Background: Development of topical microbicides is a promising approach to prevent sexually transmitted HIV infection. DC-SIGN, expressed by dendritic cells at mucosal tissues, captures HIV by binding envelope glycoprotein gp120. Then DCs migrate to lymph nodes where mediate trans infection of CD4 T lymphocytes, promoting HIV dissemination. Therefore inhibition of HIV interaction with DCSIGN may represent a strategy to prevent early stages of HIV infection. The main DC-SIGN ligand on HIV gp120, is the high mannose glycan Man9. Structural analogues of high mannose terminal di or trisaccharides, able to compete with binding of DC-SIGN to HIV gp120, were synthesized. These compounds were prepared in multivalent systems to improve the affinity to DC-SIGN. Methods: Synthesized DC-SIGN inhibitors were tested in a trans infection in vitro assay. The B-THP1/ DC-SIGN cells (a B cell line transfected to express high DC-SIGN levels and supporting efficient DCSIGN-mediated HIV transmission) were pre-treated with different concentration of compounds, prior to exposure to HIV-1 R5 and X4 tropic strains, in the continued presence of compounds. Then BTHP1/DC-SIGN cells were co-coltured with CD4 T cells purified from healthy donors. After three days viral infection was evaluated by measuring p24 levels in co-culture supernatants. In a different protocol inhibitors were washed after pre-treatment, to evaluate duration of antiviral activity. Cytotoxicity of the compounds was evaluated by staining with 7AAD and cytofluorimetric analysis. Results: One of compounds tested, a tetravalent dendron containing four copies of a linear trimannoside mimic, was able to inhibit HIV trans infection of CD4 T lymphocytes at low micromolar range, with an IC50 of 5microM. At 100 microM the compound almost completely abrogated the transmission to CD4 T cells of HIV-1 laboratory strains or primary isolates, both R5 and X4 tropic. Notably the antiviral effect persisted up to 12 hours when the compound was removed after a 30 minutes pre-treatment. Moreover toxicity of the compound was neglectable at the highest concentration tested in infection assay. Conclusion: The tetravalent dendron presenting trimannoside mimic, in consequence of its anti-infective activity independent of viral tropism, absence of toxicity and long-lasting effect is potentially suitable for development as a vaginal microbicide.
A linear trimannoside mimic inhibits DC-SIGN mediated HIV infection by polyvalent presentation / A. Berzi, S. Sattin, M. Sanchez Navarro, J.F. Rojo, A. Bernardi, M. Clerici. - In: INFECTION. - ISSN 0300-8126. - 38:S1(2010 Jun), pp. CO13.17-CO13.17. ((Intervento presentato al 2. convegno ICAR : Italian Conference on AIDS and Retroviruses tenutosi a Brescia nel 2010.
|Titolo:||A linear trimannoside mimic inhibits DC-SIGN mediated HIV infection by polyvalent presentation|
BERZI, ANGELA MARIA VITTORIA (Primo)
SATTIN, SARA (Secondo)
BERNARDI, ANNA (Penultimo)
|Parole Chiave:||Acquired Immunodeficiency Syndrome; HIV Infections; Retroviridae; Retroviridae Infections; Humans|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore CHIM/06 - Chimica Organica
|Data di pubblicazione:||giu-2010|
|Enti collegati al convegno:||Società italiana di Malattie Infettive e Tropicali|
Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani
Istituto Superiore di Sanità
Società Italiana di Immunologia, Immunologia Clinica e Allergologia
Società Italiana di Virologia
|Appare nelle tipologie:||01 - Articolo su periodico|