Following ocular primary herpes simplex virus type-1 (HSV-1) infection, the virus replicates in the eye and establishes latency in the trigeminal ganglia (TG). In a latently infected individual, the virus can occasionally reactivate and travel back to the eye causing recurrent disease. This reactivation from latency is the major cause of corneal scarring (CS) in HSV-1 infection of the eye. We have shown previously that the elicitation of neutralizing antibody alone can protect immunized mice from eye disease and death; however, it does not protect the immunized mice from virus replication in the eye and the establishment of latency in the TG. We therefore focused on the mechanisms by which HSV-1 may subvert the ability of the immune system to clear the virus, limit viral load, and prevent establishment of latency. We have generated compelling preliminary data that suggest the novel hypothesis that HSV-1 viral gB suppresses the host CD80 co-stimulatory molecule and that this leads to reduced CD8+ CTL activity in the eye and TG of ocularly infected mice, which in turn leads to less effective and delayed clearance of virus and susceptibility to establishment of latency. We will test this hypothesis and its corollary that provision of exogenous CD80 can reverse the negative effects of gB on ocular HSV-1 infection. We propose to: (1) Determine whether downregulation of CD80 by HSV-1 gB is responsible for the absence of a robust effector CD8+ T-cell response in the corneas and TG of ocularly infected mice during primary infection. This will include analysis of the mechanism by which gB suppresses the transcription of CD80; (2) Determine whether expression of CD80 by a recombinant HSV-1 (HSV-CD80) will compensate for the suppressive effects of HSV-1 gB leading to a significant reduction of virus replication in the corneas and TG of infected mice; and (3) Determine whether binding of expressed CD80 to PD-L1 on DCs will reduce the binding of PD-L1 to PD-1 on T cells thus leading to reduced T-cell exhaustion and improved virus clearance in the eye and TG. CLINICAL SIGNIFICANCE: HSV-1 infections are among the most frequent serious viral eye infections in the U.S. and are a major cause of viral-induced blindness. The results generated by this study will potentially establish a previously undescribed mechanism underlying viral immune evasion that could be exploited to better manage HSV infection. In light of recent failure of a large scale phase III HSV-1 vaccine trial, our approach may help design a more efficacious vaccine.
Because of the problems associated with recurrent ocular infection, reducing establishment of latency and reactivation should be a major goal of controlling ocular HSV-1 infection. We now plan to determine that increase of virus replication in the eye and higher latency-reactivation is due to suppression of CD80 and thus CD8 responses by HSV-1 glycoprotein B (gB). We also plan to reduce gB negative effect by inclusion of CD80 as a molecular adjuvant.
| Wang, Shaohui; Ljubimov, Alexander V; Jin, Ling et al. (2018) Herpes Simplex Virus 1 Latency and the Kinetics of Reactivation Are Regulated by a Complex Network of Interactions between the Herpesvirus Entry Mediator, Its Ligands (gD, BTLA, LIGHT, and CD160), and the Latency-Associated Transcript. J Virol 92: |
