218: Mechanisms of lytic HSV-1 clearance during primary infection of the trigeminal ganglia

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen worldwide. HSV-1 remains lytic and resists entry into latency within neurons of the trigeminal ganglia (TG) in the absence of type I interferon (IFN). However, the immunologic mechanisms involved in clearing lytic virus in the TG during primary infection remain poorly defined. HSV-1 is able to develop progeny virus during primary infection in the TG, suggesting that the establishment of HSV-1 latency is not simply due to infection of a non-permissive neuron. To address this issue, the immune response to HSV-1 in the TG was examined in a murine model of ocular infection. Viral titer and leukocyte infiltration in TG were surveyed in bone marrow (BM) chimeras generated from C57BL/6 wildtype (WT) mice and mice deficient in the type I IFN receptor alpha chain (CD118⁻/⁻) to determine the contribution of type I IFN signaling in resident and BM-derived cells. Data show that both resident and BM-derived cells contribute to type I IFN-mediated clearance of lytic virus within the TG. Moreover, HSV-1 titers correlated inversely with infiltrating NK cells, CD8⁺ T cells and HSV-specific CD8⁺ T cells. These results were supported by the observation that gBT-I.1 TCR transgenic mice in which CD8⁺ T cells are specific for the immunodominant epitope of HSV-1 glycoprotein B have significantly less virus in the TG compared to WT following infection. CD8 T cell depletion at the site of infection showed a trend towards increased virus in the TG and systemic depletion is currently being pursued. Infection of WT and STING-deficient mouse TG in situ revealed that the innate sensing pathway critical for production of type I IFN in peripheral tissues is dispensable in the TG. Understanding the immune response to lytic HSV-1 infection in the TG is critical for rational prophylactic HSV-1 vaccine design.