D. A. Harbour

Herpes simplex virus latency

The epidemiology of herpes simplex virus (HSV) infections in man has a number of unusual features (see Whitley, this volume). In particular, the recurrent lesions (herpes labialis, herpes genitalis, and herpes keratitis) often appear at the same peripheral site, the recurrences are often precipitated by particular stimuli, e. g., fever, excess exposure to sunlight, etcetera, and serum antibodies to the virus remain constant throughout life irrespective of the frequency of recurrent disease. Moreover, during intervals of clinical normality it has proved difficult to isolate virus from peripheral tissues such as the skin where lesions are prone to occur (see Section II.B). Such observations led to the concept that recurrent herpetic disease arises from an endogenous, lifelong, “hidden” or latent infection rather than from frequent exogenous reinfection with the virus (Burnet and Williams, 1939). This “natural history” of the virus infection poses a number of fascinating questions: What tissue or tissues harbor the latent infection? How is the latent infection established and maintained? What mechanisms underlie the reactivation of latency and the production of recurrent disease? Such questions have intrigued virologists since the early part of this century but definitive answers only began to appear during the last decade. In particular, the experimental confirmation of the role of the nervous system in latent infections with HSV has prompted a number of recent excellent reviews (Stevens and Cook, 1973a,b; Docherty and Chopan, 1974; Baringer, 1975; Stevens, 1975, 1978, 1980; Klein, 1976; Longson, 1978; Wildy et al., 1982).

Trauma to the skin causes recurrence of herpes simplex in the mouse.

Mild trauma was induced in the skin of mice latently infected with herpes simplex virus type I by stripping the originally infected ear with cellophane tape. Recurrent herpes simplex developed at this site 2 to 5 days later. It was detected clinically by the development of erythema and vesicles and by the appearance of virus in the skin. On any one occasion about 30% of mice showed reactivated disease and increasing the severity of trauma did not increase this proportion. However the majority of animals developed reactivated disease on some occasions when stripping was repeated at monthly intervals. The results are discussed in relation to the skin trigger theory of reactivation of herpes simplex.

Reactivation of Herpes Simplex Virus Infection by Ultraviolet Light and Possible Involvement of Prostaglandins

Herpes simplex infection in the mouse ear was used to investigate whether various treatments would reactivate the disease. Immunosuppressive drugs failed to induce clinical signs of reactivation but irradiation of the skin of the originally infected ear with ultraviolet light or injection of prostaglandin E2 or PBSA into this site, caused reactivation of infection. This was detected by the appearance of infectious virus in the skin 2 to 3 days after these treatments. The results are discussed in relation to the mechanism of herpes reactivation in man.

Recurrent herpes simplex in the mouse: inflammation in the skin and activation of virus in the ganglia following peripheral stimulation.

The originally infected ear of mice latently infected in the cervical ganglia with herpes simplex virus (HSV) was treated with one of five stimuli: stripping with cellophane tape, irradiation with u.v. light, or the application of xylene, dimethyl sulphoxide (DMSO) or retinoic acid. Each of these stimuli induced the appearance of infectious virus in the ganglia 1 to 5 days later, most frequently after 1 to 3 days. Virus was also isolated from the treated ears, most frequently 3 to 5 days after stimulation. In a proportion of mice treated with cellophane tape stripping, xylene, retinoic acid or DMSO, clinical recurrent disease was observed, although in the case of DMSO this proportion was low. Some of the physiological changes induced in the skin by the five stimuli were studied. Treatment with DMSO, cellophane tape stripping or xylene induced almost immediate inflammation in the skin as judged by extravasation of Evans blue dye. Studies with inhibitors suggested that this was mediated by a neurogenic factor together with histamine or 5-hydroxytryptamine, or both of these. In addition, with the exception of mice treated with DMSO, the levels of prostaglandins of the E and F classes in the skin of the ear were elevated 1 to 3 days after treatment. These results are discussed with reference to the mechanisms by which recurrent herpetic disease develops.

Prostaglandins Enhance Spread of Herpes Simplex Virus in Cell Cultures

Stimuli such as u.v. light or trauma which induce recurrence of herpes simplex may act by affecting virus replication in the skin. Such stimuli release pharmacologically active agents in the skin, including prostaglandins (PGs) such as PGE2. These agents, and other compounds which alter levels of adenosine cyclic monophosphate (cyclic AMP), were tested for their effect on the replication of herpes simplex virus (HSV) in Vero cells. Prostanglandin E2 (PGE2) and prostaglandin F2alpha both increase the size of HSV plaques; PGE2 also increases the yield of virus inoculated at low m.o.i. Moreover, inhibitors of prostanglandin synthesis decrease plaque size and inhibit the growth of virus inoculated at low m.o.i.; such inhibition can be partially overcome by adding PGE2. Analysis of the results suggest that prostaglandins can enhance cell-to-cell spread of HSV, but that cyclic AMP is probably not involved in this effect.

Pathogenesis of zosteriform spread of herpes simplex virus in the mouse.

Zosteriform spread of herpes simplex virus (HSV) infection occurs after primary inoculation of the skin of both outbred and inbred mice. With HSV type 1 strain SC16 few outbred animals died if they were inoculated when 8 weeks old whereas up to 50% of animals died if inoculated when 4 weeks old. However, at either age, zosteriform spread of infection occurred in almost all animals as it did when 4-week-old outbred animals were inoculated with the avirulent strain KOS. Thus, control of zosteriform spread must act by different mechanisms from those controlling the encephalitis which leads to death. During replication in the epidermis virus enters axons and could first be found in sensory ganglia 2 days after inoculation of the skin. Thereafter, it was found in the nerve roots and in skin within the same dermatome but remote from the site of inoculation. When sensory nerves to this latter area were cut during the 4 days after primary inoculation lesions developing as a result of zosteriform spread were either completely inhibited or, with later section, decreased in incidence. Mortality was not affected by such nerve section. Latent infection must be established in neurons serving areas of skin remote from the inoculation site since with HSV-1 strain SC16, recrudescent lesions on the pinna could be induced by stripping the skin of the ear when the original inoculation had been in the skin of the neck. Such recrudescent disease was not demonstrated in animals infected with HSV-1 strain KOS even though this virus efficiently established latent infection in sensory ganglia.

Isolation of Herpes Simplex Virus from the Skin of Clinically Normal Mice During Latent Infection

Herpes simplex virus (HSV) was isolated from the ears of clinically normal, latently infected mice by culturing the skin in vitro. The results are discussed with reference to current theories of HSV latency.

Acute and recurrent herpes simplex in several strains of mice.

Acute and recurrent herpes simplex was studied after infection in the ear of two outbred and five inbred strains of mice. In all strains tested there was clinical evidence of infection, and a proportion of the mice became latently infected in the cervical ganglia. Six weeks after infection, when attempts were made to induce recurrent desease by stripping the ears of the mice with cellophange tape, a proportion of animals of each strain developed recurrent disease, characterized by erythema in the skin. At monthly intervals thereafter, the ears were stripped again and, on each occasion, a proportion of the animals developed recurrent disease, with the exception of Balb/c mice. The different reaction of Balb/c and other inbred strains might prove useful in studies on the mechanism of control of recurrent herpes simplex.

Effect of acyclovir on recurrence of herpes simplex skin lesions in mice.

Acyclovir (ACV) was effective in preventing recurrence of herpes simplex in mice whose skin was stripped with cellophane tape. Treatment with ACV did not eliminate latent herpes simplex virus from the cervical ganglia.

Latency and other Consequences of Infection of the Nervous System with Herpes Simplex Virus

Publisher Summary The phenomenon of neurotropism, first noted in laboratory animals, reflects the requirement of the virus to reach the nervous system to establish latency. In such animals, the controls, which direct the virus into the latent state, are less effective than in man and thereby, the likelihood of a destructive infection of the central nervous system is greater. As a result of this different balance a considerable proportion of experimentally infected animals suffer a productive infection of the peripheral nervous system (PNS) and central nervous system (CNS) during primary infection and recover, though carrying a latent infection. The consequences of both active and latent infection can, therefore, be studied. This chapter describes the spread of active infection through the nervous system and discusses the demyelination resulting from this spread. The chapter also describes some consequences of latent infection and its reactivation.