Herpes simplex virus type 1 ICP0 induces CD83 degradation in mature dendritic cells independent of its E3 ubiquitin ligase function

Abstract

Mature dendritic cells (mDCs) are the most potent antigen-presenting cells known today, as they are the only antigen-presenting cells able to induce naïve T-cells. Therefore, they play a crucial role during the induction of effective antiviral immune responses. Interestingly, the surface molecule CD83 expressed on mDCs is targeted by several viruses. As CD83 has been shown to exert co-stimulatory functions on mDCs, its downmodulation represents a viral immune escape mechanism. Mechanistically, it has been shown that herpes simplex virus type 1 infection leads to proteasomal degradation of CD83, resulting in a strongly diminished T-cell stimulatory capacity of the infected mDC. Previous data suggest that the viral immediate-early protein ICP0 (infected-cell protein 0) plays an important role in this process. In the present study, we showed that ICP0 is sufficient to induce CD83 degradation in the absence of any other viral factor. However, the mechanism of ICP0-mediated CD83 degradation is not yet understood. Here, we provide evidence that ubiquitination of lysine residues is, despite the published E3 ubiquitin ligase activity of ICP0, not necessary for CD83 degradation. This finding was underlined by the observation that expression of an ICP0 mutant lacking the E3 ubiquitin ligase domain in mDCs still induced CD83 degradation. Finally, inhibition of E1 activating enzyme using the specific inhibitor 4[4-(5-nitrofuran-2-ylmethylene)-3.5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester did not prevent CD83 degradation. Taken together, our data provide strong evidence that ICP0 alone induces CD83 degradation independent of its E3 ubiquitin ligase function and of the ubiquitin machinery.

L Particles Transmit Viral Proteins from Herpes Simplex Virus 1-Infected Mature Dendritic Cells to Uninfected Bystander Cells, Inducing CD83 Downmodulation

“…This CD83 downmodulation is not due to a secondary infection and is independent of phagocytosis. Finally, we were able to show that CD83 reduction in HSV-1-negative bystander DCs is mediated by L particles, which transmit viral proteins, including ICP0, which has previously been reported to be involved in CD83 degradation in HSV-1-infected mDCs (37,38). Therefore, here we provide for the first time evidence that during lytic replication, L particles are able to transfer important biological functions to uninfected bystander cells.…”

“…This hypothesis was supported by the finding that uninfected bystander DCs contain viral proteins, including ICP0, ICP4, and gB, but no viral transcripts. As ICP0 was shown previously to be involved in CD83 degradation (37,38), we hypothesized that, among others, ICP0 may be transmitted from infected to uninfected cells to induce CD83 degradation. Considering the detected viral proteins in uninfected DCs and the lack of capsid proteins, L particles came into focus as possible carriers of viral proteins (46).…”

“…Peripheral blood mononuclear cells (PBMCs) were isolated from different healthy donors using a Lymphoprep gradient (Nycomed Pharma AS, Oslo, Norway) as described previously (37).…”

“…These observations led to the hypothesis that ND10 domains might repress viral replication and that disruption of these structures by viral proteins might represent a strategy to overcome this repression (36). We showed earlier that during HSV-1 infection of mDCs, ICP0 induces the degradation of CD83 in a proteasome-dependent but ubiquitin-independent manner (20,37,38).…”

Oncolytic herpes simplex virus interactions with the host immune system

“…HSV activates β2 integrins in infected mature human monocyte-derived DCs, which enhances adhesion, and down-regulates expression of CCR7, which mediates CCL19 chemotaxis to lymph nodes, thereby impeding migration and T-cell activation [70]. ICP0 induces degradation of CD83, a marker of DC maturation, resulting in reduced T-cell stimulation [71]. ICP47 down-regulates MHC I-peptide presentation by blocking transporter associated with antigen presentation (TAP) in infected human cells, including cancer cells [7].…”