081 Granzyme K: A potential mediator of psoriasis

Abstract

The propagation of HIV-1 is driven in part by cell-to-cell transmission most frequently observed in dendritic cells (DC) and their subsets -one of the earliest immune cells likely to encounter HIV-1 during acute infection at mucosal surfaces. DCs are capable of highly effective viral transfer to target CD4+ T-cells across the virological synapse, a specialised virus-induced cell junction, which enables wide-spread viral dissemination and accelerated disease progression. Our previous findings have implicated a major role for cytokines and chemokines in the infection and transmission of HIV-1 from DC subsets, though a global study of their molecular functions has yet to be completed. In this study, we screened 319 individual genes using the Human ON-TARGET plus SMARTpool cytokine & chemokine siRNA library to investigate the differential effects on HIV-1 transfer from monocyte-derived DCs (MDDC) to a CD4+ SupT1 T-lymphoblastic cell line. Using integrative, data-driven approaches we successfully identified several cytokine superfamilies with potent restrictive properties against HIV-1 trans-infection from MDDC to SupT1. The activities of these candidates were validated using three key loss-of-function assays including genetic downregulation, neutralisation by biologics and pharmacological inhibition in trans-to both SupT1 and autologous CD4+ T-cells. Disruption of specific cytokine-driven mechanisms in MDDC results in dramatic changes in the capacity for cell-to-cell transfer to CD4+ T-cells. These findings add to a growing body of evidence linking the cytokine network which will inform novel therapeutic strategies against early-stage HIV-1 infection and transmission