Background: DC-SIGN is involved in the initial stages of infection by HIV. DC-SIGN, by binding high mannose glycan on HIV gp120, mediates trans infection of CD4 T cells. HIV interaction with DC-SIGN promote immunosuppressive responses that interfere with TLRs signalling, so favouring the persistence of the virus. We synthesized pseudo-mannosylated compounds in the attempt to compete with binding of DC-SIGN to HIV gp120 and interfere with the immunosuppressive DC-SIGN signalling. Methods: The ability of the compounds to block HIV-1 infection and their toxicity were assessed in cellular and human cervical explant models. Laboratory strain and primary isolates both R5 tropic and X4 tropic were tested. Gene expression profile after treatment of MDDCs with the compounds was evaluated. Results: Two of the compounds abrogated almost completely the transmission of different HIV strains to CD4 T cells and the infection of cervical explants. This activity was associated with a significant increase in the production of the antiviral cytokine IFNβ and of β chemokines. The production of inflammatory cytokines (IL-6, IL-1 β, TNFα and IFNγ) was increased, whereas IL-10, CCR5 and CXCR4 expression was not modified. The toxicity of the compounds was neglectable. Conclusion: Pseudo-manosylated compounds competitively inhibit HIV binding to DC-SIGN, blocking infection in trans. Furthermore, by interacting with DC-SIGN, the compounds induce immune activation and proinflammatory responses. The production of β chemokines CCL3, CCL4 and RANTES, that compete with the virus binding to CCR5 co-receptor, contributes to antiviral activity. These features make such compounds good candidates to develop new topical microbicides.

Pseudo-mannosylated compounds inhibit DC-SIGN mediated HIV infection by competitive inhibition and by interfering with DC-SIGN signal / A. Berzi, N. Varga, P. Antonazzo, I. Cetin, M. Biasin, D. Trabattoni, A. Bernardi, M. Clerici. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - 4:Suppl. 1(2013), pp. 168.1-168.1. ((Intervento presentato al 15. convegno International congress of immunology tenutosi a Milano nel 2013 [10.3389/conf.fimmu.2013.02.00168].

Pseudo-mannosylated compounds inhibit DC-SIGN mediated HIV infection by competitive inhibition and by interfering with DC-SIGN signal

A. Berzi
Primo
;
N. Varga
Secondo
;
P. Antonazzo;I. Cetin;M. Biasin;D. Trabattoni;A. Bernardi
Penultimo
;
M. Clerici
Ultimo
2013

Abstract

Background: DC-SIGN is involved in the initial stages of infection by HIV. DC-SIGN, by binding high mannose glycan on HIV gp120, mediates trans infection of CD4 T cells. HIV interaction with DC-SIGN promote immunosuppressive responses that interfere with TLRs signalling, so favouring the persistence of the virus. We synthesized pseudo-mannosylated compounds in the attempt to compete with binding of DC-SIGN to HIV gp120 and interfere with the immunosuppressive DC-SIGN signalling. Methods: The ability of the compounds to block HIV-1 infection and their toxicity were assessed in cellular and human cervical explant models. Laboratory strain and primary isolates both R5 tropic and X4 tropic were tested. Gene expression profile after treatment of MDDCs with the compounds was evaluated. Results: Two of the compounds abrogated almost completely the transmission of different HIV strains to CD4 T cells and the infection of cervical explants. This activity was associated with a significant increase in the production of the antiviral cytokine IFNβ and of β chemokines. The production of inflammatory cytokines (IL-6, IL-1 β, TNFα and IFNγ) was increased, whereas IL-10, CCR5 and CXCR4 expression was not modified. The toxicity of the compounds was neglectable. Conclusion: Pseudo-manosylated compounds competitively inhibit HIV binding to DC-SIGN, blocking infection in trans. Furthermore, by interacting with DC-SIGN, the compounds induce immune activation and proinflammatory responses. The production of β chemokines CCL3, CCL4 and RANTES, that compete with the virus binding to CCR5 co-receptor, contributes to antiviral activity. These features make such compounds good candidates to develop new topical microbicides.
HIV ; DC-SIGN ; glycomimetic compounds ; dendritic cells ; Toll-like receptors
Settore MED/04 - Patologia Generale
Settore CHIM/06 - Chimica Organica
Settore BIO/13 - Biologia Applicata
International union of immunological societies
Società Italiana Immunologia, Immunologia Clinica e Allergologia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/239211
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