Ocular HSV-1 is a leading cause of corneal blindness due to an infectious agent. Our long term goal is to understand how HSV-1 evades the immune response thereby enhancing latency and recurrent disease even in the face of local and systemic immunity. The antigen presenting dendritic cells (DC) play a central role in initiation and modulation of local and systemic immunity. HSV-1 can infect DC and interfere with their maturation (a process critical to DC function). This may help HSV-1 evade the host immune response. As the only HSV-1 gene abundantly transcribed at all times, LAT is a candidate, for modulating DC activity during both acute and latent infection. Preliminary studies suggest that LAT can alter DC cytokine expression. Thus, LAT can affect DC. We hypothesize here that LAT is critical for HSV-1's ability to interfere with DC maturation. We further hypothesize that HSV-1 can inhibit DC trafficking (another critical DC function), and that LAT is also critical for this viral activity. If correct, these hypotheses would reveal a novel immune evasion strategy and open new doors to novel immunotherapeutic interventions against acute and recurrent HSV-1 infections. This would lead to the development of methods to greatly alleviate suffering and loss of vision due to recurrent ocular HSV-1.
Our Specific Aims i nclude: 1. Determine if the ability of HSV-1 to interfere with DC maturation is due to LAT. In vitro and in vivo studies will be done to determine if infection of DC with HSV-1 LAT+, but not HSV-1 LAT-, will block membrane expression of MHC and co-stimulatory molecules, and inhibit HSV and non-HSV antigen presentation by DC. The ability of plasmids expressing LAT to block MHC and co-stimulatory molecule expression and inhibit antigen presentation will also be examined. 2: Determine if LAT alters DC migration. (a)Determine if LAT modulates cytokine and chemokine secretion by DC and chemokine-receptor expression on DC, all of which are involved in migratory activity of DC. (b)Determine if LAT changes the observed migratory activity of DC.
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