PD-L1/B7-H1 Inhibits Viral Clearance by Macrophages in HSV-1–Infected Corneas

Jeon, Seung Hyuck; Rowe, Alexander M.; Carroll, Kate; Harvey, S.; Hendricks, Robert L.

doi:10.4049/jimmunol.1700417

Cited by 25 publications

(16 citation statements)

References 28 publications

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“…We also noticed that PD-L1 was up-regulated in the epithelium and stroma of untreated mice after HSV-1 infection in consistent with previous observations (Supplementary Fig. 9) 29 . Increased local PD-L1 expression may inhibit virus clearance by immune cells highlighting the importance of direct DNA degradation by CRISPR.…”

Section: Figuresupporting

confidence: 93%

Intracorneal delivery of HSV-targeting CRISPR/Cas9 mRNA prevents herpetic stromal keratitis

Yin

Ling

Wang

et al. 2020

Preprint

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1Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious blindness. Current 2 treatments for HSV-1 do not eliminate the virus and are incapable of modulating the virus 3 reservoir. Here, we target HSV-1 genome directly using mRNA-carrying lentiviral particle 4 (mLP) that simultaneously delivers spCas9 mRNA and two viral genes-targeting gRNAs 5 (designated HSV-1-erasing lentiviral particles, HELP). We showed HELP efficiently blocked 6 HSV-1 replication in both acute and recurrent infection models, and prevented occurrence of 7 herpetic stromal keratitis (HSK). We further showed retrograde transportation of HELP from 8 corneas to trigeminal ganglia (TG) where HSV-1 established latency and found evidence of 9 HELP modulating herpes reservoir. Additionally, the potent antiviral activity of HELP was 10 also replicable in human-derived corneas. These results strongly support clinical development 11 of HELP as a new antiviral therapy and may accelerate mRNA-based CRISPR therapeutics. 12

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Section: Figuresupporting

confidence: 93%

Intracorneal delivery of HSV-targeting CRISPR/Cas9 mRNA prevents herpetic stromal keratitis

Yin

Ling

Wang

et al. 2020

Preprint

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“…Previously, we have shown that ectopic expression of CD80 by HSV-1 increased CD80 binding to PD-L1 on DCs, allowing efficient infection and lysis of infected cells (19). Recently it was reported that PD-L1 Ϫ/Ϫ mice had lower virus replication in their eyes than WT mice, suggesting that PD-L1 expression on corneal cells negatively impacts the ability of the innate immune system to clear HSV-1 from infected corneas (59). This report is in line with our results of exacerbation of CS in HSV-CD80-infected mice due to the binding of HSV-CD80 to PD-L1 in the cornea (19).…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

Matundan

Ghiasi

2019

J Virol

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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.

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“…3A). This could also be a result of sequestering PD-L1, because Jeon et al reported a negative effect of PD-L1 expression on viral clearance (62).…”

Section: Discussionmentioning

confidence: 99%

CD80 Plays a Critical Role in Increased Inflammatory Responses in Herpes Simplex Virus 1-Infected Mouse Corneas

Tormanen

Wang

Ghiasi

2020

J Virol

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We recently reported that herpes simplex virus 1 (HSV-1) infection suppresses CD80 but not CD86 expression in vitro and in vivo. This suppression required the HSV-1 ICP22 gene. We also reported that overexpression of CD80 by HSV-1 exacerbated corneal scarring in BALB/c mice. We now show that this recombinant virus (HSV-CD80) expressed high levels of CD80 both in vitro in cultured rabbit skin cells and in vivo in infected mouse corneas. CD80 protein was detected on the surface of infected cells. The virulence of the recombinant HSV-CD80 virus was similar to that of the parental strain, and the replication of HSV-CD80 was similar to that of control virus in vitro and in vivo. Transcriptome analysis detected 75 known HSV-1 genes in the corneas of mice infected with HSV-CD80 or parental virus on day 4 postinfection. Except for significantly higher CD80 expression in HSV-CD80-infected mice, levels of HSV-1 gene expression were similar in corneas from HSV-CD80-infected and parental virus-infected mice. The number of CD8+ T cells was higher, and the number of CD4+ T cells was lower, in the corneas of HSV-CD80-infected mice than in mice infected with parental virus. HSV-CD80-infected mice displayed a transient increase in dendritic cells. Transcriptome analysis revealed mild differences in dendritic cell maturation and interleukin-1 signaling pathways and increased expression of interferon-induced protein with tetratricopeptide repeats 2 (Ifit2). Together, these results suggest that increased CD80 levels promote increased CD8+ T cells, leading to exacerbated eye disease in HSV-1-infected mice. IMPORTANCE HSV-1 ocular infections are the leading cause of corneal blindness. Eye disease is the result of a prolonged immune response to the replicating virus. HSV-1, on the other hand, has evolved several mechanisms to evade clearance by the host immune system. We describe a novel mechanism of HSV-1 immune evasion via ICP22-dependent downregulation of the host T cell costimulatory molecule CD80. However, the exact role of CD80 in HSV-1 immune pathology is not clear. In this study, we show that eye disease is independent of the level of HSV-1 replication and that viral expression of CD80 has a detrimental role in corneal scarring, likely by increasing CD8+ T cell recruitment and activation.

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PD-L1/B7-H1 Inhibits Viral Clearance by Macrophages in HSV-1–Infected Corneas

Cited by 25 publications

References 28 publications

Intracorneal delivery of HSV-targeting CRISPR/Cas9 mRNA prevents herpetic stromal keratitis

Intracorneal delivery of HSV-targeting CRISPR/Cas9 mRNA prevents herpetic stromal keratitis

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

CD80 Plays a Critical Role in Increased Inflammatory Responses in Herpes Simplex Virus 1-Infected Mouse Corneas

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