2005

2005. leading to defective T-cell activation. Herpes simplex virus 1 (HSV-1) is usually a human pathogen responsible for localized mucocutaneous lesions and encephalitis (51). Following primary infection, HSV-1 establishes a latent or lytic contamination in which the computer virus interacts with host cells, which include dendritic cells (DCs), required to initiate adaptive immune responses (36). Immature DCs, which reside in almost all peripheral SOCS-1 tissues, are able to capture and process viral antigens (15). In this process, DCs migrate to LF3 lymph nodes, where they mature and LF3 present antigens to T cells. Mature DCs display high levels of major histocompatibility complex class II (MHC-II) and costimulatory molecules such as CD40, CD80, and CD86. Additionally, DCs release proinflammatory cytokines such as interleukin-12 (IL-12), tumor necrosis factor alpha, alpha interferon (IFN-), and IFN-, which promote DC maturation and activation. An important feature of functional DCs is usually to activate na?ve T cells, and myeloid submucosal and lymph node resident DCs are responsible for HSV-specific T-cell activation (2, 45, 52). Moreover, DCs play a direct role in innate antiviral immunity by secreting type I IFN. HSV-1 is usually capable of infecting both immature and mature DCs (20, 24, 34, 38, 42). A previous study suggested that HSV entry into DCs requires viral receptors HVEM and nectin-2 (42). Upon HSV contamination, plasmacytoid DCs detect viral genome through Toll-like receptor 9 (TLR9) and produce high levels of IFN- (16, 23, 30, 40). In contrast, myeloid DCs, which are major antigen-presenting cells, recognize viral components through distinct pathways, independently of TLR9 (16, 36, 40). It has been suggested previously that HSV proteins or RNA intermediates produced during viral replication trigger myeloid DCs (16, 40). Indeed, a protein complex that consists of HSV glycoproteins B, D, H, and L stimulates the expression of CD40, CD83, CD86, and cytokines in myeloid DCs (41). Hence, DCs sense HSV through TLR-dependent and -impartial mechanisms (16, 40, 41). Nevertheless, HSV replication compromises DC functions and subsequent T-cell activation (3, 20, 24, 42). HSV-1 conversation with immature DCs results in the downregulation of costimulatory molecules and cytokines (20, 34, 38, 42). While HSV-2 induces rapid apoptosis, HSV-1 does so with a delayed kinetics in human LF3 DCs (4, 20, 38). HSV-1 is also reported to interfere with functions of mature DCs (24, 39). Upon contamination, HSV-1 induces the degradation of CD83 but not CD80 or CD86 in mature DCs (24, 25). Additionally, HSV-1 reduces levels of the chemokine receptors CCR7 and CXCR4 on mature DCs and subsequently impairs DC migration to the respective chemokine ligands CCL19 and CXCL12 (39). Although HSV contamination impairs DC functions, viral components responsible for this impairment have not been thoroughly investigated. It has been suggested previously that this virion host shut-off protein (vhs) of HSV-1 contributes partially to the viral block of DC activation (43). This activity is usually thought to stem from the ability of vhs to destabilize host mRNA. Emerging evidence suggests that ICP0 perturbs the function of mature DCs, where it mediates CD83 degradation via cellular proteasomes (25). Findings from related studies LF3 show that ICP0 inhibits the induction of IFN-stimulated genes mediated by IFN regulatory factor 3 (IRF3) or IRF7 in other cell types (11, 27, 32, 33). However, the link of ICP0 activities to DC maturation remains to be established. Recently, we found that 134.5, an HSV virulence factor, associates with and inhibits TANK-binding kinase 1 (TBK1), an essential component of TLR-dependent and -independent pathways that activates IRF3 and cytokine expression (49). Interestingly, an HSV mutant lacking 134.5 stimulates MHC-II surface expression in glioblastoma cells (47). These observations raise the hypothesis that 134.5 may modulate DC maturation during HSV infection. In this study, we report that 134.5 is required to perturb DC maturation during HSV contamination, leading to impaired T-cell activation. Wild-type computer virus, but not the 134.5 null mutant, suppresses the expression of costimulatory molecules as well as cytokines in DCs. We provide evidence that this viral block of DC maturation is usually associated with reduced IFN-/ secretion. Furthermore, the expression of 134.5 inhibits DC-mediated allogeneic T-cell activation and IFN- production. IFN-neutralizing antibodies partially reverse DC maturation induced by the 134.5 null mutant. These.