Mucosal Epithelial Cells Provide the Critical Link for Dendritic Cell-mediated Amplification of HIV (45.19)

Abstract

Abstract An estimated 30-40% of all new HIV-1 infections occur in women through the vaginal mucosa even though it carries a lower transmission probability per exposure rate (1/200 - 1/2,000) than both rectal and mother to child transmission (1/10 - 1/300). Paradoxically, the mucosal epithelial cells express low to negligible levels of the HIV receptors and the mucosal tissue microenvironment is laden with numerous antiviral factors. We obtained in vitro and in vivo evidence of HIV manipulating the mucosal microenvironment to sustain and increase infection by inducing genital mucosal epithelial cells to produce thymic stromal lymphopoietin (TSLP), a cytokine known to activate DC to induce robust CD4+ T cell homeostatic expansion. We provide molecular evidence for the involvement of NFκB signaling pathway in HIV-induced TSLP expression. In rhesus macaques we observed dramatic increases in TSLP expression concurrent with increases in DC and CD4+ T cell numbers, and viral replication in the vaginal tissues within the first two weeks after vaginal SIV exposure. Our studies demonstrate that HIV-mediated TSLP production by mucosal epithelial cells is a critical trigger for DC-mediated amplification of HIV-infection in activated CD4+ T cells. The cross talk between mucosal epithelial cells and DC, mediated by HIV induced TSLP, is a novel mechanism important for AIDS pathology that should be explored for therapeutic potential.