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

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.

A Novel CXCR4 Targeting Protein SDF-1/54 as an HIV-1 Entry Inhibitor

“…It participates in many biological activities through signal transduction after binding to SDF-1 [33]. For example, SDF-1/CXCR4 plays roles in immune [34], hematopoietic [35], brain development [36], angiogenesis [37,38], HIV-1 infection [39], autoimmune diseases [34,40], cancer [41,42], inflammation [43] and other pathological processes [44]. Due to the multifunctional nature of SDF-1, the risk of SDF-1 inducing inflammatory side effects or interfering with the physiological nature of homeostasis chemokine system potentially limits its therapeutic application.…”

Mast Cell Responses to Viruses and Pathogen Products

“…These observations proved controversial [63] and may be more important in the context of pregnancy associated immune suppression. The potential for MCs to aid in the spread of HIV has also been examined and both the transfer of virus to T cells by MC-dependent mechanisms and the recruitment of MCs by HIV-derived Nef protein has been reported [20,64]. Although all of these processes are of interest to understanding disease pathology and help us to understand the roles of MCs in infection, there remains little direct evidence for a critical clinical role for MCs in the susceptibility to or course of HIV infection.…”

Mast Cells in Early Rheumatoid Arthritis

“…MCs have the capacity to rapidly perceive immunologic and metabolic insults and initiate different biochemical programs of homeostasis or inflammation. These cells can be activated by a plethora of immunologic and non-immunologic stimuli such as danger associated molecular patterns (DAMPs)-, viral and bacterial proteins [44,45], and endogenous ligands [46]. In the context of RA, specifically, laboratory evidence shows that MCs can produce pro-inflammatory (pro-arthritogenic) molecules [47], while on the other hand many stimuli can activate MCs in vitro, inducting the production of pro-inflammatory mediators.…”