Herpes simplex virus type 1 (HSV-1) has the ability to delay its clearance from the eye during ocular infection. Here, we show that ocular infection of mice with HSV-1 suppressed expression of the costimulatory molecule CD80 but not CD86 in the cornea. The presence of neutralizing anti-HSV-1 antibodies did not alleviate this suppression. At the cellular level, HSV-1 consistently downregulated the expression of CD80 by dendritic cells (DCs) but not by other antigen-presenting cells. Furthermore, flow cytometric analysis of HSV-1-infected corneal cells during a 7-day period reduced CD80 expression in DCs but not in B cells, macrophages, or monocytes. This suppression was associated with the presence of virus. Similar results were obtained using infected or transfected spleen cells or bone marrow-derived DCs. A combination of roscovitine treatment, transfection with immediate early genes (IE), and infection with a recombinant HSV-1 lacking the ICP22 gene shows the importance of ICP22 in downregulation of the CD80 promoter but not the CD86 promoter in vitro and in vivo. At the mechanistic level, we show that the HSV-1 immediate early gene ICP22 binds the CD80 promoter and that this interaction is required for HSV-1-mediated suppression of CD80 expression. Conversely, forced expression of CD80 by ocular infection of mice with a recombinant HSV-1 exacerbated corneal scarring in infected mice. Taken together, these studies identify ICP22-mediated suppression of CD80 expression in dendritic cells as central to delayed clearance of the virus and limitation of the cytopathological response to primary infection in the eye. IMPORTANCE HSV-1-induced eye disease is a major public health problem. Eye disease is associated closely with immune responses to the virus and is exacerbated by delayed clearance of the primary infection. The immune system relies on antigen-presenting cells of the innate immune system to activate the T cell response. We found that HSV-1 utilizes a robust and finely targeted mechanism of local immune evasion. It downregulates the expression of the costimulatory molecule CD80 but not CD86 on resident dendritic cells irrespective of the presence of anti-HSV-1 antibodies. The effect is mediated by direct binding of HSV-1 ICP22, the product of an immediate early gene of HSV-1, to the promoter of CD80. This immune evasion mechanism dampens the host immune response and, thus, reduces eye disease in ocularly infected mice. Therefore, ICP22 may be a novel inhibitor of CD80 that could be used to modulate the immune response.
PURPOSE. We previously have reported that ICP22, an immediate early gene of herpes simplex virus type 1 (HSV-1), binds to the CD80 promoter to suppress CD80 expression in antigenpresenting cells, leading to reduced T-cell function and protection. In contrast, overexpression of CD80 exacerbates corneal scarring (CS) in ocularly infected mice. In this study we tested the hypothesis that the absence of ICP22 could increase disease severity. METHODS. To test our hypothesis, BALB/c mice were ocularly infected after corneal scarification with a recombinant HSV-1 lacking the ICP22 gene with its parental wild-type (WT) virus (KOS) as a control. Virus replication in the eye, CS, angiogenesis, latency, and reactivation between ICP22 null virus and WT KOS were determined. In addition, expression of IL-2, IL-4, IFN-c, IFNa, granzyme A, granzyme B, and perforin by CD4 and CD8 T cells in corneas of infected mice on days 3, 5, 7, 10, 14, 21, and 28 postinfection were determined by flow cytometry. RESULTS. We found similar levels of eye disease and angiogenesis in mice following corneal scarification and ocular infection with the ICP22 null virus or parental WT virus despite reduced virus replication in the eye and reduced latency and reactivation in mice ocularly infected with ICP22 null virus. The similar level of eye disease in ICP22 null virus-and WT virus-infected mice correlated with expression of various proinflammatory cytokines that infiltrated the eye after HSV-1 infection. CONCLUSIONS. Our study identified a critical role for ICP22 in HSV-1 pathogenicity and suggests that HSV-1-associated CS is more dependent on host immune responses to infection than to virus replication in the eye. Thus, HSV-1 as means of survival uses ICP22 as a mechanism of immune escape that protects the host from increased pathology.
Despite dramatic advances in adjuvant therapies, patients with malignant glioma face a bleak prognosis. Because many adjuvant therapies seek to induce glioma apoptosis, strategies that lower thresholds for the induction of apoptosis may improve patient outcomes. Therefore, elucidation of the biological mechanisms that underlie resistance to current therapies is needed to develop new therapeutic strategies. Here we proposed a novel mechanism of proapoptotic effect induced by a pharmacological peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist, troglitazone, that facilitates caspase signaling in human glioma cells. Troglitazone activates protein-tyrosine phosphatase (PTP)-1B, which subsequently reduces phosphotyrosine 705 STAT3 (pY705-STAT3) via a PPAR␥-independent pathway. Reduction of pY705-STAT3 in glioma cells caused down-regulation of FLIP (FADD-like IL-1-converting enzyme-inhibitory protein) and Bcl-2. Furthermore, troglitazone induced Ser-392 phosphorylation of p53 via a PPAR␥-dependent pathway and up-regulation of Bax in a p53 wild-type glioma. When given with tumor necrosis factor-related apoptosisinducing ligand or caspase-dependent chemotherapeutic agents, such as etoposide and paclitaxel, troglitazone exhibited a synergistic effect by facilitating caspase-8/9 activities. A PPAR␥ antagonist, GW9662, did not block this effect, although a PTP inhibitor abrogated it. Knockdown of STAT3 by STAT3-small interfering RNA negated the inhibitory effect of PTP inhibitor on troglitazone, indicating that troglitazone uses a STAT3 inactivation mechanism that makes caspase-8/9 activities susceptible to cytotoxic agents in glioma cells and that PTP1B plays a critical role in the down-regulation of activated STAT3, as well as FLIP and Bcl-2. When taken with caspase-dependent anti-neoplastic agents, troglitazone may be a promising drug for use against malignant gliomas because it facilitates the caspase cascade, thereby lowering thresholds for the apoptosis induction of glioma cells.
F ollowing ocular infection with herpes simplex virus type 1 (HSV-1), the virus travels in a retrograde direction toward neuronal cell bodies and establishes latency in trigeminal ganglia (TG) of infected mice (1-3). After establishment of latency in neurons, the latency-associated transcript (LAT) is the only viral product consistently detected in abundance in infected mouse, rabbit, and human TG (4-9). LAT is important for the high, wildtype (WT) rate of in vivo spontaneous (10) and induced (4) reactivation from latency. At various times throughout the life of the latently infected individual, the latent virus spontaneously reactivates and returns to the eye in an anterograde direction (1-3). The eye disease that is broadly referred to as herpes stromal keratitis (HSK) or corneal scarring (CS) occurs mainly as the result of virus reactivation rather than primary ocular infection in humans (11-15).Neurovirulence of HSV-1 strains can influence the eye disease in ocularly infected mice (16,17). Based on neurovirulence in animal studies, HSV-1 strains can be classified into two main categories: (i) avirulent HSV-1 strains, such as strains KOS and RE, which do not kill BALB/c mice or New Zealand White (NZW) rabbits following ocular infection and do not replicate efficiently in the eye without corneal scarification, and (ii) virulent HSV-1 strains, such as McKrae and its LAT (Ϫ) -derived virus, dLAT2903, that kill ϳ80% and ϳ50% of BALB/c mice and NZW rabbits, respectively, following ocular infection (18-21) and do not require corneal scarification for efficient ocular infection. Thus, in addition to the presence of LAT, the degree of HSV-1 virulence can also influence the level of recurrence.Following ocular infection, latent HSV genomes express LAT in a portion of those neurons maintaining them, and virus can be recovered by cocultivation of ex-planted ganglia (22-24). In contrast to spontaneous reactivation in rabbits and humans, spontaneous reactivation in the murine model of ocular HSV-1 is rare (25). Previously, it was suggested that the HSV-1 genome is maintained in a quiescent state in sensory neurons during latency in mice due to the absence of detectable viral protein synthesis. However, studies from mice indicate that lytic transcripts and proteins
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