Inhibition of Langerhans cell maturation by human papillomavirus type 16: a novel role for the annexin A2 heterotetramer in immune suppression (VIR1P.961)

Abstract

Abstract Human papillomaviruses (HPV) are associated with several cancers. During its life cycle HPV16 infects the epithelial basal cells through a receptor we recently identified, the annexin A2 heterotetramer (A2t). During infection, HPV16 also interacts with Langerhans cells (LC), the antigen presenting cells of the epithelium, and induces immune suppression mediated by the HPV16 L2 minor capsid protein. Despite the importance of these virus-immune cell interactions, the specific mechanisms of HPV16 entry into LC and HPV16-induced immune suppression remain undefined. An N-terminal peptide of HPV16 L2 has been shown to specifically interact with A2t. Here, we show that incubation of human LC with this peptide blocks binding of HPV16. Inhibiting this interaction with an A2t ligand or by siRNA down-regulation of A2t, significantly decreases HPV16 internalization into LC in an L2-dependent manner. A2t is associated with inhibition of LC maturation as demonstrated through attenuated secretion of Th1-associated cytokines and decreased surface expression of MHC II on LC exposed to A2t. Conversely, small molecule inhibition of A2t prevents HPV16-induced inhibition of LC immune function as indicated by increased secretion of inflammatory cytokines and surface expression of MHC II and CD86 in HPV16 treated LC pre-exposed to A2t inhibitors. These results demonstrate that HPV16 suppresses LC maturation through an interaction with A2t, revealing a novel immune suppressive role for this protein.