Circulating Nef Induces Dyslipidemia in Simian Immunodeficiency Virus–Infected Macaques by Suppressing Cholesterol Efflux

Abstract

HIV infection and subsequent antiretroviral therapy have been associated with an increased incidence of dyslipidemia and cardiovascular disease and has been shown to suppress cholesterol efflux from virus-infected macrophages by inducing Nef-dependent downregulation of ABCA1. The SIV/macaque model was used to examine consequences and mechanisms involved. SIV infection drove a significant remodeling of high-density lipoprotein profiles suggesting systemic inhibition of the ABCA1-dependent reverse cholesterol transport pathway. The ABCA1 cholesterol transporter was significantly down regulated in the livers of the SIV-infected macaques and the viral protein Nef could be detected in the liver as well as in plasma of infected animals. Extracellular myristoylated HIV Nef inhibited cholesterol efflux from macrophages and hepatocytes. Moreover, sera from SIV-infected macaques also suppressed cholesterol efflux in a Nef-dependent fashion. These results indicate that SIV infection is a significant contributor to primary dyslipidemia, likely through the ability of Nef to suppress ABCA1-dependent reverse cholesterol transport.

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

“…HIV, via the viral accessory protein Nef, inhibits activity of the ATP binding cassette transporter A1 (ABCA1), an integral transmembrane lipid transporter ( 4 ), and impairs cholesterol effl ux from macrophages, causing accumulation of cholesterol in these cells and their transformation into foam cells, a hallmark of atherosclerosis ( 3 ). Furthermore, extracellular Nef secreted by HIV-infected cells can inhibit cholesterol efflux from uninfected cells and cause impairment of systemic reverse cholesterol transport ( 5 ). On the other hand, stimulation of cholesterol effl ux through activation of ABCA1 suppresses HIV-1 infection ( 6 ).…”

HIV-1 Protein Nef Inhibits Activity of ATP-binding Cassette Transporter A1 by Targeting Endoplasmic Reticulum Chaperone Calnexin

“…HIV-1 infection is associated with a high risk of developing atherosclerosis (1), and studies in animal models and in vitro demonstrated that Nef-mediated impairment of ATP-binding cassette transporter A1 (ABCA1) 3 function may contribute to this side effect of HIV infection (2)(3)(4). ABCA1 mediates transport of cholesterol and phospholipids to lipid-poor apolipoprotein A-I (apoA-I), which is the initial step in the process of reverse cholesterol transport and HDL formation (5).…”

Molecular Localization Techniques in the Diagnosis and Characterization of Nonhuman Primate Infectious Diseases

“…In these cases, viral infection is observed in epithelial cells and can be associated with marked cytomegaly and the presence of intranuclear inclusion bodies, which vary in size and characteristics based on adenovirus genotype (Figs. [1][2][3][4]. A mixed inflammatory cell infiltrate that can be primarily mononuclear or neutrophilic may be observed, although in cases of severe immunodeficiency, the inflammatory reaction may be minimal.…”