HIV-1 Nef promotes migration and chemokine synthesis of human basophils and mast cells through the interaction with CXCR4.

Francescopaolo Granata,Carmine Selleri,Amato de Paulis,Francesca Wanda Rossi,Nella Prevete,Filomena Napolitano,Antonio Lobasso,Felice Rivellese

doi:10.1186/s12948-016-0052-1

Abstract

BackgroundThe Nef protein can be detected in plasma of HIV-1-infected patients and plays a role in the pathogenesis of HIV-1. Nef produced during the early stages of infection is fundamental in creating the ideal environment for viral replication, e.g. by reducing the ability of infected cells to induce an immune response.AimBased on previous experience showing that both Tat and gp41 of HIV-1 are potent chemotactic factors for basophils and mast cells, and gp120 is a powerful stimulus for the release of histamine and cytokines (IL-4 and IL-13) from basophils, in this study we aimed to verify if the HIV Nef protein can exert some effects on basophils and mast cells purified from healthy volunteers through the interaction with the CXCL12 receptor, CXCR4.MethodsBasophils purified from peripheral blood cells of 30 healthy volunteers and mast cells obtained from lung tissue of ten healthy volunteers were tested by flow cytometric analysis, chemotaxis and chemokine production by ELISA assays.ResultsNef is a potent chemoattractant for basophils and lung mast cells obtained from healthy, HIV-1 and HIV-2 seronegative individuals. Incubation of basophils and mast cells with Nef induces the release of chemokines (CXCL8/IL-8 and CCL3/MIP-1α). The chemotactic activity of Nef on basophils and mast cells is mediated by the interaction with CXCR4 receptors, being blocked by preincubation of FcεRI+ cells with an anti-CXCR4 Ab. Stimulation with Nef or CXCL12/SDF-1α, a CXCR4 ligand, desensitizes basophils to a subsequent challenge with an autologous or heterologous stimulus.ConclusionsThese results indicate that Nef, a HIV-1-encoded α-chemokine homolog protein, plays a direct role in basophils and mast cell recruitment and activation at sites of HIV-1 replication, by promoting directional migration of human FcεRI+ cells and the release of chemokines from these cells. Together with our previous results, these data suggest that FcεRI+ cells contribute to the dysregulation of the immune system in HIV-1 infection.

Highlights

The Nef protein can be detected in plasma of HIV-1-infected patients and plays a role in the pathogenesis of HIV-1
These results indicate that Nef, a HIV-1-encoded α-chemokine homolog protein, plays a direct role in basophils and mast cell recruitment and activation at sites of HIV-1 replication, by promoting directional migration of human high affinity receptor for IgE (FcεRI)+ cells and the release of chemokines from these cells
We have investigated the role of basophils and mast cells in the context of HIV infection, suggesting that FcεRI+ cells may be a source of Th2 cytokines, contributing to the dysregulation of the immune system in HIV-1

Summary

Introduction

The Nef protein can be detected in plasma of HIV-1-infected patients and plays a role in the pathogenesis of HIV-1. The accessory protein Nef, is a crucial determinant of viral pathogenesis and disease progression to full-blown AIDS by optimizing the cellular environment for viral replication [4]. The key role of Nef is to control the expression levels of various cell surface molecules that play important roles in immunity and virus life cycle [5]. Nef activities support viral replication and survival while at the same time favor viral dissemination [10]. Many of these activities of extracellular Nef might be mediated indirectly or directly by the interaction with the chemokine receptor CXCR4 [2, 11, 12]

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