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HIV-1 Protein linked to insulin resistance
By Dean L. Winslow, MD, FACP, FIDSA
Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine
Dr. Winslow is a speaker for Cubist Pharmaceuticals and GSK, and is a consultant for Siemens Diagnostics.
Synopsis: The HIV-1 regulatory protein, Nef, was shown in cell cultures of adipocytes to cause reduced glucose uptake, inhibition of glucose transporter protein 4 (GLUT 4), decreased phosphorylation of signal transducing proteins, and alteration in cortical actin organization.
Source: Cheney L, et al. Nef inhibits glucose uptake in adipocytes and contributes to insulin resistance in human immunodeficiency virus type I infection. J Infect Dis 2011;203:1824-1831.
3T3L1 pre-adipocytes in cell culture were treated overnight with myristoylated or non-myristoylated recombinant Nef. Glucose uptake was measured with and without insulin stimulation. Adipocytes transfected with a Myc-GLUT4-green fluorescent protein (GFP) were studied after treatment with Nef with or without insulin stimulation. Actin polymerization was studied using rhodamine-stained cells. Immunoblot analysis of phosphorylation of signal transduction proteins Akt and AS160 was performed.
Nef was shown to inhibit insulin-stimulated glucose uptake in a dose-dependent manner. Nef also inhibited GLUT4 fusion with the plasma membrane in insulin-stimulated adipocytes. Finally, Nef was shown to alter the proximal signal transduction pathway of insulin and to disrupt F-Actin at the cortical actin ring.
While a number of antiretroviral agents have been implicated in contributing to both insulin resistance and lipid abnormalities, HIV also directly causes metabolic disturbances. Nef, a 27 kDa nonstructural protein essential for replication and evasion of host responses, is one of several regulatory proteins encoded by HIV-1 and modulates a number of cellular processes by protein-protein interactions. Nef has been shown to down-regulate CD4 and MHC1 molecules, alter signal transduction pathways, interact with the actin cytoskeleton, and affect actin polymerization. These processes are important for insulin action and glucose homeostasis. Nef is secreted into the extracellular compartment and can be measured in plasma. Insulin resistance is found in ARV-naïve patients, and HIV viral load is a predictor of metabolic syndrome.1
This in vitro study presents a nice demonstration of what is most likely a clinically relevant mechanism contributing to the problem of insulin resistance with resultant Type 2 diabetes and dyslipidemia so commonly seen in HIV-infected patients.