New cholesterol-specific antibodies remodel HIV-1 target cells’ surface and inhibit their in vitro virus production

Gábor Mocsár,Emese Izsépi,Glória László,Zoltán Beck,György Vámosi,Andrea Kis,Janos Matko,George Füst,Károly Liliom,Andrea Balogh,László Cervenak,Adrienn Bíró

doi:10.1194/jlr.m000372

Abstract

The importance of membrane rafts in HIV-1 infection is still in the focus of interest. Here, we report that new monoclonal anticholesterol IgG antibodies (ACHAs), recognizing clustered membrane cholesterol (e.g., in lipid rafts), rearrange the lateral molecular organization of HIV-1 receptors and coreceptors in the plasma membrane of HIV-1 permissive human T-cells and macrophages. This remodeling is accompanied with a substantial inhibition of their infection and HIV-1 production in vitro. ACHAs promote the association of CXCR4 with both CD4 and lipid rafts, consistent with the decreased lateral mobility of CXCR4, while Fab fragments of ACHAs do not show these effects. ACHAs do not directly mask the extracellular domains of either CD4 or CXCR4 nor do they affect CXCR4 internalization. No significant inhibition of HIV production is seen when the virus is preincubated with the antibodies prior to infection. Thus, we propose that the observed inhibition is mainly due to the membrane remodeling induced by cholesterol-specific antibodies on the target cells. This, in turn, may prevent the proper spatio-temporal juxtaposition of HIV-1 glycoproteins with CD4 and chemokine receptors, thus negatively interfering with virus attachment/entry.

Highlights

The importance of membrane rafts in HIV-1 infection is still in the focus of interest
Since in a recent work [13] another antilipid antibody, a mAb against phosphatidylinositol-4-phosphate, was reported to inhibit infection of peripheral blood mononuclear cells (PBMCs) with two HIV-1 primary isolates, we investigated whether the new cholesterol-specific antibodies can affect in vitro HIV-1 infection/production of primary monocyte-derived macrophages (MDMs) and T-cells in cultures
Binding properties of anticholesterol IgG antibodies (ACHAs) to cholesterol-rich surfaces assessed by surface plasmon resonance

Summary

Introduction

The importance of membrane rafts in HIV-1 infection is still in the focus of interest. We report that new monoclonal anticholesterol IgG antibodies (ACHAs), recognizing clustered membrane cholesterol (e.g., in lipid rafts), rearrange the lateral molecular organization of HIV-1 receptors and coreceptors in the plasma membrane of HIV-1 permissive human T-cells and macrophages. This remodeling is accompanied with a substantial inhibition of their infection and HIV-1 production in vitro. We reported on new IgG-type monoclonal antibodies, AC1 and AC8, which are highly specific to clustered cholesterol and some 3␤-OHcontaining sterols and do not cross-react with other lipids [2] These antibodies, in contrast to the IgM-type ACHAs reported earlier, have a unique property of spontaneous binding to live phagocytes and T-cells.

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