TY - JOUR
T1 - Inhibition of intra- and extra-cellular Tat function and HIV expression by pertussis toxin B-oligomer
AU - Rizzi, Chiara
AU - Alfano, Massimo
AU - Bugatti, Antonella
AU - Camozzi, Maura
AU - Poli, Guido
AU - Rusnati, Marco
PY - 2004/2
Y1 - 2004/2
N2 - 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.
AB - 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.
KW - B-oligomer of pertussis toxin
KW - HIV
KW - IL-8
KW - Tat
UR - http://www.scopus.com/inward/record.url?scp=1642382920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1642382920&partnerID=8YFLogxK
U2 - 10.1002/eji.200324142
DO - 10.1002/eji.200324142
M3 - Article
C2 - 14768058
AN - SCOPUS:1642382920
VL - 34
SP - 530
EP - 536
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 2
ER -