313   The Binding Subunit of Pertussis Toxin Is a Potent Broad-Spectrum Inhibitor of R5 and X4 HIV-1 Replication.

M. Alfano¹, G. Vallanti¹, E. Vicenzi¹, A. Lazzarin¹, R. Rappuoli², M. Bukrinsky³, and G. Poli*¹.
¹San Raffaele Scientific Inst., Milan, Italy;²IRIS Res. Ctr., Siena, Italy; and³The Picower Inst. for Med. Res., Manhasset, NY.

Background:We have recently shown that the binding subunit of pertussis toxin (PTX-B) inhibits the entry and replication of macrophage-tropic (R5) HIV-1 strains in activated primary T lymphocytes. Furthermore, PTX-B suppressed the replication of T-cell tropic (X4) viruses at a post-entry level in the same cells (. Alfano et al., J. Exp. Med. f190:597, 1999; M. Alfano et al., J. Virol.74:8767, 2000).

Methods and Results:In the present study we demonstrate that PTX-B profoundly impairs entry and replication of the HIV-1ADA (R5), as well as of HIV pseudotyped with either murine leukemia virus or vesicular stomatitis virus envelopes in primary monocyte-derived macrophages. In addition, PTX-B strongly inhibited X4 HIV-1 replication in U937 promonocytic cells and virus expression in the U937-derived chronically infected U1 cell line stimulated with cytokines, such as tumor necrosis factor-α;(TNF-α;) and interleukin-6. Of interest, TNF-α;- mediated activation of the cellular transcription factor NF-kB was unaffected by PTX-B.

Conclusions:Therefore, PTX-B may represent a novel and potent inhibitor of HIV-1 replication to be tested for efficacy in infected individuals. In support of this proposition, the PTX mutant PT-9K/129G, which is safely administered for prevention of Bordetella pertussis infection, showed an in vitro anti-HIV profile superimposable on that of PTX-B.