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Harry Matundan, Ujjaldeep Jaggi, Shaohui Wang, Homayon Ghiasi; Suppression of CD80 in the eye by HSV-1 ICP22 plays a protective role against eye disease. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4620.
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© ARVO (1962-2015); The Authors (2016-present)
Herpes simplex virus (HSV) infection is a protracted disease that can lead to blindness. HSV has the ability to delay its clearance from the eye during ocular infection and thus evade eradication. We investigated if any specific HSV-1 gene is involved in the mechanism of local immune evasion.
The effect of ocular HSV-1 infection on expression of various genes in cornea of C57BL/6 and BALB/c mice was investigated. Mice were ocularly infected with 2x105 pfu/eye of HSV-1 strain McKrae or KOS D22 lacking ICP22. Expression of various infiltrates and genes in cornea of infected mice were determined on days 1-7, 10, 14, 21 and 28 post infection. Roscovitine treatment, transfection with immediate early (IE) genes and infection with D22 were used to assess the importance of ICP22 on the suppression of CD80 promoter by luciferase activity. Binding of ICP22 to CD80 promoter was determined by chromatin-IP analysis. Effects of ICP22 on infiltrates, corneal scarring (CS) and angiogenesis were determined. In addition, the effect of ICP22 on viral replication in the eye and time to reactivation in infected mice was characterized.
After ocular infection with HSV-1, corneal CD80 RNA expression was suppressed and presence of neutralizing anti-HSV-1 antibodies did not relieve this suppression. Flow cytometric analysis of infected splenocytes revealed suppression of CD80 in dendritic cells (DC) and B cells. Roscovitine experiments along with analysis of IE genes after infection with D22 verified that ICP22 is involved in down-regulation of CD80 promoter but not CD86 in vivo and in vitro. Conversely, infection with a recombinant expressing CD80 virus (HSV-CD80) exacerbated CS in infected mice. At a functional level, D22 enhanced levels of effector CD8 T cell population and affected infiltrates in a time-dependent fashion. Despite lower replication of D22 virus and delayed reactivation, the D22 produced CS and angiogenesis in the cornea on par with parental virus.
We show for the first time that: 1) HSV-1 suppresses expression of CD80 but not CD86 on DC following ocular infection; 2) Suppression requires local presence of infectious virus but is unaffected by anti-HSV-1 antibodies; 3) The suppression is mediated by ICP22, which binds to the CD80 promoter; 4) HSV-CD80 exacerbates CS in mice; and 5) D22 remains virulent based on CS despite poor replication and delayed reactivation time.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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