Use Of HIV Protease Inhibitors Research Articles

The Impact of Human Papilloma Viruses, Matrix Metallo-Proteinases and HIV Protease Inhibitors on the Onset and Progression of Uterine Cervix Epithelial Tumors: A Review of Preclinical and Clinical Studies.

Infection of uterine cervix epithelial cells by the Human Papilloma Viruses (HPV) is associated with the development of dysplastic/hyperplastic lesions, termed cervical intraepithelial neoplasia (CIN). CIN lesions may regress, persist or progress to invasive cervical carcinoma (CC), a leading cause of death worldwide. CIN is particularly frequent and aggressive in women infected by both HPV and the Human Immunodeficiency Virus (HIV), as compared to the general female population. In these individuals, however, therapeutic regimens employing HIV protease inhibitors (HIV-PI) have reduced CIN incidence and/or clinical progression, shedding light on the mechanism(s) of its development. This article reviews published work concerning: (i) the role of HPV proteins (including HPV-E5, E6 and E7) and of matrix-metalloproteinases (MMPs) in CIN evolution into invasive CC; and (ii) the effect of HIV-PI on events leading to CIN progression such as basement membrane and extracellular matrix invasion by HPV-positive CIN cells and the formation of new blood vessels. Results from the reviewed literature indicate that CIN clinical progression can be monitored by evaluating the expression of MMPs and HPV proteins and they suggest the use of HIV-PI or their derivatives for the block of CIN evolution into CC in both HIV-infected and uninfected women.

Contemporary protease inhibitors and cardiovascular risk.

To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted with ritonavir (/r)], darunavir/r has been shown to be associated with increased CVD risk. The effect is cumulative with longer exposure increasing risk and an effect size comparable to what has been observed for previously developed protease inhibitors. Biological mechanisms may be overlapping and include perturbed lipid metabolism and accumulation of cholesterol derivatives within macrophages. Conversely, atazanavir/r has not been shown to be associated with CVD, possibly because of its ability to increase cardioprotective bilirubin levels. Evidence linking protease inhibitors to CVD is based on observational studies only, whereas plausible biological explanations are well established and derived from randomized trials and controlled experiments. Given the possible association with clinical disease, a conservative approach to apply the data in daily practise is proposed which is focused on individualization of care based on underlying risk of CVD.

Naringin prevents HIV-1 protease inhibitors-induced metabolic complications in vivo

BackgroundInsulin resistance, glucose intolerance and overt diabetes are known metabolic complications associated with chronic use of HIV-Protease Inhibitors. Naringin is a grapefruit-derived flavonoid with anti-diabetic, anti-dyslipidemia, anti-inflammatory and anti-oxidant activities.ObjectivesThe study investigated the protective effects of naringin on glucose intolerance and impaired insulin secretion and signaling in vivo.MethodsMale Wistar rats were divided into six groups (n = 6) and were daily orally treated with distilled water {3.0 ml/kg body weight (BW)}, atazanavir (133 mg/kg BW), saquinavir (333 mg/kg BW) with or without naringin (50 mg/kg BW), respectively for 56 days. Body weights and water consumption were recorded daily. Glucose tolerance tests were carried out on day 55 of the treatment and thereafter, the rats were sacrificed by halothane overdose.ResultsAtazanavir (ATV)- or saquinavir (SQV)-treated rats exhibited significant weight loss, polydipsia, elevated Fasting blood glucose (FBG), reduced Fasting Plasma Insulin (FPI) and expression of phosphorylated, Insulin Receptor Substrate-1 (IRS-1) and Akt proteins, hepatic and pancreatic glucokinase levels, and also increasing pancreatic caspase-3 and -9 as well as UCP2 protein expressions compared to controls, respectively. These effects were completely reversed by naringin treatment.ConclusionNaringin prevents PI-induced glucose intolerance and impairment of insulin signaling and as nutritional supplement it could therefore alleviate metabolic complications associated with antiretroviral therapy.

HIV-protease inhibitors for the treatment of cancer: Repositioning HIV protease inhibitors while developing more potent NO-hybridized derivatives?

The possible use of HIV protease inhibitors (HIV-PI) as new therapeutic option for the treatment of cancer primarily originated from their success in treating HIV-related Kaposi's sarcoma (KS). While these findings were initially attributed to immune reconstitution and better control of oncogenic viral infections, the number of reports on solid tumors, KS, lymphoma, fibrosarcoma, multiple myeloma and prostate cancer suggest other mechanisms for the anti-neoplastic activity of PIs. However, a major drawback for the possible adoption of HIV-PIs in the therapy of cancer relies on their relatively weak anticancer potency and important side effects. This has propelled several groups to generate derivatives of HIV-PIs for anticancer use, through modifications such as attachment of different moieties, ligands and transporters, including saquinavir-loaded folic acid conjugated nanoparticles and nitric oxide (NO) derivatives of HIV-PIs. In this article, we discuss the current preclinical and clinical evidences for the potential use of HIV-PIs, and of novel derivatives, such as saquinavir-NO in the treatment of cancer.

Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults.

HIV protease inhibitor use in pediatrics is challenging due to the poor palatability and/or toxicity of concomitant low-dose ritonavir. Atazanavir without ritonavir (unboosted) is not recommended for patients with prior virologic failure, a common problem for perinatally-infected adolescents. Atazanavir 400 mg once-daily provided suboptimal exposure. Higher unboosted doses or splitting the daily dose to twice-daily warrants investigation in this treatment-experienced population.

Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction

The use of HIV protease inhibitors (PIs) has extended the duration and quality of life for HIV-positive individuals. However there is increasing concern that this antiviral therapy may promote premature cardiovascular disease by impairing endothelial cell (EC) function. In the present study, we investigated the effect of HIV PIs on EC function and determined if the enzyme heme oxygenase (HO-1) influences the biological action of these drugs. We found that three distinct PIs, including ritonavir, atazanavir, and lopinavir, stimulated the expression of HO-1 protein and mRNA. The induction of HO-1 was associated with an increase in NF-E2-related factor-2 (Nrf2) activity and reactive oxygen species (ROS). PIs also stimulated HO-1 promoter activity and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant-negative Nrf2. In addition, the PI-mediated induction of HO-1 was abolished by N-acetyl-l-cysteine and rotenone. Furthermore, PIs blocked EC proliferation and migration and stimulated the expression of intercellular adhesion molecule-1 and the adhesion of monocytes on ECs. Inhibition of HO-1 activity or expression potentiated the anti-proliferative and inflammatory actions of PIs which was reversed by bilirubin but not carbon monoxide. Alternatively, adenovirus-mediated overexpression of HO-1 attenuated the growth-inhibitory and inflammatory effect of PIs. In contrast, blocking HO-1 activity failed to modify the anti-migratory effect of the PIs. Thus, induction of HO-1 via the ROS–Nrf2 pathway in human ECs counteracts the anti-proliferative and inflammatory actions of PIs by generating bilirubin. Therapeutic approaches targeting HO-1 may provide a novel approach in preventing EC dysfunction and vascular disease in HIV-infected patients undergoing antiretroviral therapy.

Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies?

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.

Evaluation of HIV Protease Inhibitor Use and the Risk of Sudden Death or Nonhemorrhagic Stroke

Concerns have arisen about possible effects of protease inhibitors (PIs) on cardiac conductivity. We found no significant association between current or recent PI exposure and sudden death or nonhemorrhagic stroke (adjusted rate ratio, 1.22; 95% confidence interval, .95-1.57), whereas cumulative exposure to PIs was associated with an increased risk (adjusted rate ratio, 1.06 per year of exposure; 95% confidence interval, 1.01-1.11).

Effects of Tipranavir, Darunavir, and Ritonavir on Platelet Function, Coagulation, and Fibrinolysis in Healthy Volunteers

The use of HIV protease inhibitors (PIs) as part of antiretroviral therapy in the treatment of HIV-1 infection may be associated with an increased risk of bleeding. This prospective, randomized, open-label trial in healthy volunteers compared the effects of tipranavir/ritonavir (TPV/r), darunavir/ritonavir (DRV/r), and ritonavir (RTV) alone on platelet aggregation after a single dose and at steady-state concentrations. Subjects were selected on the basis of normal platelet aggregation and arachidonic acid (AA)-induced platelet aggregation inhibition after administration of a single 325-mg dose of aspirin. All 3 PI therapies were administered twice daily for 10 days.In some but not all subjects, TPV/r inhibited AA-induced platelet aggregation and prolonged PFA-100® closure time with collagen-epinephrine cartridge, which was of lesser magnitude and consistency compared with aspirin, but greater when compared to DRV/r and RTV. At least 2 subjects in each treatment arm showed complete inhibition of AA-induced platelet aggregation on treatment, and the magnitude of change in all platelet-function tests did not correlate with PI plasma concentrations. Effects of TPV/r on platelet aggregation were reversed 24 hours after the last TPV/r dose. None of the PI treatments tested were associated with increases in bleeding time, decreases in plasma coagulation factors, or increase in fibrinolysis. There was large inter-patient variability in antiplatelet effect for all PI treatments, ranging from no effect to complete inhibition of AA-induced platelet aggregation.

Effects of the HIV Protease Inhibitor Ritonavir on GLUT4 Knock-out Mice

HIV protease inhibitors acutely block glucose transporters (GLUTs) in vitro, and this may contribute to altered glucose homeostasis in vivo. However, several GLUT-independent mechanisms have been postulated. To determine the contribution of GLUT blockade to protease inhibitor-mediated glucose dysregulation, the effects of ritonavir were investigated in mice lacking the insulin-sensitive glucose transporter GLUT4 (G4KO). G4KO and control C57BL/6J mice were administered ritonavir or vehicle at the start of an intraperitoneal glucose tolerance test and during hyperinsulinemic-euglycemic clamps. G4KO mice exhibited elevated fasting blood glucose compared with C57BL/6J mice. Ritonavir impaired glucose tolerance in control mice but did not exacerbate glucose intolerance in G4KO mice. Similarly, ritonavir reduced peripheral insulin sensitivity in control mice but not in G4KO mice. Serum insulin levels were reduced in vivo in ritonavir-treated mice. Ritonavir reduced serum leptin levels in C57BL/6J mice but had no effect on serum adiponectin. No change in these adipokines was observed following ritonavir treatment of G4KO mice. These data confirm that a primary effect of ritonavir on peripheral glucose disposal is mediated through direct inhibition of GLUT4 activity in vivo. The ability of GLUT4 blockade to contribute to derangements in the other molecular pathways that influence insulin sensitivity remains to be determined.

The Bile Acid Sensor FXR Protects against Dyslipidemia and Aortic Plaques Development Induced by the HIV Protease Inhibitor Ritonavir in Mice

BackgroundAlthough human immunodeficiency virus (HIV)–related morbidity and mortality rates in patients treated with a combination of high active antiretroviral therapy (HAART) have declined, significant metabolic/vascular adverse effects associated with the long term use of HIV protease inhibitors (PIs) have emerged as a significant side effect. Here we illustrate that targeting the bile acid sensor farnesoid X receptor (FXR) protects against dyslipidemia and vascular injury induced HIV-PIs in rodents.Methodology/Principal FindingsAdministration of the HIV PI ritonavir to wild type mice increased plasma triacylglycerols and cholesterol levels and this effect was exacerbated by dosing ritonavir to mice harbouring a disrupted FXR. Dyslipidemia induced by ritonavir associated with a shift in the liver expression of signature genes, Sterol Regulatory Element-Binding Protein (SREBP)-1 and fatty acid synthase. Treating wild type mice with the FXR agonist (chenodeoxycholic acid, CDCA) protected against development of dyslipidemia induced by ritonavir. Administration of ritonavir to ApoE−/− mice, a strain that develop spontaneously atherosclerosis, increased the extent of aortic plaques without worsening the dyslipidemia. Treating these mice with CDCA reduced the extent of aortic plaques by 70% without changing plasma lipoproteins or the liver expression of signature genes. A beneficial effect on aortic plaques was also obtained by treating ApoE−/− mice with gemfibrozil, a PPARα agonist. FXR activation counter-regulated induction of expression/activity of CD36 caused by HIV-PIs in circulating monocytes and aortic plaques. In macrophages cell lines, CDCA attenuated CD36 induction and uptake of acetylated LDL caused by ritonavir. Natural and synthetic FXR ligands reduced the nuclear translocation of SREBP1c caused by ritonavir.Conclusions/SignificanceActivation of the bile acid sensor FXR protects against dyslipidemia and atherosclerotic caused by ritonavir, a widely used HIV PI. From a mechanistic stand point it appears that besides reducing the liver expression of genes involved in fatty acid synthesis, FXR activation counter-regulates the expression/activity of CD36 on monocytes. FXR ligands might hold promise in the treatment dyslipidemia induced by ritonavir.

Toxicity of HIV protease inhibitors: clinical considerations

To review recent studies reporting toxicity, adverse events, side effects, and drug-drug interactions related to the use of HIV protease inhibitors, with particular focus on possible clinical implications. Toxicity-associated adverse events still remain a major concern when prescribing HIV protease inhibitors. Among those, diarrhea, lipid, and liver enzyme elevations are predominant. Also, with protease inhibitors being metabolized by the hepatic cytochrome P450, a significant number of drug-drug interactions has to be taken into account in patients who often require coadministration of drugs to treat supplementary diseases, for example, tuberculosis. Hence, scientific interest in this area continues to be high, especially in characterizing individual toxicities of particular protease inhibitors as well as in comparing them among each other. Protease inhibitors are still a cornerstone of combination antiretroviral therapy. A profound knowledge of the unwanted, but manageable, effects of protease inhibitor therapy is required to maintain an otherwise efficient and well tolerated antiretroviral therapy. Further research will elucidate the potential role of protease inhibitors both in double-boosted salvage therapy and in resource-limited settings.

HIV protease inhibitors and insulin resistance: lessons from in-vitro, rodent and healthy human volunteer models

Although the use of HIV protease inhibitors is linked to the development of insulin resistance and other metabolic changes that greatly increase the risk for cardiovascular disease, the molecular mechanisms responsible remain incompletely understood. This review summarizes recent advances that have been made in understanding the relative contributions of individual protease inhibitors to both acute and chronic insulin resistance together with newly identified cellular mediators. Individual protease inhibitors, alone and in combination, have differing propensities to induce insulin resistance, reflecting relative differences in both affinities for identified molecular targets and pharmacokinetic profiles. Several of the most recent protease inhibitors approved for clinical use or in development appear to be less likely to induce insulin resistance. In addition to direct effects on glucose transporter-4 activity, induction of oxidative stress, proteosome inhibition, alteration of adipokine levels, and changes in suppressors of cytokine signaling-1 have been implicated. A better understanding of the propensity of individual HIV protease inhibitors to produce insulin resistance will allow the tailoring of individual treatment plans based upon overall risk for diabetes. The elucidation of the molecular mechanisms for alterations in glucose homeostasis will facilitate the development of newer generations of HIV protease inhibitors that maintain their clinical efficacy without contributing to the development of diabetes mellitus and other proatherogenic effects.

HIV protease inhibitors that block GLUT4 precipitate acute, decompensated heart failure in a mouse model of dilated cardiomyopathy

The clinical use of HIV protease inhibitors is associated with insulin resistance and other metabolic changes that increase long-term cardiovascular risk. Since the failing heart has increased reliance on glucose, the influence of drug exposure on glucose homeostasis, myocardial glucose uptake, cardiac function, and survival was determined in TG9 mice, an established transgenic model of dilated cardiomyopathy generated by cardiac-specific overexpression of Cre-recombinase, as these animals progressed to overt heart failure. Beginning on day of life 75, TG9 mice and nontransgenic littermate controls were given a daily 10 mg/kg intraperitoneal injection of HIV protease inhibitors (ritonavir, lopinavir/ritonavir 4:1, atazanavir, atazanavir/ritonavir 4:1) or vehicle. Glucose tolerance testing, measurement of in vivo myocardial 2-deoxyglucose uptake, and echocardiography were performed before and 30 min following drug administration. The progression of dilated cardiomyopathy in TG9 animals was accompanied by impaired glucose tolerance, which was acutely exacerbated by exposure to ritonavir. Ritonavir and lopinavir precipitated acute, decompensated heart failure and death from pulmonary edema in TG9 mice. However, atazanavir, which does not inhibit glucose transport, had no effect. These studies demonstrate that, in the presence of dilated cardiomyopathy, HIV protease inhibitors that impair glucose transport induce acute, decompensated heart failure. The potential for HIV protease inhibitors to contribute to or exacerbate cardiomyopathy in human patients warrants further investigation.

Molecular Mechanisms of HIV Protease Inhibitor-Induced Endothelial Dysfunction

Highly active antiretroviral therapy incorporating protease inhibitors (PIs) is successful in controlling HIV infection and has dramatically improved the prognosis of HIV-infected patients. The therapeutic benefit of long-term use of HIV PIs is compromised by an increased risk of cardiovascular disease, however, including metabolic syndrome and endothelial dysfunction. Although clinical evidence strongly suggests an association of the use of HIV PIs with endothelial dysfunction, the underlying molecular mechanisms have not been fully elucidated yet. In this review, we describe recent advances in the molecular mechanisms of PI-induced endothelial dysfunction. The available evidence demonstrates that certain HIV PIs could induce endothelial dysfunction, including a decrease of endothelium-dependent vasorelaxation, inhibition of the nitric oxide synthase system, increase of oxidative stress, and activation of mitogen-activated protein kinases. HIV infection itself may also induce endothelial dysfunction and injury. These new discoveries provide a better understanding of the molecular mechanisms of the interaction between HIV PIs and vascular cells and may suggest potential approaches to control HIV PI-associated cardiovascular complications.

Antiretroviral treatment for HIV infection/AIDS and the risk of developing hyperglycemia and hyperlipidemia

A cross-sectional study with internal comparison groups was conducted to describe sociodemographic characteristics, as well as verify the association between the type of antiretroviral treatment used and hyperglycemia and hyperlipidemia, with special attention to the use of HIV protease inhibitors. The data was obtained through an interview questionnaire, as well as blood and urine samples that were collected for the laboratory exams. A total of 418 patients were interviewed. 46 of these, however, met the exclusion criteria. The sample was therefore composed by 372 HIV positive patients, attended at the laboratory of the Correia Picanço State Hospital for the collection of blood, to estimate the HIV viral load and/or TCD4 cell counts from August to November 2000. The association between the variables was tested using the chi-square test and the p-value. A multiple logistic regression analysis was carried out to adjust for potential confounding factors. A greater frequency of patients with high glucose levels was observed among those making use of antiretroviral therapy without protease inhibitors, but the number of patients limited the comparisons. An association was verified between the total serum cholesterol level and the use of HIV protease inhibitors (p=0.047) even after controlling for age. An association was also observed between the triglyceride levels and the use of HIV protease inhibitors, which remained after adjustment for age, sex and creatinine levels (p<0.001). The levels of glucose and TSH, the presence of proteinuria and the practice of physical activity were not associated either with the levels of cholesterol or with the levels of tryglicerides thus they were not confounders of the associations described.

Tipranavir Without Ritonavir Does Not Acutely Induce Peripheral Insulin Resistance in a Rodent Model

Tipranavir Without Ritonavir Does Not Acutely Induce Peripheral Insulin Resistance in a Rodent Model

Nelfinavir induces liposarcoma apoptosis and cell cycle arrest by upregulating sterol regulatory element binding protein-1

"HIV protease-induced lipodystrophy syndrome" is associated with the use of HIV protease inhibitors for treatment of HIV infection. In-vitro studies suggest that alteration of sterol regulatory element binding protein-1 levels underlie its pathogenesis. We postulated that HIV protease inhibitors may represent a novel class of antiliposarcoma agents. SW872, FU-DDLS-1 and LiSa-2 liposarcoma, and HT1080 and 293 nonliposarcoma cell lines were treated with HIV protease inhibitors (nelfinavir, ritonavir, saquinavir, indinavir and amprenavir), and clonogenic assays were performed. Nelfinavir exhibited the most potent inhibition of clonogenicity, and further assays for proliferation, cell cycle and apoptosis were performed with nelfinavir. Immunoblots were performed for sterol regulatory element binding protein-1, proapoptotic and cell cycle-related protein expression after nelfinavir treatment. Finally, a sterol regulatory element binding protein-1-inducible SW872 cell line was developed to examine the phenotype resulting from upregulated sterol regulatory element binding protein-1. Nelfinavir selectively inhibited clonogenicity and proliferation, and induced G1 cell cycle block and induced apoptosis in a dose-dependent manner in SW872 and LiSa-2 cells, whereas it had minimal or no effect on these parameters in FU-DDLS-1 or nonliposarcoma cells. Nelfinavir induced significant sterol regulatory element binding protein-1 expression in a dose-dependent and time-dependent fashion in sensitive SW872 and LiSa-2 cells, modestly in HT1080 cells, but not in nelfinavir-insensitive FU-DDLS-1 and 293 cells without inducing adipocytic differentiation. Forced expression of sterol regulatory element binding protein-1 in inducible-SW872 cells led to the induction of proapoptotic and antiproliferative proteins, and consequent reduction of cellular proliferation. Our data indicate that nelfinavir represents a novel class of antiliposarcoma agent that acts by selectively upregulating sterol regulatory element binding protein-1 expression in liposarcomas.

HIV Protease Inhibitor‐Specific Alterations in Human Adipocyte Differentiation and Metabolism

Human immunodeficiency virus (HIV) patients on antiretroviral regimens frequently develop a syndrome of abnormal fat distribution, insulin resistance, and dyslipidemia. This lipodystrophic syndrome has been most closely linked to the use of HIV protease inhibitors (PIs). Several mechanisms have been postulated to explain these adverse effects of PIs, based largely on studies of rodent adipocytes. Intriguingly, atazanavir, a newer PI equally effective against HIV, is associated with fewer signs of lipodystrophy. We hypothesized that the less deleterious clinical effects of atazanavir would be reflected in physiological differences observed in PI-treated adipocytes. We compared the effects of atazanavir and an older PI associated with lipodystrophy, ritonavir, on differentiation, gene expression, adipocytokine secretion, and insulin signaling in a human adipocyte cell line. Ritonavir inhibited human adipocyte differentiation and induced apoptosis to a greater extent than atazanavir. Treatment of mature adipocytes with ritonavir, but not atazanavir, also selectively decreased insulin signaling. Moreover, ritonavir also selectively decreased expression of adiponectin, an insulin-sensitizing adipocytokine, while inducing interleukin-6, a proinflammatory cytokine implicated in insulin resistance. These data suggest that the distinct metabolic side effect profiles of these PIs could be a consequence of their differential effects on adipocyte physiology.

Cellular mechanisms of lipodystrophy induction by HIV protease inhibitors

Increasing clinical evidence indicates that the use of HIV protease inhibitors (PIs) as part of highly active antiretroviral therapy (HAART) is linked closely to the pathogenesis of dyslipidemia, insulin resistance and lipodystrophy in HIV patients. However, the underlying cellular and molecular mechanisms remain elusive. Recent clinical and in vitro studies suggest that HIV PIs have multiple effects on different types of cells in the body, and that individual HIV PIs differ in their ability to induce dyslipidemia, insulin resistance and lipodystrophy. This review summarizes the recent evidence for potential cellular mechanisms of HIV PI-associated lipodystrophy. Understanding of the cellular mechanisms of HIV PI-induced side effects is of great clinical importance and will provide novel information for the development of improved therapeutic strategies.