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

Angela Berzi, José J. Reina, Roberta Ottria, Ieva Sutkeviciute, Patrizio Antonazzo, MacArena Sanchez-Navarro, Eric Chabrol, Mara Biasin, Daria Trabattoni, Irene Cetin, Javier Rojo, Franck Fieschi, Anna Bernardi, Mario Clerici

Research output: Contribution to journalArticle

Abstract

OBJECTIVE:: Dendritic cell-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) participates in the initial stages of sexually transmitted HIV-1 infection by recognizing highly mannosylated structures presented in multiple copies on HIV-1 gp120 and promoting virus dissemination. Inhibition of HIV interaction with DC-SIGN thus represents a potential therapeutic approach for viral entry inhibition at the mucosal level. DESIGN:: Herein we evaluate the efficacy in inhibiting HIV-1 infection and the potential toxicity of a multimeric glycomimetic DC-SIGN ligand (Dendron 12). METHODS:: The ability of Dendron 12 to block HIV-1 infection was assessed in cellular and human cervical explant models. Selectivity of Dendron 12 towards DC-SIGN and langerin was evaluated by surface plasmon resonance studies. β chemokine production following stimulation with Dendron 12 was also analyzed. Toxicity of the compound was evaluated in cellular and tissue models. RESULTS:: Dendron 12 averted HIV-1 trans infection of CD4 T lymphocytes in presence of elevated viral loads and prevented HIV-1 infection of human cervical tissues, under conditions mimicking compromised epithelial integrity, by multiple clades of R5 and X4 tropic viruses. Treatment with Dendron 12 did not interfere with the activity of langerin and also significantly elicited the production of the β chemokines MIP-1α, MIP-1β and RANTES. CONCLUSION:: Dendron 12 thus inhibits HIV-1 infection by competition with binding of HIV to DC-SIGN and stimulation of β-chemokine production. Dendron 12 represents a promising lead compound for the development of anti-HIV topical microbicides.

Original languageEnglish
Pages (from-to)127-137
Number of pages11
JournalAIDS (London, England)
Volume26
Issue number2
DOIs
Publication statusPublished - Jan 14 2012

Fingerprint

HIV Infections
HIV-1
Chemokines
HIV
Viruses
Chemokine CCL5
Local Anti-Infective Agents
Surface Plasmon Resonance
dendron
DC-specific ICAM-3 grabbing nonintegrin
Cell Adhesion Molecules
Sexually Transmitted Diseases
Viral Load
Dendritic Cells
Ligands
T-Lymphocytes
Infection

Keywords

  • cervical explants
  • DC-SIGN
  • glycomimetic drugs
  • HIV
  • topical microbicides

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models. / Berzi, Angela; Reina, José J.; Ottria, Roberta; Sutkeviciute, Ieva; Antonazzo, Patrizio; Sanchez-Navarro, MacArena; Chabrol, Eric; Biasin, Mara; Trabattoni, Daria; Cetin, Irene; Rojo, Javier; Fieschi, Franck; Bernardi, Anna; Clerici, Mario.

In: AIDS (London, England), Vol. 26, No. 2, 14.01.2012, p. 127-137.

Research output: Contribution to journalArticle

Berzi, A, Reina, JJ, Ottria, R, Sutkeviciute, I, Antonazzo, P, Sanchez-Navarro, M, Chabrol, E, Biasin, M, Trabattoni, D, Cetin, I, Rojo, J, Fieschi, F, Bernardi, A & Clerici, M 2012, 'A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models', AIDS (London, England), vol. 26, no. 2, pp. 127-137. https://doi.org/10.1097/QAD.0b013e32834e1567
Berzi A, Reina JJ, Ottria R, Sutkeviciute I, Antonazzo P, Sanchez-Navarro M et al. A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models. AIDS (London, England). 2012 Jan 14;26(2):127-137. https://doi.org/10.1097/QAD.0b013e32834e1567
Berzi, Angela ; Reina, José J. ; Ottria, Roberta ; Sutkeviciute, Ieva ; Antonazzo, Patrizio ; Sanchez-Navarro, MacArena ; Chabrol, Eric ; Biasin, Mara ; Trabattoni, Daria ; Cetin, Irene ; Rojo, Javier ; Fieschi, Franck ; Bernardi, Anna ; Clerici, Mario. / A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models. In: AIDS (London, England). 2012 ; Vol. 26, No. 2. pp. 127-137.
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T1 - A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models

AU - Berzi, Angela

AU - Reina, José J.

AU - Ottria, Roberta

AU - Sutkeviciute, Ieva

AU - Antonazzo, Patrizio

AU - Sanchez-Navarro, MacArena

AU - Chabrol, Eric

AU - Biasin, Mara

AU - Trabattoni, Daria

AU - Cetin, Irene

AU - Rojo, Javier

AU - Fieschi, Franck

AU - Bernardi, Anna

AU - Clerici, Mario

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N2 - OBJECTIVE:: Dendritic cell-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) participates in the initial stages of sexually transmitted HIV-1 infection by recognizing highly mannosylated structures presented in multiple copies on HIV-1 gp120 and promoting virus dissemination. Inhibition of HIV interaction with DC-SIGN thus represents a potential therapeutic approach for viral entry inhibition at the mucosal level. DESIGN:: Herein we evaluate the efficacy in inhibiting HIV-1 infection and the potential toxicity of a multimeric glycomimetic DC-SIGN ligand (Dendron 12). METHODS:: The ability of Dendron 12 to block HIV-1 infection was assessed in cellular and human cervical explant models. Selectivity of Dendron 12 towards DC-SIGN and langerin was evaluated by surface plasmon resonance studies. β chemokine production following stimulation with Dendron 12 was also analyzed. Toxicity of the compound was evaluated in cellular and tissue models. RESULTS:: Dendron 12 averted HIV-1 trans infection of CD4 T lymphocytes in presence of elevated viral loads and prevented HIV-1 infection of human cervical tissues, under conditions mimicking compromised epithelial integrity, by multiple clades of R5 and X4 tropic viruses. Treatment with Dendron 12 did not interfere with the activity of langerin and also significantly elicited the production of the β chemokines MIP-1α, MIP-1β and RANTES. CONCLUSION:: Dendron 12 thus inhibits HIV-1 infection by competition with binding of HIV to DC-SIGN and stimulation of β-chemokine production. Dendron 12 represents a promising lead compound for the development of anti-HIV topical microbicides.

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