Lytic granule components are required for the maintenance of HSV-1 neuronal latency (43.35)

Abstract

Abstract Using a murine model of HSV-1 corneal infection, our data suggest that secretion of CD8 T cell lytic granules (LGs), in addition to IFN-γ, is required for the maintenance of viral latency within trigeminal ganglia (TG). First, HSV-specific CD8 T cells (HSV-CD8), which recognize an immunodominant HSV-1 glycoprotein B (gB498–505) epitope, surround neurons within latently infected TG and contain functional LGs, with GrB polarizing to the contact site with these neurons. HSV-CD8 use GrB and IFN-γ to block HSV-1 reactivation from latency in a non-redundant manner in ex vivo TG cultures, possibly due to a lack of IFN-γ receptors on some latently infected neurons. Like WT mice, Pfn and GrB KO mice establish latency in the TG by 8 days post-infection (dpi) with a similar viral genome copy number, but by 14 dpi, they exhibit a transient rise in viral genome copy number not seen in WT mice suggestive of HSV-1 reactivation from latency. A similar transient rise in copy number is also seen in WT mice depleted of CD8 T cells. Further, neither endogenous CD8 T cells within Pfn KO nor exogenous HSV-CD8 from GrB KO latently infected TG maintain latency as efficiently as CD8 T cells from WT TG in ex vivo TG cultures. Based on the current lack of evidence that CD8 T cell protection leads to neuronal death, we hypothesize a non-lethal LG-mediated block in HSV-1 reactivation from latency and are currently investigating possible mechanisms of protection.