Inhibition of intra- and extra-cellular Tat function and HIV expression by pertussis toxin B-oligomer

Chiara Rizzi, Massimo Alfano, Antonella Bugatti, Maura Camozzi, Guido Poli, Marco Rusnati

Research output: Contribution to journalArticlepeer-review

Abstract

HIV-1-transactivating factor Tat contributes to virus replication and to the onset of AIDS-associated pathologies by targeting different infected and uninfected cell types. We previously demonstrated that the B-oligomer of pertussis toxin (PTX-B) inhibits HIV infection and replication in primary T cells and macrophages and Tat-dependent HIV-1 long terminal repeat (LTR) transactivation in T lymphoid Jurkat cells. Here we demonstrate that PTX-B inhibits Tat-dependent NF-κB activation and HIV-1 LTR-transactivation in non-permissive epithelial HL3T1 cells in a phosphatidylinositol 3′-kinase-dependent way. PTX-B exerts its inhibition both when Tat is produced enclogenously in transfected cells and in cells incubated with the extracellular Tat protein. In this latter case, PTX-B does not interfere with extracellular Tat uptake by cells. PTX-B inhibited also interleukin-8 secretion and virus expression stimulated in chronically infected U1 promonocytic cells by intra- and/or extracellular Tat. The genetically modified holotoxin PT-9 K/129G retains the capacity to inhibit Tat transactivating activity and HIV replication in both HIV-permissive and non-permissive cells. In conclusion, PTX-B acts as a " pleiotropic" inhibitor of Tat, and this may significantly contribute to the broad spectrum of anti-HIV-1 effects exerted by PTX-B in different cell types, and suggests PTX-B and its derivatives as prototypic for the development of anti-Tat drugs.

Original languageEnglish
Pages (from-to)530-536
Number of pages7
JournalEuropean Journal of Immunology
Volume34
Issue number2
DOIs
Publication statusPublished - Feb 2004

Keywords

  • B-oligomer of pertussis toxin
  • HIV
  • IL-8
  • Tat

ASJC Scopus subject areas

  • Immunology

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