Expanding the functional CD8+ T cell repertoire reduces HSV-1 reactivation from latency in sensory ganglia

Following corneal infection, herpes simplex virus (HSV)-1 establishes latency in sensory neurons of the trigeminal ganglia (TG). In humans, spontaneous and recurrent reactivation of HSV-1 from latency has the potential to cause lesions on the gums (stomatitis), lips (cold sores, fever blisters), cornea (stromal keratitis), and brain (encephalitis). Latently infected neurons were once thought be largely ignored by the host immune system. Existing evidence shows that not only do HSV-specific CD8 T cells recognize latently infected neurons; they actively maintain viral latency using proinflammatory cytokines and lytic granules containing granzymes. The premise of this study further characterized the nature of the CD8 T cell response. Previous studies displayed that in the C57BL/6 mouse; CD8 T cells infiltrate the TG and become situated in direct apposition to infected neurons. It was known that 50 % of the CD8 T cells recognized the immunodominant epitope on glycoprotein B (gB) while the specificities of the remaining CD8 T cells were undefined. In this study, we observed that the non-gB CD8 T cell repertoire was confined to 18 epitopes on 11 viral proteins. During acute infection, these cells, similar to gB498-505-specific CD8 T cells, readily produce cytokines and release lytic granules upon stimulation. Conversely, during latency, even though these cells remain in the TG, they lose the ability to produce cytokines and release lytic granules upon stimulation suggesting functional compromise, unlike gB498-505-specific CD8 T cells. We show that the immunosuppressive cytokine, IL-10, preferentially suppresses the non-gB498-505-specific CD8 T cell population. Upon administration of an antibody against the IL-10 receptor, we see a dramatic increase in functional non-gB498-505-specific CD8 T cells without apparent effect in the gB498-505-specific CD8 T cell population. This increase in functional CD8 T cells leads to a 50% reduction in viral reactivation from latency suggesting the possibility of anti-IL10R as a treatment of recurrent reactivation of HSV-1 from latency

Herpes simplex virus and varicella zoster virus, the house guests who never leave.

Human alphaherpesviruses including herpes simplex viruses (HSV-1, HSV-2) and varicella zoster virus (VZV) establish persistent latent infection in sensory neurons for the life of the host. All three viruses have the potential to reactivate causing recurrent disease. Regardless of the homology between the different virus strains, the three viruses are characterized by varying pathologies. This review will highlight the differences in infection pattern, immune response, and pathogenesis associated with HSV-1 and VZV

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen. HSV-1 genomes persist in trigeminal ganglia neuronal nuclei as chromatinized episomes, while epithelial cells are typically killed by lytic infection. Fluctuations in anti-viral responses, broadly defined, may underlay periodic reactivations. The ganglionic immune response to HSV-1 infection includes cell-intrinsic responses in neurons, innate sensing by several cell types, and the infiltration and persistence of antigen-specific T-cells. The mechanisms specifying the contrasting fates of HSV-1 in neurons and epithelial cells may include differential genome silencing and chromatinization, dictated by variation in access of immune modulating viral tegument proteins to the cell body, and protection of neurons by autophagy. Innate responses have the capacity of recruiting additional immune c

Influence of an immunodominant herpes simplex virus type 1 CD8+ T cell epitope on the target hierarchy and function of subdominant CD8+ T cells.

Herpes simplex virus type 1 (HSV-1) latency in sensory ganglia such as trigeminal ganglia (TG) is associated with a persistent immune infiltrate that includes effector memory CD8+ T cells that can influence HSV-1 reactivation. In C57BL/6 mice, HSV-1 induces a highly skewed CD8+ T cell repertoire, in which half of CD8+ T cells (gB-CD8s) recognize a single epitope on glycoprotein B (gB498-505), while the remainder (non-gB-CD8s) recognize, in varying proportions, 19 subdominant epitopes on 12 viral proteins. The gB-CD8s remain functional in TG throughout latency, while non-gB-CD8s exhibit varying degrees of functional compromise. To understand how dominance hierarchies relate to CD8+ T cell function during latency, we characterized the TG-associated CD8+ T cells following corneal infection with a recombinant HSV-1 lacking the immunodominant gB498-505 epitope (S1L). S1L induced a numerically equivalent CD8+ T cell infiltrate in the TG that was HSV-specific, but lacked specificity for gB498-505. Instead, there was a general increase of non-gB-CD8s with specific subdominant epitopes arising to codominance. In a latent S1L infection, non-gB-CD8s in the TG showed a hierarchy targeting different epitopes at latency compared to at acute times, and these cells retained an increased functionality at latency. In a latent S1L infection, these non-gB-CD8s also display an equivalent ability to block HSV reactivation in ex vivo ganglionic cultures compared to TG infected with wild type HSV-1. These data indicate that loss of the immunodominant gB498-505 epitope alters the dominance hierarchy and reduces functional compromise of CD8+ T cells specific for subdominant HSV-1 epitopes during viral latency