Department of 1 Cell Biology and Physiology and 2 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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- (C/EBP
), peroxisome proliferator-activated receptor-
(PPAR
), 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/EBP
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 PPAR 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 PPAR and RXR, respectively, to
stimulate either aP2 expression or PPAR
/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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
![]() |
HYPERLIPIDEMIA |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 PPAR, 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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).
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abbott Laboratories.Norvir (ritonavir capsules) Product
Monograph. North Chicago, IL, 2000.
2.
Bonfanti, P,
Valsecchi L,
Parazzini F,
Carradori S,
Pusterla L,
Fortuna P,
Timillero L,
Alessi F,
Ghiselli G,
Gabbuti A,
Di Cintio E,
Martinelli C,
Faggion I,
Landonio S,
and
Quirino T.
Incidence of adverse reactions in HIV patients treated with protease inhibitors: a cohort study. Coordinamento Italiano Studio Allergia e Infezione da HIV (CISAI) Group.
J Acquir Immune Defic Syndr Hum Retrovirol
23:
236-245,
2000.
3.
Bouchard, C,
Despres JP,
and
Mauriege P.
Genetic and nongenetic determinants of regional fat distribution.
Endocr Rev
14:
72-93,
1993[Abstract].
4.
Burant, CF,
Sreenan S,
Hirano K,
Tai TA,
Lohmiller J,
Lukens J,
Davidson NO,
Ross S,
and
Graves RA.
Troglitazone action is independent of adipose tissue.
J Clin Invest
100:
2900-2908,
1997
5.
Carr, A,
Miller J,
Law M,
and
Cooper DA.
A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome.
AIDS
14:
F25-F32,
2000[ISI][Medline].
6.
Carr, A,
Samaras K,
Chisholm DJ,
and
Cooper DA.
Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.
Lancet
351:
1881-1883,
1998[ISI][Medline].
7.
Domingo, P,
Matias-Guiu X,
Pujol RM,
Francia E,
Lagarda E,
Sambeat MA,
and
Vazquez G.
Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy.
AIDS
13:
2261-2267,
1999[ISI][Medline].
8.
Dowell, P,
Flexner C,
Kwiterovich PO,
and
Lane DM.
Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors.
J Biol Chem.
275:
41325-41332,
2000
9.
James, DE,
Strube M,
and
Mueckler M.
Molecular cloning and characterization of an insulin regulatable glucose transporter.
Nature
338:
83-87,
1989[ISI][Medline].
10.
Katz, EB,
Stenbit AE,
Hatton K,
DePinho R,
and
Charron MJ.
Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4.
Nature
377:
151-155,
1995[ISI][Medline].
11.
Lenhard, JM,
Furfine ES,
Jain RG,
Ittoop O,
Orband-Miller LA,
Blanchard SG,
Paulik MA,
and
Weiel JE.
HIV protease inhibitors block adipogenesis and increase lipolysis in vitro.
Antiviral Res
47:
121-129,
2000[ISI][Medline].
12.
Lenhard, JM,
Weiel JE,
Paulik MA,
and
Furfine ES.
Stimulation of vitamin A1 acid signaling by the HIV protease inhibitor indinavir.
Biochem Pharmacol
59:
1063-1068,
2000[ISI][Medline].
13.
Madge, S,
Kinloch-de-Loes S,
Mercey D,
Johnson MA,
and
Weller, IV
Lipodystrophy in patients naive to HIV protease inhibitors.
AIDS
13:
735-737,
1999[ISI][Medline].
14.
Marshall, BA,
Hansen PA,
Ensor NJ,
Ogden MA,
and
Mueckler M.
GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but do not prevent insulin resistance.
Am J Physiol Endocrinol Metab
276:
E390-E400,
1999
15.
Martinez, E,
Conget I,
Lozano L,
Casamitjana R,
and
Gatell J.
Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine.
AIDS
13:
805-810,
1999[ISI][Medline].
16.
Martinez, E,
and
Gatell J.
Metabolic abnormalities and use of HIV-1 protease inhibitors.
Lancet
352:
821-822,
1998[ISI][Medline].
17.
Merck & Co. Crivixan (Indinavir Sulfate) Capsules Product
Monograph. West Point, PA, 1997.
18.
Moitra, J,
Mason MM,
Olive M,
Krylov D,
Gavrilova O,
Marcus-Samuels B,
Feigenbaum L,
Lee E,
Aoyama T,
Eckhaus M,
Reitman ML,
and
Vinson C.
Life without white fat: a transgenic mouse.
Genes Dev
12:
3168-3181,
1998
19.
Montague, CT,
and
O'Rahilly S.
The perils of portliness: causes and consequences of visceral adiposity.
Diabetes
49:
883-888,
2000[Abstract].
20.
Mueckler, M.
Glucose transport and glucose homeostasis: new insights from transgenic mice.
News Physiol Sci
10:
22-29,
1995
21.
Mulligan, K,
Grunfeld C,
Tai VW,
Algren H,
Pang M,
Chernoff DN,
Lo JC,
and
Schambelan M.
Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection.
J Acquir Immune Defic Syndr Hum Retrovirol
23:
35-43,
2000.
22.
Murata, H,
Hruz PW,
and
Mueckler M.
The mechanism of insulin resistance caused by HIV protease inhibitor therapy.
J Biol Chem
275:
20251-20254,
2000
23.
Noor, M,
Lo JC,
Mulligan K,
Halvorsen R,
Schwarz JM,
Shambelan M,
and
Grunfeld C.
Metabolic effects of indinavir in healthy HIV-seronegative subjects.
Antiviral Therapy
5:
8,
2000.
24.
Palella, FJ, Jr,
Delaney KM,
Moorman AC,
Loveless MO,
Fuhrer J,
Satten GA,
Aschman DJ,
and
Holmberg SD.
Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators.
N Engl J Med
338:
853-860,
1998
25.
Penzak, SR,
and
Chuck SK.
Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment.
Scand J Infect Dis
32:
111-123,
2000[ISI][Medline].
26.
Petit, JM,
Duong M,
Duvillard L,
Piroth L,
Grappin M,
Verges B,
Chavanet P,
Brun JM,
and
Portier H.
HIV-1 protease inhibitors induce an increase of triglyceride level in HIV-infected men without modification of insulin sensitivity: a longitudinal study.
Horm Metab Res
32:
367-372,
2000[ISI][Medline].
27.
Rosen, ED,
Walkey CJ,
Puigserver P,
and
Spiegelman BM.
Transcriptional regulation of adipogenesis.
Genes Dev
14:
1293-1307,
2000
28.
Rossetti, L,
Stenbit AE,
Chen W,
Hu M,
Barzilai N,
Katz EB,
and
Charron MJ.
Peripheral but not hepatic insulin resistance in mice with one disrupted allele of the glucose transporter type 4 (GLUT4) gene.
J Clin Invest
100:
1831-1839,
1997
29.
Safrin, S,
and
Grunfeld C.
Fat distribution and metabolic changes in patients with HIV infection.
AIDS
13:
2493-2505,
1999[ISI][Medline].
30.
Saint-Marc, T,
Partisani M,
Poizot-Martin I,
Bruno F,
Rouviere O,
Lang J,
Gastaut J,
and
Touraine J.
A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue tharapy.
AIDS
13:
1659-1667,
1999[ISI][Medline].
31.
Saint-Marc, T,
Partisani M,
Poizot-Martin I,
Rouviere O,
Bruno F,
Avellaneda R,
Lang J,
Gastaut J,
and
Touraine J.
Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study.
AIDS
14:
37-49,
2000[ISI][Medline].
32.
Schwarcz, SK,
Hsu LC,
Vittinghoff E,
and
Katz MH.
Impact of protease inhibitors and other antiretroviral treatments on acquired immunodeficiency syndrome survival in San Francisco, California, 1987-1996.
Am J Epidemiol
152:
178-185,
2000
33.
Seip, M,
and
Trygstad O.
Generalized lipodystrophy, congenital and acquired (lipoatrophy).
Acta Paediatr Scand
413:
2-28,
1996.
34.
Shimomura, I,
Hammer RE,
Richardson JA,
Ikemoto S,
Bashmakov Y,
Goldstein JL,
and
Brown MS.
Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy.
Genes Dev
12:
3182-3194,
1998
35.
Stricker, RB,
and
Goldberg B.
Fat accumulation and HIV-1 protease inhibitors.
Lancet
352:
1392,
1998[ISI][Medline].
36.
Thiebaut, R,
Dabis F,
Malvy D,
Jacqmin-Gadda H,
Mercie P,
and
Valentin VD.
Serum triglycerides, HIV infection, and highly active antiretroviral therapy, Aquitaine Cohort, France, 1996 to 1998. Groupe d'Epidemiologie Clinique du Sida en Aquitaine (GECSA).
J Acquir Immune Defic Syndr Hum Retrovirol
23:
261-265,
2000.
37.
Tomasselli, AG,
and
Heinrikson RL.
Targeting the HIV-protease in AIDS therapy: a current clinical perspective.
Biochim Biophys Acta
1477:
189-214,
2000[ISI][Medline].
38.
Tsiodras, S,
Mantzoros C,
Hammer S,
and
Samore M.
Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study.
Arch Intern Med
160:
2050-2056,
2000
39.
Walli, R,
Michl GM,
Muhlbayer D,
Brinkmann L,
and
Goebel FD.
Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus.
Res Exp Med (Berl)
199:
253-262,
2000[ISI][Medline].
40.
Wentworth, JM,
Burris TP,
and
Chatterjee VKK
HIV protease inhibitors block human preadipocyte differentiation, but not via the PPAR/RXR heterodimer.
J Endocrinol
164:
R7-R10,
1999[ISI].
41.
Yanovski, JA,
Miller KD,
Kino T,
Friedman TC,
Chrousos GP,
Tsigos C,
and
Falloon J.
Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy.
J Clin Endocrinol Metab
84:
1925-1931,
1999
42.
Ye, JM,
Samara K,
Bonner KM,
Cooney DJ,
Chisholm DJ,
and
Kraegen EW.
Ritonovir has paradoxical effects on lipid metabolism and insulin sensitivity in rats compared with humans.
AIDS
12:
2236-2237,
1998[ISI][Medline].
43.
Zhang, B,
Macnaul K,
Szalkowski D,
Li Z,
Berger J,
and
Moller D.
Inhibition of adipocyte differentiation by HIV protease inhibitors.
J Clin Endocrinol Metab
84:
4274-4277,
1999