Salmonellosis is a major cause of morbidity in patients with the Acquired immune Deficiency Syndrome (AIDS). The results of our initial experiments demonstrate that Salmonella bacteria, as opposed to several other Gram-negative bacterial species, induce a dramatic increase in HIV replication in primary human monocytes and cell line macrophages latently with the virus. This action of Salmonella is mediated by two signals, a secreted polypeptide that induces the production of tumor necrosis factor alpha (TNFalpha) and a second signal that is delivered by bacteria that possess the ability to not only invade the macrophage, but also survive within the host cell. With the overall goal of defining the mechanism by which Salmonella induce HIV replication in HIV-infected macrophages, we propose the following specific aims: 1) To characterize the stimulatory effect of Salmonella on HIV replication in human peripheral blood monocytes; 2) To clone the gene(s) for the Salmonella-derived TNFalpha -inducer (STI); 3) To characterize the mechanism of TNFalpha induction by the Salmonella-derived TNFalpha - inducer; and 4) To determine the nature of the Salmonella signal that acts in concert with the TNFalpha - inducer to promote high level HIV production in HIV-infected U1 cells. The studies outlined in this application should provide new and important insights into the interplay between the macrophage, HIV, and Salmonella that results in enhanced replication of the virus. In addition, the results from these studies will establish a strong foundation for future studies on the signaling pathway(s) by which internalized Salmonella communicate with the cell nucleus and trigger HIV replication. In summary, the understanding of the impact of Salmonella infection on HIV replication in macrophages may provide new insights into the factors that regulate the progression of the disease process in patients infected with the virus.
| Ciacci-Woolwine, F; McDermott, P F; Mizel, S B (1999) Induction of cytokine synthesis by flagella from gram-negative bacteria may be dependent on the activation or differentiation state of human monocytes. Infect Immun 67:5176-85 |
