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

Abstract

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.

Expression of Murine CD80 by Herpes Simplex Virus 1 in Place of Latency-Associated Transcript (LAT) Can Compensate for Latency Reactivation and Anti-apoptotic Functions of LAT

“…Thus, similar to BALB/c mice (35), overexpression of CD80 in C57BL/6 mice, which are less susceptible to eye disease, also exacerbated eye disease compared with WT virus. These results confirm our overall finding that CD80 plays a pathogenic role in the eye (34)(35)(36). Thus, in contrast to LAT, CD80 overexpression exacerbates eye disease in ocularly infected mice.…”

“…Thus, the replacement of LAT with CD80 did not affect viral replication. Similar results were obtained in BALB/c mice (34).…”

“…We have shown previously that CD80 is expressed in the corneas and TG of BALB/c mice ocularly infected with HSV-CD80 virus (34). To verify that CD80 is also expressed in the corneas and TG of C57BL/6 mice ocularly infected with HSV-CD80 virus, qRT-PCR was performed on isolated RNA as described above ( Fig.…”

“…LAT-null viruses do not establish latency as efficiently as WT viruses (18,19,31). We previously showed that BALB/c mice infected with HSV-CD80 had higher levels of latency than mice infected with the parental, LAT(Ϫ) virus (34). To determine if CD80 could rescue LAT function to establish latency, mice were ocularly infected as described above, and the gB copy number was determined in TG on day 28 p.i.…”

“…We recently showed that viral expression of CD80, a host T cell costimulatory molecule, restores latency and reactivation in a LAT-null virus (34). We also demonstrated that CD80, but not CD86, is downregulated upon HSV-1 ocular infection in mice (35).…”