A pseudo-glycodendrimer inhibits DC-sign-mediated HIV trans-infection and interferes with DC-sign signal

Background: DC-SIGN is involved in the initial stages of mucosal HIV infection. DC-SIGN, by binding mannosylated residues (high mannose glycan) on HIV gp120, mediates trans-infection of CD4 T cells. Furthermore HIV interaction with DC-SIGN subverts its normal immune-activating functions shifting the Th1/Th2 balance towards a Th2 response that favours the persistence of the virus. HIV binding to DC-SIGN induces intracellular signalling pathways that trigger activities required to viral replication and promote immunosuppressive responses by interfering with TLR signalling. Pseudo-mannosylated compounds were synthesized in the attempt to compete with the binding of DC-SIGN to HIV gp120 and interfere with the immunosuppressive DC-SIGN signalling. Methods: A hexavalent pseudo-glycodendrimer (PM26) able to interact selectively with DC-SIGN was synthesized. The ability of PM26 to inhibit HIV-1 trans-infection was assessed in cellular models based on DC-SIGN expressing B-THP-1 cells. To study the effects of PM26 on DC-SIGN signal, gene expression profile after treatment of human monocyte-derived DCs with PM26 in presence/absence of TLR agonist (LPS and Poly:IC) was evaluated. The cytotoxicity of the compound was also assessed. Results: PM26 abrogated almost completely (>98%) the transmission of different HIV strains (Bal, Du174) to CD4 T cells at 1 \u3bcM, with an IC50 of 25 nM. Treatment of DCs with PM26 in presence/absence of LPS or Poly:IC strongly increased the expression of cytokines that regulate innate immunity, such as IL-1\u3b2, IL-6, TNF\u3b1 and IL-12. Interestingly, an upregulation of IRF8, involved in the regulation of IL-12 expression, was observed. PM26 also induced IFN\u3b3 and CCL3, CCL4 and CCL7. TAPBP, involved in antigen presentation, and TLR9, were up regulated as well. In contrast, the compound did not augment IL-10, CCR5, CXCR4 and DC-SIGN expression. No toxicity was observed at the concentrations tested in the cellular assays. Conclusion: The pseudo-glycodendrimer PM26 inhibits HIV-1 trans-infection by competing with the binding of the virus to DC-SIGN. Furthermore, PM26 both alone and in synergy with TLR agonist stimulates early immune responses that contribute to counteract HIV infection and activate adaptive immunity. These features make the compound a potential candidate for the development as topical microbicide