The B-oligomer of pertussis toxin inhibits HIV-1 replication at multiple stages.
Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. TuOrA404)
Bukrinsky M, Alfano M, Pushkarsky T, Poli G M. Bukrinsky, The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, United States, Tel.: +1 516 562 94 38, Fax: +1 516 365 02 86, E-mail: mbukrinsky@picower.edu
Pertussis toxin (PTX) is a pentameric protein, which can be functionally divided into two (A and B) subunits. The A (active) protomer exhibits adenine diphosphate (ADP) ribosyltransferase activity responsible for ribosylation and inactivation of Gi-like proteins, whereas the role of the B (binding)-oligomer was initially perceived to be limited to binding of PTX to target cells. We now demonstrate that the B-oligomer of PTX (PTX-B) deactivates CCR5 and inhibits entry of R5 HIV-1 strains in activated primary T lymphocytes and macrophages. In addition, PTX-B also affects a post-entry step of HIV-1 replication. While PTX-B inhibited fusion induced by R5, but not by X4 envelopes, it blocked infection of T cells with recombinant HIV-1 particles pseudotyped with R5, X4, or even MLV or VSV-G envelopes. It also suppressed viral expression in U1 cells stimulated with TNF-α by reducing the levels of HIV-1-specific RNAs; however, it did not diminish TNF-α-induced activation of the cellular transcription factor NF-kB. These activities of PTX-B appear to be mediated by a signal transduction pathway originating from the PTX receptor and involving protein kinase C. Taken together, these results indicate that PTX-B inhibits entry of R5 HIV-1 strains and mRNA accumulation and replication of both R5 and X4 viruses. Therefore, B-oligomer and nontoxic derivatives of PTX may prove potent inhibitors of HIV-1 replication in vivo.
Keywords: AEGIS, Pertussis Toxin, Virus Replication, HIV-1, Leukemia Virus, Murine, Macrophages, T-Lymphocytes, Signal Transduction, NF-kappa B, Tumor Necrosis Factor, virology 000709
TuOrA404
