Inhibition of intra- and extra-cellular Tat function and HIV expression by pertussis toxin B-oligomer.
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 inT lymphoid Jurkat cells. Here we demonstrate that PTX-B inhibits Tat-dependent NF-kappaB 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 endogenously 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. Inconclusion, 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.
Rizzi
Chiara
C
AIDS Immunopathogenesis Unit, Department of Immunology and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
Alfano
Massimo
M
Bugatti
Antonella
A
Camozzi
Maura
M
Poli
Guido
G
Rusnati
Marco
M
D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D016325:HIV Long Terminal Repeat / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000276:immunology; D037342:Pertussis Toxin / Q000276:immunology* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus
D019743:Chemokines, CXC; D002867:Chromones; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; D016328:NF-kappa B; D054322:tat Gene Products, Human Immunodeficiency Virus; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D037342:Pertussis Toxin