Neisseria gonorrhoeae effectively blocks HIV‐1 replication by eliciting a potent TLR9‐dependent interferon‐α response from plasmacytoid dendritic cells

Summary Clinical and epidemiological research provides evidence for a positive correlation between Neis- seria gonorrhoeae infection and HIV transmission; however, mechanistic studies examining this relationship have yielded conflicting results. To explore this interaction, we exposed ex vivo cultured peripheral blood cells from acute HIV + individuals to N. gonorrhoeae. Unexpectedly, we observed a profound inhibition in HIV-1 replication in the ex vivo cultures, and this was recapitulated when peripheral blood mononuclear cells (PBMCs) from healthy donors were co-infected with HIV-1 and N. gonorrhoeae. Next, we established that gonococcal-infected PBMCs liberated a soluble factor that effectively blocked HIV-1 repli- cation. Cytokine analyses and antibody blocking experiments revealed that the type I interferon, interferon-a (IFNa), was expressed upon exposure to N. gonorrhoeae and was responsible for the inhibition of HIV-1. Intracellular staining, TLR9- blocking and cell depletion-based studies demon- strated that the IFNa was elicited by plasmacytoid dendritic cells (pDCs) in a TLR9-dependent manner. The pDC response to N. gonorrhoeae was unexpected given pDCs more established role in innate defence against intracellular pathogens, suggesting this may be a bacterial immune evasion strategy. In the context of HIV, this over- comes the virus's otherwise effective avoidance of the interferon response and represents a previ- ously unrecognized intersection between these two sexually transmitted pathogens.