Monday, January 13, 2025
1/13/2025
Project Summary 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 eye infections. We have shown previously that 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 shown that HSV-1 viral ICP22 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 increased susceptibility to establishment of latency but at the same time protect host from HSV-1-induced pathology. Our published and preliminary studies identified immune response regulatory mechanisms that could be targeted to enhance the vaccine’s ability to reduce HSV-1 replication in the eye and prevent latency- reactivation. By completing these studies, we expect to identify a novel approach to generating a vaccine with both prophylactic and therapeutic applications that may control acute and latent infection without adverse effects. This will be achieved by understanding how ICP22 and CD80 coordinately regulate virus replication in the eye, eye disease, and latency-reactivation. Collectively, our Specific Aims focus on understanding mechanisms of immune escape that protect the host from increased pathology while reducing viral clearance. We propose to: (1) Determine whether blocking binding of ICP22 to the CD80 promoter will increase primary HSV-1 infection, latency-reactivation, and eye disease in ocularly infected mice; and (2) Determine whether exacerbation of CS by a recombinant HSV-1 expressing CD80 (HSV-CD80) or by viruses lacking the ICP22 suppressive effect is associated with the presence of PD-L1 but not CD28 or CTLA4. 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 trials, our approach may help design a more efficacious vaccine.
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