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

ABSTRACT Substitution of leucine for isoleucine at residue 50 (I50L) of human immunodeficiency virus (HIV) protease is the signature substitution for atazanavir (ATV) resistance. A unique phenotypic profile has been associated with viruses containing the I50L substitution, which produces ATV-specific resistance and increased susceptibility to most other approved HIV protease inhibitors (PIs). The basis for this unique phenotype has not been clearly elucidated. In this report, a direct effect of I50L on the susceptibility to the PI class is described. Cell-based protease assays using wild-type and PI-resistant proteases from laboratory and clinical isolates and in vitro antiviral assays were used to demonstrate a strong concordance between changes in PI susceptibility at the level of protease inhibition and changes in susceptibility observed at the level of virus infection. The results show that the induction of ATV resistance and increased susceptibility to other PIs by the I50L substitution is likely determined at the level of protease inhibition. Moreover, the I50L substitution functions to increase PI susceptibility even in the presence of other primary and secondary PI resistance substitutions. These findings may have implications regarding the optimal sequencing of PI therapies necessary to preserve PI treatment options of patients with ATV-resistant HIV infections.

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HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00167.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. E558-E567 ◽

Cited By ~ 27

Author(s):

Michael J. Carper ◽

W. Todd Cade ◽

Margaret Cam ◽

Sheng Zhang ◽

Anath Shalev ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Protease Inhibitors ◽

Hiv Protease ◽

Signaling Cascade ◽

Cytokine Signaling ◽

Hiv Protease Inhibitors ◽

Suppressor Of Cytokine Signaling ◽

Zdf Rats

Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60–80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty ( fa/fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-α and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.

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Effect of α1 -acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro

British Journal of Clinical Pharmacology ◽

10.1046/j.1365-2125.2001.01324.x ◽

2001 ◽

Vol 51 (1) ◽

pp. 99-102 ◽

Cited By ~ 24

Author(s):

K. Jones ◽

P. G. Hoggard ◽

S. Khoo ◽

B. Maher ◽

D. J. Back

Keyword(s):

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Intracellular Accumulation ◽

Acid Glycoprotein

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Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Clinical and Vaccine Immunology ◽

10.1128/cvi.00130-07 ◽

2007 ◽

Vol 14 (11) ◽

pp. 1515-1521 ◽

Cited By ~ 12

Author(s):

Nurit Hadad ◽

Rachel Levy ◽

Francisc Schlaeffer ◽

Klaris Riesenberg

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitors ◽

Neutrophil Function ◽

Significant Inhibition ◽

Hiv Protease ◽

Minor Effect ◽

Hiv Protease Inhibitors ◽

Calpain Activity ◽

Immunodeficiency Virus

ABSTRACT Impairment of neutrophil functions and high levels of apoptotic neutrophils have been reported in human immunodeficiency virus (HIV) patients. The aim of the present study was to investigate the direct in vitro effects of the different HIV protease inhibitors (PIs) on neutrophil functions and apoptosis and to explore their mechanisms of action. The effects of nelfinavir (NFV), saquinavir (SQV), lopinavir (LPV), ritonavir (RTV), and amprenavir (APV) in the range of 5 to 100 μg/ml on neutrophil function, apoptosis, and μ-calpain activity were studied. The neutrophil functions studied included superoxide production stimulated by 5 ng/ml phorbol myristate acetate, 5 × 10−7 M N-formyl-methionyl-leucyl-phenylalanine, and 1 mg/ml opsonized zymosan; specific chemotaxis; random migration; and phagocytosis. Apoptosis was determined by DNA fragmentation, fluorescein isothiocyanate-annexin V binding, and nuclear morphology. All three neutrophil functions, as well as apoptosis, were similarly affected by the PIs. SQV and NFV caused marked inhibition and LPV and RTV caused moderate inhibition, while APV had a minor effect. μ-Calpain activity was not affected by the PIs in neutrophil lysate but was inhibited after its translocation to the membranes after cell stimulation. SQV, which was the most potent inhibitor of neutrophil functions and apoptosis, caused significant inhibition of calpain activity, while APV had no effect. The similar patterns of inhibition of neutrophil functions and apoptosis by the PIs, which coincided with inhibition of calpain activity, suggest the involvement of calpain activity in the regulation of these processes.

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