Herpes simplex virus latency

There are two closely related types of herpes simplex virus: type 1 (facial, HSV-1) and type 2 (genital, HSV-2). Both establish latent infections in humans, and reactivation from such infections is important to virus spread. Some details concerning latent infection by herpes simplex

Fig. 3.5 Visualization of rabies virus-infected neurons in experimentally infected animals. (a) A schematic representation of the pathogenesis of rabies in an experimentally infected laboratory animal. (b) Immunofluorescent detection of rabies virus proteins in neurons of infected animals. As described in Chapters 7 and 12, the ability of an antibody molecule to specifically combine with an antigenic protein can be visualized in the cell using the technique of immunofluorescence. The cell and the antibody bound to it are then visualized in the microscope under ultraviolet light, which causes the dye to fluoresce (a yellow-green color). The top left panel shows replication of rabies virus in a sensory nerve body in a dorsal root ganglion along the spine of an animal infected in the footpad. The bottom left panel shows the virus replicating in a neuron of the cerebellum, while the top right panel shows infected neurons in the cerebral medulla. Infection of the brain leads to the behavior changes so characteristic of rabies infections. Finally, the sensory nerve endings in the soft palate of a hamster infected with rabies virus at a peripheral site contains virus, as shown by the fluorescence in the bottom right panel. This virus can move to the saliva where it can be spread to another animal. The arrows point to selected cells showing the variation in signal intensity that is typical of infections in tissues.

virus are discussed in Chapter 17, Part IV. Different animal models demonstrate both general similarities and specific differences. These differences illuminate a major limitation of many animal models for human disease: A model often only partially reflects the actual course of disease in the natural host — in this case, in humans.

Murine models

HSV infection in the eye or the footpad of mice can lead to a localized infection with spread of virus to the CNS and then to the brain. Although some animals die, as shown in Fig. 3.6, survivors maintain a latent infection in sensory nerve ganglia. During this latent infection, no infectious virus can be recovered from nerve tissue, but if the nerve ganglia are explanted (dissected, dissociated and maintained on a feeder layer of cultured cells), virus will eventually appear and begin to replicate. This observation demonstrates both that the viral genome is intact in the latently infected neuron, and that virus is not present in infectious form until something else occurs.

This model is quite useful for the study of genetic and other parameters during establishment and maintenance of a latent infection. For example, the sensory neurons can be isolated and viral DNA can be recovered. But since mice do not clinically reactivate HSV, the physiological process of reactivation, where virus can be recovered at the site of initial infection, cannot be effectively studied in mice.

Viral genomes in dorsal root ganglia

Fig. 3.6 Analysis of the establishment and maintenance of latent HSV infections in mice. A number of mice are inoculated in the footpad, and following the symptoms of primary disease, which includes foot swelling and minor hindquarter paralysis, many mice recover. Those that do not recover have infectious virus in their CNS. The mice that recover are latently infected and no infectious virus can be detected, even with high-sensitivity measurements of nervous and other tissue. HSV genomes, but not infectious virus, can be detected in nuclei of sensory nerve dorsal root ganglia. When these ganglia are cultured with other cells that serve both as an indicator of virus replication and as a feeder layer for the neurons (i.e., explanted), a significant number demonstrate evidence of virus infection and infectious virus can be recovered, as shown on the inset graph (two separate experiments are shown, with essentially the same results).

Viral genomes in dorsal root ganglia

Survives (no virus apparent)

Rabbit models

Infection of rabbit eyes with HSV leads to localized infection and recovery. The rabbits maintain virus in their trigeminal ganglia, and viral DNA or virus or both can be recovered using methods described for the murine model. Unlike mice, rabbits spontaneously reactivate HSV and virus occasionally can be recovered from the rabbit's tear film. Further, this reactivation can be induced by iontophoresis of epinephrine with high frequency. Rabbits, because HSV can reactivate in them, are vital to the design of experiments to investigate induced reactivation, although they are more expensive to purchase and keep than mice.

Guinea pig models

Guinea pigs are favored experimental animals for the study of infection and disease because they are readily infected with many human pathogens. They are an important model for the study of HSV-2, which cannot be studied effectively in the murine and rabbit models just described.

Guinea pigs can be infected vaginally with inoculation of virus, and following a localized infection, latency can be established. As occurs in the murine and rabbit models, virus or viral DNA can be recovered from latently infected neurons (those enervating the vaginal area in this case). As in rabbits, latent infection in guinea pigs will spontaneously reactivate, and periodic examination can be used to measure reactivation rates. Unlike rabbits, however, guinea pig reactivation cannot be induced. Also, HSV-2 reactivates much more frequently than does HSV-1 in the guinea pig model; therefore, this model may be of some value in establishing the subtle genetic differences between these two types of viruses that manifest as a differential tropism for mucosa.

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