Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

Epidemiological studies have clearly demonstrated that gonorrhea increases transmission of HIV-1, likely due to a combination of its propensity to increase viral replication by infected white blood cells and due to its ability to directly affect those immune responses that normally combat HIV-1 infection. Given the frequency of gonorrhea on a global scale (>100 million new infections/year), and the high potential for co-infection with HIV-1, the impact of gonorrhea on the HIV-1 pandemic is potentially enormous. For example, researchers predict that up to 26% of new HIV infections detected in a Baltimore sexually transmitted disease clinic would be averted if Neisseria gonorrhoeae could be eradicated, and estimates as high as 44% reduction have been proposed in Africa. Remarkably, the molecular processes that mediate this relationship remain almost completely uncharacterized. Recently, we have shown that a small metabolite actively shed by N. gonorrhoeae stimulates HIV replication from co-infected CD4+ T cells. This is not a general effect of bacteria, since the enhanced HIV replication is apparent when HIV-infected T cells are exposed to N. gonorrhoeae, yet no similar effect is apparent in response to non-neisserial bacteria. While this metabolite has not previously been recognized to influence the immune response, we have observed that it is actually recognized as a danger signal by certain white blood cells, prompting them to trigger an inflammatory response. Our research plan aims to reveal how white blood cells detect this danger signal, and why this enhances the spread of HIV. Once complete, our findings will explain the deadly molecular synergy between these two important human pathogens, and will provide us with a new pathway by which to interfere with both gonorrhea and HIV replication within the human cells.