Infection of mature dendritic cells with herpes simplex virus type 1 dramatically reduces lymphoid chemokine-mediated migration

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Mature dendritic cells (DCs) are the most potent antigen-presenting cells within the human immune system. However, Herpes simplex virus type 1 (HSV-1) is able to interfere with DC biology and to establish latency in infected individuals. In this study, we provide new insights into the mechanism by which HSV-1 disarms DCs by the manipulation of CD83, a functionally important molecule for DC activation. Fluorescence-activated cell sorter (FACS) analyses revealed a rapid downmodulation of CD83 surface expression within 6 to 8 h after HSV-1 infection, in a manner strictly dependent on viral gene expression. Soluble CD83 enzyme-linked immunosorbent assays, together with Western blot analysis, demonstrated that CD83 rapidly disappears from the cell surface after contact with HSV-1 by a mechanism that involves protein degradation rather than shedding of CD83 from the cell surface into the medium. Infection experiments with an ICP0 deletion mutant demonstrated an important role for this viral immediate-early protein during CD83 degradation, since this particular mutant strain leads to strongly reduced CD83 degradation. This hypothesis was further strengthened by cotransfection of plasmids expressing CD83 and ICP0 into 293T cells, which led to significantly reduced accumulation of CD83. In strong contrast, transfection of plasmids expressing CD83 and a mutant ICP0 defective in its RING finger-mediated E3 ubiquitin ligase function did not reduce CD83 expression. Inhibition of the proteasome, the cellular protein degradation machinery, almost completely restored CD83 surface expression during HSV-1 infection, indicating that proteasome-mediated degradation and HSV-1 ICP0 play crucial roles in this novel viral immune escape mechanism.

“…1D). Finally, it should be noted that infection of mDCs with HSV-1 does not lead to rapid induction of apoptosis; thus, the observed effects are not a consequence of cell death (32,55).…”

Section: Resultsmentioning

confidence: 99%

Herpes Simplex Virus Type 1 Induces CD83 Degradation in Mature Dendritic Cells with Immediate-Early Kinetics via the Cellular Proteasome

Kummer

Turza

Mühl-Zürbes

et al. 2007

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“…Upon infection, 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 infection impairs DC functions, viral components responsible for this impairment have not been thoroughly investigated.…”

mentioning

confidence: 99%

“…While HSV-2 induces rapid apoptosis, HSV-1 does so with a delayed kinetics in human DCs (4,20,38). HSV-1 is also reported to interfere with functions of mature DCs (24,39). Upon infection, HSV-1 induces the degradation of CD83 but not CD80 or CD86 in mature DCs (24,25).…”

mentioning

confidence: 99%

The γ₁34.5 Protein of Herpes Simplex Virus 1 Is Required To Interfere with Dendritic Cell Maturation during Productive Infection

Jin¹,

Ma²,

Prabhakar³

et al. 2009

The ␥ 1 34.5 protein of herpes simplex virus 1 is an essential factor for viral virulence. In infected cells, this viral protein prevents the translation arrest mediated by double-stranded RNA-dependent protein kinase R. Additionally, it associates with and inhibits TANK-binding kinase 1, an essential component of Toll-like receptor-dependent and -independent pathways that activate interferon regulatory factor 3 and cytokine expression. Here, we show that ␥ 1 34.5 is required to block the maturation of conventional dendritic cells (DCs) that initiate adaptive immune responses. Unlike wild-type virus, the ␥ 1 34.5 null mutant stimulates the expression of CD86, major histocompatibility complex class II (MHC-II), and cytokines such as alpha/beta interferon in immature DCs. Viral replication in DCs inversely correlates with interferon production. These phenotypes are also mirrored in a mouse ocular infection model. Further, DCs infected with the ␥ 1 34.5 null mutant effectively activate naïve T cells whereas DCs infected with wild-type virus fail to do so. Type I interferon-neutralizing antibodies partially reverse virus-induced upregulation of CD86 and MHC-II, suggesting that ␥ 1 34.5 acts through interferon-dependent and -independent mechanisms. These data indicate that ␥ 1 34.5 is involved in the impairment of innate immunity by inhibiting both type I interferon production and DC maturation, leading to defective T-cell activation.

“…HSV-1 also induces apoptosis of DCs, whereas HSV-2 exerts this activity more rapidly (5,26,44). Further, HSV-1 perturbs mature DCs (28,45), where it induces degradation of CD83 (28,29). Moreover, HSV-1 reduces levels of chemokine receptors CCR7 and CXCR4, which impedes DC migration (45).…”

mentioning

confidence: 99%

“…Further, HSV-1 perturbs mature DCs (28,45), where it induces degradation of CD83 (28,29). Moreover, HSV-1 reduces levels of chemokine receptors CCR7 and CXCR4, which impedes DC migration (45). Therefore, the interaction of HSV and DCs is a key step that dictates the outcome of viral infection.…”

mentioning

confidence: 99%

Activation of NF-κB in CD8 ⁺ Dendritic Cells Ex Vivo by the γ ₁ 34.5 Null Mutant Correlates with Immunity against Herpes Simplex Virus 1

Jin

Yan

et al. 2012

The ␥ 1 34.5 protein of herpes simplex viruses (HSV) is essential for virulence. Accordingly, an HSV mutant lacking ␥ 1 34.5 is attenuated in vivo. Despite its vaccine potential, the mechanism by which the ␥ 1 34.5 null mutant triggers protective immunity is unknown. In this report we show that vaccination with the ␥ 1 34.5 null mutant protects against lethal challenge from wild-type virus via IB kinase in dendritic cells (DCs), which sense virus-associated molecular patterns. Unlike mock-treated DCs, DCs primed with the ␥ 1 34.5 null mutant ex vivo mediate resistance to wild-type HSV after adoptive transfer into naïve mice. Furthermore, the ␥ 1 34.5 null mutant activates IB kinase, which facilitates p65/RelA phosphorylation and nuclear translocation, resulting in DC maturation. While unable to produce infectious virus in DCs, this mutant virus expresses early and late genes. In its abortive infection, the ␥ 1 34.5 null mutant induces protective immunity more effectively in CD8 ؉ DCs than in CD8 ؊ DCs. This is mirrored by a higher level of interleukin-6 (IL-6) and IL-12 secretion by CD8 ؉ DCs than CD8 ؊ DCs. Remarkably, inhibition of p65/RelA phosphorylation or nuclear translocation in CD8 ؉ DCs disrupts protective immunity. These results suggest that engagement of the ␥ 1 34.5 null mutant with CD8 ؉ DCs elicits innate immunity to activate NF-B, which translates into protective immunity. Herpes simplex viruses (HSVs) are human pathogens responsible for a spectrum of diseases, including ocular lesions, genital herpes, and encephalitis (11). HSV infection is also a risk factor in HIV acquisition and transmission. Following infection, HSV initiates a lytic cycle in the mucosal tissues, where viral gene transcription, replication, assembly, and egress ensue. This is followed by a latency in sensory ganglia, where reactivation occurs intermittently, resulting in recurrent infections (11). In this process, HSV interacts with host cells, including dendritic cells (DCs), which capture, process, and present viral antigens. Upon maturation, DCs express high levels of costimulatory molecules. Additionally, DCs release inflammatory cytokines to induce T cell responses that restrict viral infection (1, 54, 68).DCs detect HSV through multiple pathways (22,48,50). For example, plasmacytoid DCs detect HSV through Toll-like receptor 9 (TLR9), whereas conventional DCs sense virus via TLRdependent and -independent pathways (22,32,48). It is thought that HSV proteins or RNA intermediates trigger conventional DCs (22,48). Notably, a complex consisting of HSV glycoproteins B, D, H, and L stimulates DC maturation (50). On the other hand, HSV blocks DC activities (3,26,28,52). In immature DCs, HSV type 1 (HSV-1) downregulates cell surface molecules and cytokines, impairing T cell activation (10, 26, 38, 44, 52). HSV-1 also induces apoptosis of DCs, whereas HSV-2 exerts this activity more rapidly (5, 26, 44). Further, HSV-1 perturbs mature DCs (28, 45), where it induces degradation of CD83 (28, 29). Moreover, HSV-1 reduces levels of che...