Impact of Neisseria gonorrhoeae on HIV-1 Replication and Immune Cell Activity in Co-infected Peripheral Blood Mononuclear Cells

Clinical and epidemiological studies have provided a large body of evidence supporting a link between HIV and other sexually transmitted co-infections. Co-infections have been associated with promoting HIV transmission and acquisition. One of the closest studied interactions is the co-infection with N. gonorrhoeae, the etiological agent of gonorrhea, yet a clear understanding of this relationship is still elusive. Studies aimed at deciphering how N. gonorrhoeae mediates these effects have provided mixed results with some suggesting co-infection promotes HIV replication, and others suggesting the opposite. The aim of this thesis is to uncover molecular mechanisms that explain these results through in vitro co-infection studies using a combination of mixed peripheral mononuclear blood cells (PBMCs) and isolated human cell types. The results presented here demonstrate that gonococcal co-infection profoundly inhibits HIV replication in co-infected PBMCs. This inhibition is due to both the release of anti-HIV IFN via TLR9-mediated activation of plasmacytoid dendritic cells (pDCs), and the activation of  T cells. In addition, I show that responses between CD4+ T cell lines, such as the Jurkat cell line, and primary CD4+ T cells can differ, which may explain some of the contrasting results seen in published literature. The results in this thesis have implications for understanding the relationship between gonococci and HIV, providing new insight into molecular and immunological interactions that influence viral transmission, and reveal new opportunities to combat HIV.Ph