Respiratory syncytial virus subverts the immune response by inhibiting myeloid dendritic cell function.
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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants and young children. Antigen presentation by dendritic cells (DCs) is critical for the establishment of antiviral immunity and DCs are frequent targets of viral immune evasion. Upon activation, DCs undergo maturation during which they highly upregulate the surface expression of MHC class II, a molecule critical for the presentation of exogenous antigen to CD4+ T cells. MHC class II biosynthesis and surface expression is a multi-stage process which is controlled by a variety of positive and negative regulatory molecules. Here we show that DC exposed to RSV both in vivo and in vitro failed to elicit a mixed leukocyte reaction (MLR). Furthermore, RSV exposed DCs inhibited allogeneic proliferation from unexposed DCs in trans, in a cell contact dependent mechanism. Consistent with their impaired antigen presenting ability, both primary blood mDCs exposed in vitro to RSV and nasal mucosa mDC from RSV patients failed to upregulate MHC class II. MHC class II levels remained low despite the apparent upregulation of other markers of DC maturation such as MHC class I, CD83, CD86 and CD40. This inhibition could not be explained by the reduced bio-synthesis of MHC class II as class II transactivator (CIITA) level remained unchanged and the total cellular HLA-DR was comparable to mDCs exposed to influenza virus (FLU). Furthermore, SDS stability assay showed similar level of MHC class II peptide complex between the two viral treatments, indicating RSV exposure did not block class II loading. Consistent with the reduced surface expression, confocal microscopy demonstrated a selective blockade of MHC class II surface translocation by RSV. Blockade of class II surface translocation was dependent on viral fusion (F) protein expression. In addition, RSV induced the expression of a novel splice variant of HLA-DO, a negative regulatory molecule in the MHC class II presentation pathway. Taken together, these results demonstrate that RSV blocks DC antigen presentation by inhibiting surface class II peptide complex formation at multiple stages and suggest a novel mechanism of viral immune evasion.