A Glycomimetic compound inhibits DC-SIGN mediated HIV infection in cellular and cervical explant models

Background: Development of topical microbicides and entry inhibitors is a promising approach to prevent sexually transmitted HIV infection. Mucosal dendritic cells (DCs) internalize HIV through DC-SIGN and, on arrival to lymphoid tissues, transmit the virus in trans to CD4 T lymphocytes, promoting HIV dissemination. DC-SIGN, thus, is a potential therapeutic target and the inhibition of HIV interaction with DC-SIGN may efficiently prevent the early stages of HIV infection. The DC-SIGN ligand is the HIV gp120 high mannose glycan Man9. We synthesized structural analogues of this glycan (using polyvalent presentations of di- and tri-mannoside mimics) in the attempt to compete with binding of DC-SIGN to HIV gp120. Methods: Different experimental models were designed: 1) inhibition of trans infection was assessed by using B-THP-1/ DC-SIGN cells. Ability of compounds to block lab and primary HIV-1 strains transmission to CD4 T cells was evaluated; 2) human endocervical explant tissues were treated with the compounds and then exposed to different HIV-1 strains in a non polarised manner. Infection was determined by measuring p24 levels in co-culture and in explant culture supernatants; 3) cytokines and chemokines production following stimulation of monocyte-derived DCs was analyzed. Toxicity of the compounds was evaluated in cellular and tissue models. Results: One of the compounds tested, a tetravalent dendron containing four copies of a linear trimannoside mimic (compound 12), almost completely (>98%) abrogated the transmission of R5- and X4-tropic HIV-1 lab strains and primary isolates to CD4 T cells at 100M. Notably the antiviral effect persisted up to 12 hours after compound removal. Compound 12 also prevented, in a dose-response manner, HIV-1 infection of human cervical tissues under conditions which mimic compromised epithelial integrity. Treatment with this compound significantly increased MIP-1 production as well. Toxicity of compound 12 was neglectable at the highest concentration tested in infection assay. Conclusion: Compound 12, a tetravalent dendron presenting trimannoside mimic, is endowed with a potent anti HIV activity independent of viral tropism. The activity is long-lasting and observed both when CD4 T lymphocytes or cervical explants are used. Competition with the binding of HIV to DC-SIGN and stimulation of MIP-1 production both contribute to such activity. This compound is potentially suitable for development as a vaginal microbicide.