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Spontaneous reactivation of herpes simplex virus type 1 in latently infected murine sensory ganglia - PubMed

Spontaneous reactivation of herpes simplex virus type 1 in latently infected murine sensory ganglia

Todd P Margolis et al. J Virol. 2007 Oct.

Abstract

Careful studies of mouse trigeminal ganglia (TG) latently infected with herpes simplex virus type 1 (HSV-1) indicate the presence of productive cycle viral gene products and persistent immune response, suggesting ongoing spontaneous viral reactivation in these tissues. In the present study we set out to determine whether infectious virus is present in murine TG latently infected with HSV-1 (KOS). At 37 days after ocular inoculation we found a small amount of infectious virus in ca. 6% of latently infected murine TG. Furthermore, the amount of infectious virus that we detected (PFU per viral antigen-positive neuron) was similar to that detected in acutely infected ganglia. We conclude that spontaneous reactivation of infectious HSV-1 occurs in the mouse TG and is likely the principle cause of viral protein expression in these tissues. We next examined the role of latency-associated transcript (LAT) in spontaneous ganglionic reactivation by examining ganglia latently infected with KOS dlLAT1.8, a LAT deletion virus. Through the use of immunocytochemistry we found that KOS dlLAT1.8 had a rate of spontaneous ganglionic reactivation very similar to that of HSV-1 (KOS). Studying spontaneous ganglionic reactivation of HSV in the mouse TG allows a direct study of viral reactivation from latently infected neurons without the potential confounders and complicating downstream events that accompany the study of viral reactivation by explantation or peripheral viral shedding. Since most cases of human viral shedding and reactivation are not associated with a known trigger, spontaneous ganglionic reactivation of HSV-1 may be a better model of human disease than existing models.

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Figures

FIG. 1.
FIG. 1.

Immunohistochemical staining of TG 37 days postinoculation. Four examples of HSV-1 antigen staining in “latently' infected tissue. (A) HSV-1 antigen-positive neuron. (B) HSV-1 antigen and apoptotic cellular material surrounded by inflammatory cells. (C and D) HSV-1 antigen and cellular debris in foci of inflammation. These images suggest that not only are viral proteins expressed in rare neurons of “latently” infected ganglia but also that this process is associated with cellular destruction and subsequent spread to adjacent cells (glia and white blood cells). Bar, 50 μm.

FIG. 2.
FIG. 2.

Crystal violet staining of viral plaques from TG homogenates 4 and 37 days after ocular inoculation with HSV-1. The inset is a magnified view of the single plaque from the “latently” infected mouse at 37 days p.i.

FIG. 3.
FIG. 3.

Immunostaining of viral plaques from TG homogenates 4 and 37 days after ocular inoculation with HSV-1. The inset is a magnified view of the single HSV-1 antigen-positive plaque from the “latently” infected mouse at 37 days p.i.

FIG. 4.
FIG. 4.

Confocal images of a spontaneously reactivating neuron in a latently infected mouse trigeminal ganglion. (A) Nuclear staining with TO-PRO-3-iodide. (B) Neuronal specific staining with anti-NeuN antisera. (C) Staining of productively infected neuron with HSV-1 specific antisera. (D) Merged image. Bar, 100 μm.

FIG. 5.
FIG. 5.

Immunohistochemical staining of TG 37 days after ocular inoculation with either HSV-1 KOS (left) or HSV-1 KOS dl1.8 (right). As assayed in this manner, the rate of spontaneous reactivation of these two viruses was similar. Bar, 100 μm.

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References

    1. Atanasiu, D., J. R. Kent, J. J. Gartner, and N. W. Fraser. 2006. The stable 2-kb LAT intron of herpes simplex stimulates the expression of heat shock proteins and protects cells from stress. Virol. 350:26-33. - PubMed
    1. Bloom, D. C. 2006. HSV-1 Latency and the roles of the LATs, p. 325-341. In R. M. Sandri-Goldin (ed.), Alpha herpesviruses: molecular and cellular biology. Ciaster Academic Press, Norfolk, United Kingdom.
    1. Cantin, E. M., D. R. Hinton, J. Chen, and H. Openshaw. 1995. Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1. J. Virol. 69:4898-4905. - PMC - PubMed
    1. Chen, S. H., D. A. Garber, P. A. Schaffer, D. M. Knipe, and D. M. Coen. 2000. Persistent elevated expression of cytokine transcripts in ganglia latently infected with herpes simplex virus in the absence of ganglionic replication or reactivation. Virol. 278:207-216. - PubMed
    1. Farrell, M. J., A. T. Dobson, and L. T. Feldman. 1991. Herpes simplex virus latency-associated transcript is a stable intron. Proc. Natl. Acad. Sci. USA 88:790-794. - PMC - PubMed

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