Protease Inhibitor Therapy Research Articles

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

Lipodystrophic syndromes associated with mutations in LMNA, encoding A-type lamins, and with HIV antiretroviral treatments share several clinical characteristics. Nuclear alterations and prelamin A accumulation have been reported in fibroblasts from patients with LMNA mutations and adipocytes exposed to protease inhibitors (PI). As genetically altered lamin A maturation also results in premature ageing syndromes with lipodystrophy, we studied prelamin A expression and senescence markers in cultured human fibroblasts bearing six different LMNA mutations or treated with PIs. As compared to control cells, fibroblasts with LMNA mutations or treated with PIs had nuclear shape abnormalities and reduced proliferative activity that worsened with increasing cellular passages. They exhibited prelamin A accumulation, increased oxidative stress, decreased expression of mitochondrial respiratory chain proteins and premature cellular senescence. Inhibition of prelamin A farnesylation prevented cellular senescence and oxidative stress. Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers. Thus, both LMNA mutations and PI treatment result in accumulation of farnesylated prelamin A and oxidative stress that trigger premature cellular senescence. These alterations could participate in the pathophysiology of lipodystrophic syndromes and lead to premature ageing complications.

Cushing Syndrome and Severe Adrenal Suppression Caused by Fluticasone and Protease Inhibitor Combination in an HIV-Infected Adolescent

A 14-year-old female with perinatally acquired HIV on boosted protease inhibitor (PI) therapy with atazanavir and ritonavir rapidly developed cushingoid features with excessive weight gain and moon facies within 2 weeks of receiving inhaled fluticasone/salmeterol for asthma treatment. Soon after discontinuing PIs and inhaled steroid, she required hospitalization for dyspnea, headache, muscle weakness, and extreme fatigue requiring hydrocortisone replacement therapy for presumed adrenal insufficiency. Cushing syndrome and adrenal suppression were very likely caused by elevated steroid systemic concentrations resulting from the cytochrome p450 interaction between the protease inhibitors and fluticasone. The Naranjo probability scale score of 5 suggests that the event was probably drug related. This is the first case report of fluticasone and PI-induced Cushing syndrome and adrenal suppression in a pediatric patient without a history of recent or concomitant treatment with systemic steroid therapy. Additionally, this case is unique as it is the most rapid (<2 weeks) presentation documented, thus far. Health care professionals should be conscious of this important drug-drug interaction in HIV-infected children and adolescents and be aware that rapid onset of hypercortisolism and adrenal suppression are possible.

Progression of carotid artery intima–media thickening in HIV-infected and uninfected adults

To compare the rate of change in intima-media thickness (IMT) of the carotid artery among uninfected subjects and HIV-infected subjects receiving or not receiving protease inhibitor (PI) regimens over a 144 week period. This prospective, matched cohort study enrolled 133 subjects into 45 triads (groups of three subjects matched by age, sex, race/ethnicity, smoking status, blood pressure, and menopause) from university based outpatient HIV clinics. Each triad consisted of one subject from each of the following groups: 1, HIV-infected subjects with continuous use of PI therapy for > or = 2 years; 2, HIV-infected subjects without prior PI use; 3, HIV-uninfected subjects. Standardized ultrasound images of carotid IMT were collected at weeks 0, 2, 24, 48, 72, 96, and 144. The main outcome was the yearly progression rate of carotid IMT (mm/year). The median yearly IMT progression rate in groups 1, 2, and 3 was 0.0096, 0.0058, and 0.0085 mm/year, respectively. There were no statistically significant differences in progression between groups 1 and 2, or between the combined HIV-positive groups and the HIV-negative control group. A multicovariate model examining predictors of progression in carotid IMT among all subjects contained low density lipoprotein cholesterol and homocysteine. Among HIV subjects, predictors included nadir CD4 cell count and ritonavir use. HIV infection and PI use did not contribute substantially to the rate of carotid IMT progression in our matched study.

Increased carotid intima media thickness and cardiac biomarkers in HIV infected children

To assess carotid intima media thickness (IMT) and cardiac biomarkers in HIV infected children on antiretroviral therapy (ART). This was a single site, cross sectional, controlled observational study. We assessed carotid IMT, homocysteine, high-sensitivity C-reactive protein and myeloperoxidase levels in HIV infected children on stable ART for >or= 6 months. Carotid IMT was reported as internal carotid artery (ICA) and common carotid artery (CCA) thickness; left and right sides were measured separately. Groups were compared using appropriate two-sample tests. Of the 62 subjects enrolled, 31 were HIV positive (50%), 66% were female, and 69% were African-American. Median CD4% was 32% and 26 patients (84%) had HIV-1 RNA< 400 copies/ml. Sixteen patients had been taking protease inhibitors for a median duration of 27 months. None had hypertension or smoked. HIV infected children had higher HOMA-IR, waist-to-hip ratio, cholesterol, triglycerides, myeloperoxidase and lower homocysteine levels. Left and right CCA IMT, and left and right ICA IMT were significantly higher in the HIV infected group. Significant predictors of carotid IMT measurements in uninfected controls were body mass index and homocysteine, but only the duration of ARV therapy was predictive of IMT in the HIV infected group. Higher levels of carotid IMT and some cardiac markers were found in ART treated HIV infected children when compared to matched uninfected controls. These results suggest that HIV infected children receiving ART may be at increased risk of cardiovascular disease.

Abacavir sulfate/lamivudine/zidovudine fixed combination in the treatment of HIV infection

Treatment of HIV infection has typically been carried out using two nucleoside analogs and a protease inhibitor. Such regimens can be complex and have high pill burdens. Use of alternative regimens, such as triple nucleoside-based regimens, can improve adherence and decrease toxicities associated with protease inhibitor therapy. A formulation of abacavir sulfate/lamivudine/zidovudine allows a dosing schedule of one pill twice daily. The components have performed favorably compared with protease inhibitor-based regimens, such as indinavir. Compared with efavirenz-based regimens, abacavir sulfate/lamivudine/zidovudine has not performed as well. The combination is being studied as a cornerstone for induction maintenance strategies, in which switching a patient to abacavir sulfate/lamivudine/zidovudine has been associated with similar virologic outcomes as continuing with either protease inhibitor- or efavirenz-based regimens. Administration of abacavir sulfate/lamivudine/zidovudine also avoids side effects of antiretroviral therapy, such as hyperlipidemia, but its use is associated with a hypersensitivity reaction in a small number of patients. The combination of abacavir sulfate/lamivudine/zidovudine is an important part of the HIV armamentarium. Its potency and ease of administration make it worth consideration in the treatment of HIV, either by itself or in combination with other agents.

Insulin resistance and HIV infection: a review

Highly active antiretroviral therapy (HAART) has markedly improved the prognosis of people with HIV infection. However, there are long-term side effects associated with HAART. Alterations in metabolic parameters are common and include hyperlipidaemia and insulin resistance (IR), either in isolation or as part of the lipodystrophy and metabolic syndromes. Insulin resistance is common in HIV-infected people, particularly among those being treated with protease inhibitor therapy. The prevalence of hyperglycaemia and diabetes mellitus is significantly higher in people with HIV infection being treated with antiretrovirals (ARVs), as compared with the general population. Hyperglycaemia is an important risk factor for the development of secondary pathology, including cardiovascular disease. It is therefore important to consider the effects of IR in HIV-infected individuals, and take measures to prevent or manage it appropriately. There is limited evidence for the benefit of pharmacological interventions for IR alone although the metabolic changes and body shape changes of lipodystrophy might benefit from the combined use of metformin with exercise. At present, therefore, it is best to concentrate on preventative measures, including lifestyle modification, the careful selection of ARV drugs, and changing drug combinations where appropriate.

Hydrophobic Sliding: A Possible Mechanism for Drug Resistance in Human Immunodeficiency Virus Type 1 Protease

Hydrophobic residues outside the active site of HIV-1 protease frequently mutate in patients undergoing protease inhibitor therapy; however, the mechanism by which these mutations confer drug resistance is not understood. From analysis of molecular dynamics simulations, 19 core hydrophobic residues appear to facilitate the conformational changes that occur in HIV-1 protease. The hydrophobic core residues slide by each other, exchanging one hydrophobic van der Waal contact for another, with little energy penalty, while maintaining many structurally important hydrogen bonds. Such hydrophobic sliding may represent a general mechanism by which proteins undergo conformational changes. Mutation of these residues in HIV-1 protease would alter the packing of the hydrophobic core, affecting the conformational flexibility of the protease. Therefore these residues impact the dynamic balance between processing substrates and binding inhibitors, and thus contribute to drug resistance.

A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism

BackgroundHIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors.Methods and FindingsWe have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy.ConclusionsHIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy.

Structure–function analysis of the ribosomal frameshifting signal of two human immunodeficiency virus type 1 isolates with increased resistance to viral protease inhibitors

Expression of the pol-encoded proteins of human immunodeficiency virus type 1 (HIV-1) requires a programmed -1 ribosomal frameshift at the junction of the gag and pol coding sequences. Frameshifting takes place at a heptanucleotide slippery sequence, UUUUUUA, and is enhanced by a stimulatory RNA structure located immediately downstream. In patients undergoing viral protease (PR) inhibitor therapy, a p1/p6(gag) L449F cleavage site (CS) mutation is often observed in resistant isolates and frequently generates, at the nucleotide sequence level, a homopolymeric and potentially slippery sequence (UUUUCUU to UUUUUUU). The mutation is located within the stimulatory RNA downstream of the authentic slippery sequence and could act to augment levels of pol-encoded enzymes to counteract the PR deficit. Here, RNA secondary structure probing was employed to investigate the structure of a CS-containing frameshift signal, and the effect of this mutation on ribosomal frameshift efficiency in vitro and in tissue culture cells was determined. A second mutation, a GGG insertion in the loop of the stimulatory RNA that could conceivably lead to resistance by enhancing the activity of the structure, was also tested. It was found, however, that the CS and GGG mutations had only a very modest effect on the structure and activity of the HIV-1 frameshift signal. Thus the increased resistance to viral protease inhibitors seen with HIV-1 isolates containing mutations in the frameshifting signal is unlikely to be accounted for solely by enhancement of frameshift efficiency.

Virologic efficacy of boosted double versus boosted single protease inhibitor therapy

Although regimens containing two protease inhibitor (PI) together with ritonavir boosting are used with the aim of improving virologic response to salvage therapy, there is little evidence to support or reject this approach. We compared the probability of attaining an undetectable HIV RNA level after using either boosted double or boosted single PI regimens. Retrospective clinical cohort. PI-experienced subjects in a Northern California-based database who initiated either a boosted single or boosted double PI salvage therapy regimen were analysed. Traditional multivariable regression and marginal structural model analyses were used to compare the effects of the two regimens on virologic suppression 12-36 weeks after initiation of salvage therapy, controlling for confounding by baseline HIV RNA level, CD4 lymphocyte count, treatment history, drug resistance, and multiple characteristics of the salvage regimen. Fifty-one percent of boosted single PI regimens (n=805) and 51.6% of boosted double PI regimens (n=183) achieved a plasma HIV RNA level of <75 copies/ml at week 12-36. In models including multiple potentially confounding variables, estimates of the relative odds of suppression on boosted double versus boosted single PI regimens ranged from 1.17 (95% CI, 0.54-2.55) to 1.33 (95% CI, 0.82-2.14). We were not able to reject the null hypothesis that boosted double versus boosted single PI regimens, resulted in equivalent probabilities of virologic success.

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

Persistence of HIV‐1 Variants with Multiple Protease Inhibitor (PI)–Resistance Mutations in the Absence of PI Therapy Can Be Explained by Compensatory Fixation

To investigate the mechanism explaining the persistence of human immunodeficiency virus (HIV) type 1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy. Longitudinal genotypic analyses were performed on sequential samples obtained from 2 HIV-1-infected patients who had stopped PI therapy for 4 years. Replication capacity (RC) was determined using recombinant viruses. Subsequently, the effect that changing individual protease mutations back to wild type has on RC was analyzed. We observed prolonged persistence (up to 4 years) of viruses with multiple protease mutations after PI therapy was stopped, despite the fact that the RC of the viruses was severely reduced. Forcing the virus to evolve toward wild type by changing individual protease mutations to wild type was unsuccessful, because all variants displayed a decreased RC in comparison with that of their predecessors. We propose compensatory fixation as a mechanism for the in vivo persistence of variants with multiple PI-resistance mutations in the absence of PI therapy. Viruses with multiple PI mutations have (partially) compensated for the initial loss in RC. Therefore, reversion of a single mutation causes a (further) reduction in RC and, as a consequence, the route to wild type is blocked.

Lipid abnormalities in HIV/hepatitis C virus‐coinfected patients

Among HIV-infected patients, hepatitis C virus (HCV) coinfection is associated with increased rates of lipodystrophy and insulin resistance. Its impact on HIV-associated dyslipidaemia is less clear. The lipid profiles of all HIV-infected patients and a subset of HCV-infected patients seen at the VA Medical Center in Dallas from January 2003 to March 2004 were analysed. Demographic data, HCV serostatus, and HIV treatment history were recorded. Lipid profiles of HIV/HCV-coinfected patients were compared with those of HIV-monoinfected and HCV-monoinfected patients. A total of 359 HIV-infected patients, 91 (25.3%) of whom were HCV coinfected, and 112 HCV-infected patients were included in the analysis. Among the HIV-infected patients, HCV coinfection was associated with a reduced risk of hypercholesterolaemia [9.9% vs 24.8%; relative risk (RR)=0.333; 95% confidence interval (CI)=0.158-0.699; P<0.001] and hypertriglyceridaemia (48.4% vs 60.3%; RR=0.616; 95% CI=0.382-0.994; P=0.031). After controlling for duration of protease inhibitor (PI) therapy, race, alanine aminotransferase (ALT) concentration and platelet count, HCV remained an independent predictor of hypercholesterolaemia (RR=0.369; P=0.01) and any dyslipidaemia (RR=0.531; P=0.019). In addition, the rate of dyslipidaemias was lower among HCV-monoinfected than HIV/HCV-coinfected patients (29.5% vs 50.5; P=0.002). White race was also an independent predictor of dyslipidaemia (73.8% vs 50.7%; RR=2.32; 95% CI=1.44-3.76; P=0.001). HCV coinfection independently predicted lower rates of dyslipidaemia among HIV-infected patients. An analysis of lipid kinetics among mono- and coinfected patients may elucidate the mechanisms of the apparent protective effect of HCV infection.

Novel Robust Hepatitis C Virus Mouse Efficacy Model

The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-alpha combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.

Carotid Intimal Medial Thickness in Human Immunodeficiency Virus-Infected Women: Effects of Protease Inhibitor Use, Cardiac Risk Factors, and the Metabolic Syndrome

Little is known regarding carotid intimal medial thickness (IMT) in HIV-infected women and the risk factors for subclinical atherosclerosis in this population, including antiretroviral therapy and the metabolic syndrome. Our objective was to assess carotid IMT in relationship to HIV status and antiretroviral therapy in HIV-infected women in comparison with healthy age- and body mass index (BMI)-matched control subjects. The study took place at an academic medical center and included 97 HIV-infected women compared with 86 age- and BMI-matched healthy control subjects. We assessed carotid IMT, metabolic syndrome, and risk factors for increased IMT. Carotid IMT was not increased in HIV-infected women [0.62 mm (0.57-0.68); median (IQR)] compared with non-HIV-infected women [0.61 mm (0.55-0.68)] matched for age and BMI (P = 0.07) but was increased significantly among HIV patients receiving a protease inhibitor (PI) [0.65 (0.59-0.71) mm] vs. non-PI-treated patients [0.61 (0.57-0.66) mm] (P < 0.05) and vs. control subjects [0.61 (0.55-0.68) mm] (P < 0.05). The prevalence of metabolic syndrome was significantly increased among the HIV-infected women compared with control subjects and particularly in PI- vs. non-PI-treated HIV patients (45 vs. 19%, P = 0.001). Metabolic syndrome score correlated with IMT among non-HIV patients but not among the HIV group. Individual risk factors most strongly associated with IMT in multivariate regression modeling in the control group were age and waist-to-hip ratio, and among the HIV group age and waist circumference. These data demonstrate increased carotid IMT in HIV-infected women receiving PI therapy, which may be due to associated metabolic abnormalities related to PI therapy or more direct effects of this medication class on the vasculature. Additional studies of the mechanisms by which PI uses results in subclinical atherosclerosis are needed.

Body Fat Changes and Lipodystrophy in HIV-infected Children

Body Fat Changes and Lipodystrophy in HIV-infected Children

Hypertension in HIV patients

In their interesting article, Crane et al. [1] reported an increase in blood pressure among patients treated with HAART. Systolic blood pressure (SBP) during treatment with HAART, but not diastolic blood pressure, was significantly higher compared with SBP measured before initiating HAART. Among protease inhibitors (PI), lopinavir/ritonavir was associated with the greatest risk of mainly systolic elevations in blood pressure. In this work, the authors did not report specifically whether pulse pressure was different before and after therapy. Pulse pressure is considered a more sensitive measure of risk than other indexes of blood pressure [2]. Probably, many of the patients reported had an increase in pulse pressure. The increase in SBP and pulse pressure is primarily caused by an increase in large-artery stiffness and an associated increase in wave reflection amplitude. There is increasing evidence that pulse pressure is an independent predictor of the risk of coronary heart disease compared with mean arterial pressure [3]. Recent data suggest that HIV-infected patients under HAART including a PI have higher values of aortic stiffness than a matched group of HIV-uninfected control subjects, and that pulse wave velocity increased with longer exposure to PI treatment [4]. With increased arterial stiffness, central SBP increases and diastolic blood pressure falls in the central arteries as a consequence of earlier wave reflection, which shifts the augmentation of blood pressure from diastole to systole. Augmentation of central pressure is a direct determinant of increased cardiac workload and of diminished myocardial perfusion, and has recently been implicated as a powerful risk factor for cardiovascular events independently of pulse pressure and other risk markers [5]. PI treatment might selectively contribute to increase aortic stiffness. The changes in arterial stiffness may partly mediate the association between the use of PI and cardiovascular risk in patients with HIV infection. Crane et al. [1] reported that increased body mass index was significantly associated with elevated blood pressure in their patients, but do not report whether their patients met the criteria for the metabolic syndrome. We suggest that the metabolic syndrome might represent a link between the use of HAART and arterial stiffness, reflected by a selective increase in SBP and pulse pressure. In our opinion, this would be valuable information, because the metabolic syndrome is both a side-effect of PI [6] and an important determinant of large-artery stiffness [7]. In other words, PI therapy may contribute to increase arterial stiffness and the risk of developing the metabolic syndrome and the associated cardiovascular risk.

Antiretroviral Therapy in HIV-Positive Women Is Associated With Increased Apolipoproteins and Total Cholesterol

Dyslipidemia has become a common problem in HIV disease, especially in patients on combination antiretroviral (ARV) therapy. However, little data are available to evaluate lipid abnormalities in women on ARV therapy. Using a cross-sectional design, the prevalence of abnormal plasma lipid and lipoprotein concentrations as well as other biomarkers for vascular disease was determined in 184 HIV-positive women from 2 HIV clinics in Atlanta during 2002. Most of the women were African American (89%), with median age of 41 years (range 21-72); 6% were diabetic, 44% smoked, and 67% were overweight. ARV therapy defined the comparison groups that included treatment with a protease inhibitor (PI)-based regimen for more than 3 months in 76 (41%), treatment with a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen for more than 3 months in 38 (20%), and no ARV therapy for the past 3 months in 70 (38%). Women being treated with a PI or NNRTI had higher total cholesterol and triglyceride levels than patients on no therapy (P < 0.05 for each). Women treated with either PIs or NNRTIs had significantly higher apolipoprotein B and apolipoprotein C-III levels than patients on no therapy (P < 0.01 for each). In this cross-sectional study of HIV-infected women, either PI or NNRTI therapy elevated levels of total cholesterol and specific apolipoproteins. These findings, on a background of an older population with additional risk factors of smoking, obesity, and diabetes, may lead to future atherosclerotic events in these patients.

Tipranavir: A Protease Inhibitor for HIV Salvage Therapy

To review the efficacy, safety, pharmacology, virology, pharmacokinetics, and resistance of the nonpeptidic protease inhibitor (PI) tipranavir. A PubMed search (1966-February 2006) was conducted using the key words tipranavir or PNU-140690, with the limitation of English-language reports. Pharmacokinetic and randomized clinical trials originating from major HIV conferences, such as the Conference on Retroviruses and Opportunistic Infections, International AIDS Society, European AIDS Conference, and Interscience Conference on Antimicrobial Agents and Chemotherapy, published only in abstract form, from 2000 to February 2006, were reviewed for relevance and included in this review. Phase III studies have shown that tipranavir is effective in the treatment of PI-resistant HIV compared with other PI-containing regimens. Adverse effects associated with tipranavir/ritonavir therapy include gastrointestinal reactions, hepatotoxicity, and elevations in cholesterol and triglyceride levels. Resistance data suggest that tipranavir/ritonavir should be reserved for salvage therapy in antiretroviral-experienced patients who have previously failed standard PI therapies. The potential for hepatotoxicity and drug interactions and the expense of tipranavir due to required ritonavir boosting may limit its widespread use. Tipranavir/ritonavir is an essential addition to the antiretroviral armamentarium for HIV-infected patients with limited treatment options.

HIV protease inhibitor (PI) therapy for liposarcoma

9564 Background: Liposarcomas are the second most common soft-tissue sarcoma. Highly-active anti-retroviral therapy (HAART) with HIV PIs results in “HIV-1 protease inhibitor associated lipodystrophy syndrome,” characterized by peripheral fat wasting, central fat accumulation, insulin resistance, and hyperlipidemia. Based upon this syndrome, we hypothesized that HIV PIs might represent a novel liposarcoma therapy. Methods: SW872, LiSa-2, and FU-DDLS-1 liposarcoma, and control 293 embryonic kidney and HT1080 fibrosarcoma cell lines were treated with HIV PIs and subjected to cellular and molecular assays. Results: Clonogenic assays with SW872 cells using HIV PIs (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) were performed. Nelfinavir demonstrated the most potent clonogenic inhibition without affecting 293 and HT1080 clonogenicity, and was studied further. Nelfinavir inhibited SW872 and LiSa-2 proliferation dose-dependently, and HT1080 proliferation at the highest concentration, without affecting FU-DDLS-1 nor 293 proliferation. Nelfinavir induced a G1 cell cycle arrest in SW872 and HT1080, but not in 293 cells. It also induced dose-dependent apoptosis in SW872, but not in 293 nor HT1080 cells. Western analyses for sterol regulatory element binding protein-1 (SREBP-1) expression, a key transcriptional regulator of fatty acid and cholesterol synthesis, were performed. Nelfinavir induced expression of SREBP-1 in nelfinavir-sensitive SW872 and LiSa-2 cells, and modestly in HT1080 cells, but not in insensitive FU-DDLS-1 nor 293 cells. Additionally, nelfinavir reduced protein expression of proliferating cell nuclear antigen (PCNA) in sensitive SW872 and LiSa-2 cells, and induced expression of the anti-proliferative protein, p21, as well as pro-apoptotic proteins, Bax and Fas, in a dose-dependent manner. Finally, forced expression of SREBP-1 with a Tet-On inducible SW872 cell line, in the absence of nelfinavir, induced expression of p21, Bax, Fas, reduced expression of PCNA, and inhibited cell proliferation. Conclusions: These studies demonstrate that nelfinavir inhibits cellular proliferation, and induces apoptosis in sensitive-liposarcoma cells through upregulation of SREBP-1. These studies validate nelfinavir as a potential, novel targeted therapy for liposarcoma. No significant financial relationships to disclose.