Faculty Bibliography

This study challenges the concept that herpes simplex virus type 1 (HSV-1) latency represents a silent infection that is ignored by the host immune system, and suggests antigen-directed retention of memory CD8(+) T cells. CD8(+) T cells specific for the immunodominant gB(498-505) HSV-1 epitope are selectively retained in the ophthalmic branch of the latently infected trigeminal ganglion, where they acquire and maintain an activation phenotype and the capacity to produce IFN-gamma. Some CD8(+) T cells showed TCR polarization to junctions with neurons. A gB(498-505) peptide-specific CD8(+) T cell clone can block HSV-1 reactivation from latency in ex vivo trigeminal ganglion cultures. We conclude that CD8(+) T cells provide active surveillance of HSV-1 gene expression in latently infected sensory neurons.

Adhesion molecules located on the surface of blood-borne leukocytes permit adherence of leukocytes to the microvascular endothelium, diapedesis of leukocytes across vessel walls, formation of intimate multicell interactions, and enhanced transmembrane signal transduction. Since some leukocyte-mediated immune functions exhibit nocturnal intensification, the current study was conducted to investigate the hypothesis that expression of selected cell adhesion molecules (CAM) varies with circadian periodicity. Blood was collected from normal human donors over a 24-h period and CAM expression by monocytes, neutrophils, and lymphocytes evaluated by monoclonal antibody binding and flow cytometry. All leukocyte classes exhibited significant circadian-like variation (p < 0.05) in CD62L (L-selectin) expression. Similarly, a diurnal variation (p < 0.05) in monocyte and neutrophil CD54 (ICAM-1) was observed. Finally, neutrophils demonstrated a circadian-like variation (p < 0.05) in CD11a (LFA-1a). The rhythmic alterations in CAM expression may be clinically relevant, since changes in CAM expression have the potential to modulate the leukocyte-induced pathogenesis associated with disease progressions such as nocturnal asthma, the nighttime exacerbations of rheumatoid arthritis, and the high nocturnal incidence of cerebrovascular and cardiovascular crisis.

We recently demonstrated that CD8(+) T cells could block herpes simplex virus type 1 (HSV-1) reactivation from latency in ex vivo trigeminal ganglion (TG) cultures without destroying the infected neurons. Here we establish that CD8(+) T-cell prevention of HSV-1 reactivation from latency is mediated at least in part by gamma interferon (IFN-gamma). We demonstrate that IFN-gamma was produced in ex vivo cultures of dissociated latently infected TG by CD8(+) T cells that were present in the TG at the time of excision. Depletion of CD8(+) T cells or neutralization of IFN-gamma significantly enhanced the rate of HSV-1 reactivation from latency in TG cultures. When TG cultures were treated with acyclovir for 4 days to insure uniform latency, supplementation with recombinant IFN-gamma blocked HSV-1 reactivation in 80% of cultures when endogenous CD8(+) T cells were present and significantly reduced and delayed HSV-1 reactivation when CD8(+) T cells or CD45(+) cells were depleted from the TG cultures. The effectiveness of recombinant IFN-gamma in blocking HSV-1 reactivation was lost when its addition to TG cultures was delayed by more than 24 h after acyclovir removal. We propose that when the intrinsic ability of neurons to inhibit HSV-1 gene expression is compromised, HSV-specific CD8(+) T cells are rapidly mobilized to produce IFN-gamma and perhaps other antiviral cytokines that block the viral replication cycle and maintain the viral genome in a latent state.

Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8(+) T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8(+) T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8alpha monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8(+) T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8(+) T cells aborting virion production.