis (27).

Although inhibition of CRABP could conceivably explain the effects observed on adipocyte differentiation, caution should be exercised against overinterpreting the significance of sequence similarity within such a small peptide sequence. Because secondary and tertiary structures determine binding specificity, the significance of amino acid similarity within small peptides such as those noted by Carr et al. is questionable. Direct demonstration of CRABP inhibition by PIs, which would most strongly support the CRABP hypothesis, has not been reported. On the contrary, a recent study by Lenhard et al. (12) observed that indinavir paradoxically stimulated retinoic acid signaling through RXR. It is notable that this effect was specific for indinavir, thus calling into question the general significance of this finding in relation to the etiology of the metabolic syndrome. Furthermore, Wentworth et al. (40) did not observe any effect of PIs on the ability of troglitazone or BRL-49653, specific ligands for PPARgamma and RXR, respectively, to stimulate either aP2 expression or PPARgamma /RXR signaling. The observation by Lenhard et al. (11) that PI-induced inhibition of adipocyte differentiation is not affected by the addition of the RXR agonist LGD-1069 is further evidence that impaired cis-9-retinoic acid generation is not responsible for these effects. Thus a single unifying mechanism for PI-induced inhibition of adipocyte differentiation has not yet been identified. The studies to date, however, do not support the involvement of CRABP.


    VISCERAL ADIPOSITY
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The mechanism by which PIs cause lipohypertrophy (increased visceral and dorsocervical fat) is even less clear than the mechanism for peripheral lipoatrophy. Although the fat distribution is similar to that observed with glucocorticoid excess (i.e., Cushings syndrome), the hypothalamic-pituitary-adrenal axis does not appear to be perturbed in PI-treated patients (41). Martinez and Gatell (16) have speculated that hyperinsulinism, presumably from PI inhibition of insulin-degrading enzymes, is the initial event triggering the development of the lipodystrophy phenotype. As an extension of this hypothesis, Stricker and Goldberg (35) have proposed that development of the metabolic syndrome is the result of inhibition of cathepsins involved in the degradation of glucagon, insulin, and insulin-like growth factors. According to their hypothesis, this hormonal excess leads first to excess visceral adiposity, which in turn causes insulin resistance and hyperlipidemia. Although several cathepsins are remotely similar to the HIV protease in that they are aspartic endopeptidases, there is no experimental evidence to date that directly demonstrates inhibition of cathepsins by PIs.


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Elevation in serum triglyceride and cholesterol levels is among the most prevalent features of the PI-associated metabolic syndrome. Although this could be a consequence of the lipodystrophy, lipid abnormalities have been observed in patients who do not have any observable peripheral lipoatrophy or visceral lipohypertrophy (21). Although elevations in very low density lipoprotein (VLDL) triglycerides and VLDL apolipoprotein B (apoB) are typical for insulin-resistant individuals in the general population, it is not clear whether lipid abnormalities observed in PI-treated patients represent the primary defect. Hypertriglyceridemia in PI-treated patients has been observed in the absence of insulin resistance (26). Using similar reasoning for implicating CRABP inhibition, Carr et al. (6) have proposed that the low-density lipoprotein receptor-related protein (LRP), which has identity to 7 amino acids within a 12-amino acid HIV protease active-site peptide, could be inhibited by PIs. One of the functions of LRP is to interact with lipoprotein lipase, thereby promoting accumulation of free fatty acids into adipocytes. LRP also binds VLDL and apoE-enriched chylomicron remnants. Inhibition of LRP could, therefore, lead to impaired hepatic chylomicron uptake and triglyceride clearance. The resulting hyperlipidemia is then hypothesized to lead to the central adiposity. Although this theory is intriguing, direct evidence for the ability of PIs to inhibit LRP is lacking.


    INSULIN RESISTANCE
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The observation from longitudinal studies that insulin resistance often precedes lipodystrophy (21) has suggested that insulin resistance may be the proximate cause of the metabolic syndrome. This is supported by a recent report in which oral glucose tolerance tests and euglycemic clamps were performed on healthy volunteers taking indinavir. Insulin resistance was observed as soon as 4 wk after start of therapy (23), before the development of any discernible changes in body fat composition or distribution. Because the volunteers were HIV negative and were not receiving nucleoside analogs, that study suggests that the insulin resistance is a direct effect of PIs. A mechanism by which this may occur has been provided by the observation that PIs selectively inhibit the activity of the insulin-responsive facilitative glucose transporter GLUT-4 (22). As opposed to the adipocyte differentiation data, in which differing effects have been observed with different PIs, inhibition of GLUT-4 activity was observed with all three of the PIs tested (22). In this study, significant inhibition was observed at indinavir concentrations (10 µM) within the range observed in vivo in PI-treated patients (Cmax 12 µM) (17). We have subsequently observed significant inhibition of 2-deoxyglucose uptake, both in 3T3-L1 adipocytes and in Xenopus oocytes heterologously expressing GLUT-4, at indinavir levels as low as 1-2 µM (unpublished observations). We have also recently found the newest PI, lopinavir, to be equally potent in inhibiting GLUT-4 activity (unpublished observation).

The in vivo significance of GLUT-4 inhibition by PIs remains to be established. However, glucose transport is the rate-limiting step in whole body glucose disposal (20). GLUT-4 is the predominant glucose transporter in muscle and fat (9), and it has been shown that alterations in GLUT-4 expression alter in vivo insulin sensitivity (14, 28). Although Ye et al. (42) failed to observe insulin resistance in rats treated with ritonavir for 6-7 wk, the drug levels reported in that study (7-70 nM) were significantly lower than those observed in PI-treated patients (5-15 µM) (1). Because in vitro GLUT-4 inhibition is readily reversible after removal of the PI, in vivo drug levels at the time when studies of glucose sensitivity are performed could be critical to detecting insulin resistance.

Although GLUT-4 inhibition would provide a direct mechanism for PI-induced insulin resistance, it remains unknown whether this defect is sufficient to lead to lipodystrophy and hyperlipidemia. Knockout mice deficient in GLUT-4, however, are almost devoid of fat tissue (10). This suggests that GLUT-4 activity may be necessary for normal adipocyte differentiation and/or viability. The inhibition of facilitative glucose transport by PIs appears selective for GLUT-4 (22). Because GLUT-4 is not expressed in preadipocytes, it is unlikely that GLUT-4 inhibition is directly responsible for PIs' effects on preadipocyte differentiation. However, GLUT-4 inhibition may cause impaired triglyceride accumulation in adipocytes. There is significant evidence that visceral and peripheral adipocytes exhibit differences in their metabolic behavior (3, 19). We hypothesize that peripheral adipocytes may generate lipid de novo from blood glucose, whereas visceral adipocytes may obtain their lipid primarily from circulating triglycerides, thereby accounting for the pattern of fat redistribution observed with PI therapy. Further studies are required to test the hypothesis that GLUT-4 inhibition is directly responsible for the insulin resistance and other metabolic effects observed in patients treated with PIs.

Because PIs acutely and reversibly inhibit glucose transport in vitro, similar acute effects (i.e., after a single dose of a PI) should be observable in vivo if this hypothesis is correct. To date, acute effects of PIs on whole body glucose uptake have not been reported. Partial reversibility of PI-associated insulin resistance, however, has been demonstrated as soon as 6 mo after discontinuing PI therapy (15). Preliminary reports have also indicated that thiazoladinediones, which act through binding to PPARgamma , may be effective in improving insulin sensitivity and partially reversing the changes in fat distribution associated with the metabolic syndrome (39). It is unlikely that this effect is due to a direct reversal of GLUT-4 inhibition. Although GLUT-4 inhibition by PIs may be a primary event leading to insulin resistance, subsequent changes in adipose tissue distribution could further contribute to impaired insulin sensitivity. These secondary changes would not be acutely reversible after discontinuation of PI therapy but could be improved by treatment with thiazoladinediones.


    SUMMARY
TOP
ABSTRACT
INTRODUCTION
LIPOATROPHY
VISCERAL ADIPOSITY
HYPERLIPIDEMIA
INSULIN RESISTANCE
SUMMARY
REFERENCES

The currently available data, although providing insights into potential mechanisms by which PIs produce their adverse metabolic consequences, do not appear to allow a single unifying explanation for this metabolic syndrome. As data accumulate, it is becoming clear that PIs lack precision in their cellular targets, and it is likely that many of the side effects of these drugs are due to inhibition of a number of unrelated molecules. Thus there is an ongoing need to develop and test newer generations of PIs that maintain their efficacy in controlling HIV infection while avoiding their deleterious metabolic consequences. In addition to assisting in new drug design, a detailed understanding of the molecular basis for the metabolic syndrome associated with PI therapy may allow more efficient in vitro screening of these compounds for potential adverse effects before their clinical testing and postmarket surveillance.


    FOOTNOTES

Article published online before print. See web site for date of publication(http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: M. Mueckler, Dept. of Cell Biology and Physiology, Washington Univ. School of Medicine, St. Louis, MO 63110 (E-mail: mike{at}cellbio.wustl.edu).


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