A glycomimetic compound inhibits DC-sign mediated HIV infection in cellular and cervical explant models
Abstract
Data di Pubblicazione:
2011
Citazione:
A glycomimetic compound inhibits DC-sign mediated HIV infection in cellular and cervical explant models / A. Berzi, S. Sattin, J. Reina Martin, M. Sanchez-Navarro, J. Rojo, D. Trabattoni, P. Antonazzo, I. Cetin, A. Bernardi, M. Clerici. - In: INFECTION. - ISSN 0300-8126. - 39:suppl. 1(2011 Mar), pp. S11-S12. ((Intervento presentato al 3. convegno ICAR Italian Conference on AIDS and Retroviruses tenutosi a Firenze nel 2011.
Abstract:
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 DCSIGN
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
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Infection (2011) 39 (Suppl 1):S11–S91
DOI 10.1007/s15010-011-0090-z
X4-tropic HIV-1 lab strains and primary isolates to CD4 T cells at
100 lM. Notably the antiviral effect persisted up to 12 h 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-1alpha 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-
1alpha production both contribute to such activity. This compound is
potentially suitable for development as a vaginal microbicide.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Acquired Immunodeficiency Syndrome; Anti-HIV Agents; HIV Infections; Retroviridae; Animals; Humans
Elenco autori:
A. Berzi, S. Sattin, J. Reina Martin, M. Sanchez-Navarro, J. Rojo, D. Trabattoni, P. Antonazzo, I. Cetin, A. Bernardi, M. Clerici
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