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Harry Matundan, Shaohui Wang, Ujjaldeep Jaggi, Jack Yu, Homayon Ghiasi; The suppressive effect of ICP22 on CD80 promoter is altered by a recombinant virus lacking CD80 binding site. Invest. Ophthalmol. Vis. Sci. 2021;62(8):419.
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We recently reported that ICP22 plays a major role in downregulating the host CD80 expression upon HSV-1 ocular infection in mice. Our previous report demonstrated that using D22 virus which has a complete deletion of full length ICP22, maintained CD80 expression and still remained virulent despite lower viral replication and ex vivo reactivation. To further study the effect of ICP22 on viral replication and disease severity, we mapped the ICP22 binding site to CD80 and constructed a mutant HSV-1 which is not binding to CD80. We now have characterized the effect of the absence of ICP22 binding to host CD80 in vitro and in vivo. expression.
To identify the binding region of ICP22 to CD80 promoter, ICP22 gene was fragmented to shorter regions and the effect of these fragments on suppression of CD80 promoter were analyzed with luciferase assay. Based on these assays, we have constructed a recombinant HSV-1 which is not binding to CD80 (KOS-ICP22Δ40). We compared KOS-ICP22Δ40 virus replication in vitro with parental control virus. Following corneal scarification, BALB/c mice were ocularly infected with 2x105 pfu/eye of KOS-ICP22Δ40 and parental viruses and primary virus replication in the eye, corneal scarring and latency-reactivation in the infected mice were determined.
Western blot analysis of 293 HEK cells infected with KOS-ICP22Δ40 virus expressed a smaller fragment of ICP22 as compared to parental virus infected cells. CD80 expression was restored in the mice infected with KOS-ICP22Δ40 virus as compared with the parental control virus. Interestingly, primary viral replication in the eye and corneal scarring was slightly reduced in KOS-ICP22Δ40 virus infected mice as compared to the parental KOS infected mice. The level of latency and reactivation remained the same in both the infected mice groups.
We have identified HSV-1 ICP22 binding site to cellular CD80 and shown that blocking this interaction using a recombinant HSV-1 lacking CD80 binding site reduced primary virus replication in the eye and eye disease but had no effect on latency-reactivation. As there is currently no effective treatment for HSV-1 recurrences, interfering with ICP22-CD80 interaction may represent a clinically effective and expedient target in developing HSV-1 therapeutics.
This is a 2021 ARVO Annual Meeting abstract.
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