Control of herpes simplex virus type 1 specific replication and transmission mechanisms in human dendritic cells

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Dendritic cells (DC) are crucial players to elicit potent antiviral immune responses since they are the only antigen-presenting cell type able to induce also naïve T-cells. The aim of this study is to explore the interplay between DC and HSV-1 to (i) characterize viral immune escape mechanisms and (ii) strategies of the host immune system to interfere with viral replication and spread. In the long run this will help to the development new antiviral strategies. Regarding host responses, we reported that HSV-1 infects immature DC (iDC) as well as mature DC (mDC) at similar efficiencies, however, the nuclear egress of viral capsids is heavily hampered in mDC, and thus full viral replication and spread is blocked in mDC. Furthermore, we observed that HSV-1 infection leads to a down-modulation of lamin A/C in iDC but not in mDC. Since lamin A/C layers are important for the intact architecture of nuclear membranes, breakdown of this layer by HSV-1 is regulated differently in iDC versus mDC. Therefore, within aim #1 of this project we will investigate the underlying mechanism of lamin A/C breakdown in iDC and in addition investigate, why HSV-1 is not able to induce lamin A/C degradation in infected mDC.Regarding viral strategies to evade immune responses, we demonstrated that degradation of the CD83 molecule from the surface of mDC is a major immune evasion mechanism for HSV-1 as well as HCMV. We investigated further details and reported that CD83 degradation occurs in a proteasome-dependent but ubiquitin-independent mechanism. This is an unusual pathway however recent studies reported evidence for ubiquitin-independent degradation mechanisms, suggesting alternative signals targeting proteins to the proteasome. Examples are FAT10, which is expressed by mDC, as well as studies describing intrinsic degradation signals making ubiquitination dispensable in specific cases. These factors will be investigated within aim #2 of this project, to identify the mode of action underlying CD83 degradation after HSV-1 infection. As mentioned above our group reported that HSV-1 as well as HCMV degrade CD83 molecules upon infection of immunogenic mDC. Degradation of CD83 finally leads to the inhibition of potent antiviral immune responses. However, regarding the structural properties of CD83 no data were available. Thus, in collaboration with Prof. Sticht and Prof. Muller, we established the 3-D structure of the extracellular domain of CD83. Due to this unique knowledge we have now the possibility to further characterize the CD83 molecule and identify the regions which are important for its biological function and for binding to its potential ligand. Therefore, since viruses target CD83 molecules, in aim #3 of this project we aim to identify the ligand for CD83. This not only allows to gain further insights into the biological function of CD83 in general, but also into the mechanism how viral mediated CD83 modulation influences antiviral immune responses.