maurice m.b. - postgraduate medical journal · richard doerr of basle. he was satisfied that...

Postgraduate Medical Journal (September 1978) 54, 603-612

Persistence in herpes simplex virus infections

MAURICE LONGSONB.Sc. (Hons Physiol.), M.D., M.B. Ch.B.

North Manchester Regional Virus Laboratory, Manchester M13 9WL

SummaryDiseases of man caused by the virus of herpes simplexfall into two broad categories. The primary diseaseoccurs only once in any individual's life and is causedby transmission of virus from an already infectedhuman. Thereafter, the individual may be subjectto recurrent herpetic disease, the manifestationsof which are different from the primary disease.Recurrent disease varies in severity from trivial,to incapacitating and frankly lethal (as in diseasesresulting from the virus's neurotropic and oncogenicproperties). The source of the virus in recurrentherpetic disease has never been conclusively resolved,but is almost certainly endogenous to the patient.Theories, case reports and experiments exist to showthat endogenous virus may, in periods of clinicalquiescence, be latent (or persistent) at the site ofthe recurrent lesions itself, or more remotely in nervetissues related to the site of recurrence.

IntroductionWhen in the late 19th century Vidal (1873) experi-

mented with the lesions of herpes simplex and pro-duced metastatic vesicles by the re-inoculation ofherpetic material into a different anatomical site, heproved that the disease was infectious and demon-strated that an exogenous agent could cause lesionsin the (presumably) already immune individual. Thiswas to be only the first of a whole series of conun-drums presented by the virus of herpes simplex.The problems were underlined when Andrews andCarmichael (1930) found that subjects frequentlyvictims to recurrent cold sores, possessed a signifi-cant level of specific neutralizing antibody. Thisfinding was at odds with established dogma whichheld that specific antibody, once acquired, normallyconferred immunity against further infection. Simi-larly, and much more sinistrously, Leider et al.(1965) noted that fatal herpes virus encephalitisfrequently manifested itself in patients who clearlywere not experiencing their first assault by thevirus.Perhaps the first virologist seriously to worry

about the recurrent nature of herpes simplex wasRichard Doerr of Basle. He was satisfied that re-currences could not be explained on the basis of

exogenous re-infection, and he was forced to theconclusion that the virus arose de novo at eachrecurrence,'. . . it [herpes] is endogenously generatedin the human organism' (Doerr, 1938).Now, 100 years after Vidal, an understanding of

the true mechanism of recurrence in herpes simplexis perhaps within reach and this review will considerthe available information.

The problemDisease in man caused by herpesvirus simplex

(HSV) can be broadly classified into two typesaccording to epidemiological and clinical criteria.The first type, or primary disease, occurs in in-dividuals who are experiencing their first encounterwith the virus and who have no pre-existing im-munity. The clinical pattern of the diseases causedis well documented elsewhere (Longson, 1970;Juel-Jensen and MacCallum, 1972) and includesneonatal herpes, acute gingivostomatitis, keratitis,eczema herpeticum, genital herpes and perhapsCNS infection. In the majority of individuals,however, primary infection is very mild or evensub-clinical. Whether severe or mild, primary herpeticinfection is often associated with dissemination ofthe virus and a viraemia is a common feature(Ruchman and Dodd, 1950; Longson, 1970). Thedisease usually occurs in childhood and induces aprompt immunological (cellular and humoral)response.By the age of 35 years, some 90Vo of the general

population, especially in urban communities, willhave been infected and thereafter about 50°. of theaffected subjects will experience diseases of thesecond type, the recurrent episodes, characterizedby repeated recrudescences of circumscribed areasof herpetic vesiculation around the mouth or genitals,or on the cornea or elsewhere on the skin. Theseepisodes are usually strictly limited in time andusually recur at exactly the same site on eachoccasion; there is rarely a viraemia, and dissemi-nation of virus is not a feature. They are 'triggered'by a non-specific stimulus such as pyrexia (Carpenter,Boak and Warren, 1940), sunlight (Wheeler, 1975),menstruation (Scott, 1957), or psychological stress(Schneck, 1947). Occasionally recrudescences can

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be severe and extensive, they can cause severe mor-

bidity and may even threaten life (Longson, 1970;Juel-Jensen and MacCallum, 1972). Recurrence ofHSV disease can be the cause of fatal brain necrosis(Longson, 1973), it is a serious problem duringconvalescence following graft surgery (Mont-gomerie et al., 1969) and may be associated withmalignant tumours (Wyburn-Mason, 1957; Roizmanand Frenkel, 1976).

In recurrent herpetic disease (excluding neoplasm)the involvement of HSV is not in doubt; it can bereadily isolated from appropriate clinical specimens.The source of the virus is, however, difficult todetermine. In theory, it may be exogenous, or endo-genous. Ifexogenous, it may be 'caught' from anotherpatient, or it may be auto-inoculated at the site of thelesion from a focus of chronic infection elsewhere inthe same patient. If endogenous, it is believe to bechronically present, either in the affected tissue itselfor in cells in close anatomical proximity to the site ofthe lesion.Even if it can be shown that the source of the re-

current infection lies in a focus of chronic infection,a further problem will arise when the state of thevirus during periods of clinical remission is con-

sidered. Either it will be present as a sub-clinicalproductive, or persistent, infection and will demon-strate (? slow) replication but with no, or onlyminimal, damage to the host cell, or it will be re-

vealed as a non-productive latent infection in whichvirus multiplication is temporarily halted in a

manner comparable to the lysogenic phase of phageinfection of bacteria. These two possibilities cor-

respond to Roizman's (1965) hypothesis of a

dynamic and a static state for virus persistence. Thestatic or latent infection hypothesis suggests thatthe virus genome in some way integrates with, or

sequestrates in the supporting host cell.

Exogenous infectionThere is little doubt that immune individuals are

susceptible to the inoculation of exogenous virus,as witnessed by Vidal's (1873) early experiments,and by the remarkable documentation of no lessthan 400 human experiments 50 years ago in France(Tessier, Gastinel and Reilly, 1926). Indeed, theinoculation of vesicle fluid into the forearm skin andthe production of 'takes' was once an acceptedtherapeutic measure (Paulian, 1932; Hruszek,1933; Lazar, 1956; Goldman, 1961) and the litera-ture abounds with examples of similar experiencein laboratory animals. Naturally occurring exo-

genous infections include some cases of traumaticherpes, including herpetic whitlows (Stern et al.,1959; Davies and Longson, 1970) and herpesgladiatorum (Porter and Baughman, 1965; Wheelerand Cabaniss, 1965).

It is true that man may excrete infectious virus forlong periods in saliva, tears, or genital secretions,even in the absence of clinical signs (Douglas andCouch, 1970; Kaufman, Brown and Ellison, 1968;Nahmias et al., 1976) but there is no evidence tosuggest that these fluids are the cause of recrude-scent vesicles. One of the most characteristic featuresof recurrent herpes in each individual patient is theconstancy of the anatomical site of the recrudescence,be it on the lips, eye, skin or genitals. It is difficult toconceive how inoculation of exogenous virus couldexplain this phenomenon. The exogenous virustheory cannot be adequately reconciled with welldocumented 'triggers', nor with the anatomicalconstancy of the disease (Nahmias and Roizman,1973; Epstein, 1976). Whereas infected secretionsare certainly the cause of primary infection in sus-ceptible non-immune contacts, they can hardly beheld responsible for the vast majority of recurrentepisodes.

Endogenous infectionIf HSV involved in herpetic recrudescence does

not come from 'without', it presumably arises withinthe lesion itself, or within an anatomical structure inclose contiguity with the tissue involved. Such amechanism would go a long way to explain theclinical features of the disease.

Persistence ofHSV infection in superficial tissuesThe most obvious site for such an endogenous

focus of chronic infection would be the site of therecurrent lesion itself. Some support for this sug-gestion is provided by the asymptomatic excretionof virus in many human salivas (Douglas and Couch,1970), tears (Kaufman et al., 1968) and genitalspecimens (Josey, Nahmias and Naib, 1968; Centi-fanto et al., 1972) and by experimental work inanimals.

Generally speaking, the results of experiments inanimals such as mice, rabbits, guinea-pigs andCebus monkeys are contradictory, but all evidenceof virus activity usually disappears from a primarylesion six to ten days after inoculation of the virusand after healing has occurred (Wildy, 1967; Cookand Stevens, 1973; Walz et al., 1977). This gener-alization appears to be valid whether a search ismade for infectious virus or for latent virus.Exceptions to the rule are few, but have beenreported in some well known models, such asthe rabbit eye (Kaufman, Brown and Ellison, 1967).Here chronic periocular infection of the lacrimaland Hardner's glands, with intermittent sheddingof HSV for periods of up to 3 years, would appearto be the origin of recurrent cuniculine keratitis.There are similar results with genital herpes infectionin mice (Walz et al., 1977) and guinea-pigs (Scriba,

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Persistence in herpes simplex infections

1976). The anatomical relationships of genital organsare however compleX and it could be that latentvirus recovered from genital tissues was in actualfact harboured in autonomic nerve tissue associatedwith the myometrium. On the other hand, Scriba(1977) has very recently reported that she can findHSV in the foot pads of guinea-pigs up to 7 monthsafter infection, at times when they do not show anyclinical sign of recurrent disease.

Discredit for the suggestion that the site of latencyor persistence might be skin or mucous membrane,comes mainly from experiments in man. Notwith-standing many attempts made over a quarter of acentury, no evidence has accrued to suggest theconcept that recurrent herpes arises from viruspermanently harboured in underlying tissue. Therehave been frequent attempts to isolate HSV duringperiods of remission from recurrently infected areasof skin, but with invariable failure (Findlay andMacCallum, 1940; Anderson and Hamilton, 1949;Coriell, 1963; Rustigian et al., 1966). Others(Stalder and Zurukzoglu, 1936) have transplantedskin from foci of recurrent herpes labialis to distantsites in the same patient. In these experiments, therecipient sites have not manifested herpetic lesions,whereas recurrent vesicles have continued to appearon the face, at the donor site. A somewhat similarexperience was reported by Nicolau and Poincloux(1928), in the attempted surgical treatment of arecurrent herpetic whitlow. Wheeler (1975) hasunderlined the limitations of these old reports andhas considered them to be 'hardly conclusive', butBaringer (1975a) re-examined the report by Rusti-gian et al. (1966) and concluded that the methodo-logy would have been sufficient to yield latent HSV,had it been present.Although some commentators (Carton and Kil-

bourne, 1952; Sabin, 1975) argue that latent orpersistent HSV is probably harboured in skin ormucous membrane, at this stage the possibility mustbe considered unproved. The idea cannot howeverbe discarded and certainly merits further investiga-tion (Hoyt and Billson, 1976).

Clinical evidence for HS V persistence in nerve tissueof maniThe punctual development of herpes simplex as

a complication of the invasive treatment of trige-minal neuralgia, is such a commonplace feature ofneurosurgical practice, that nowadays it barelyeven evokes comment. Yet, this must surely be oneof the most striking and thought-provoking pheno-mena in all clinical virology. First documented somefifty years ago by Cushing (1904), and subsequentlystudied in detail by Carton and Kilbourne (1952) andby Ellison, Carton and Rose, (1959), the syndrome iswell described by Paine (1964) by Stevens (1975) and

by Baringei (1975a). In brief, therapeutic section ofthe sensory roots of the semilunar (trigeminal)ganglion is regularly followed by the development,3 or 4 days later, of herpes simplex around the mouthor nose, on the anaesthetized side. The eye is onlyvery rarely involved; vesicles sometimes appear onthe contralateral side. Division of one or other ofthe branches of the trigeminal nerve itself is neverassociated with ipsilateral lesions, and injection ofalcohol into the ganglion itself, prevents the induc-tion of vesicles by surgical rhizotomy. Surgically-induced herpetic recrudescences heal normally, andpatients are not subsequently inordinately proneto further attacks. Cushing (1905) knew nothingabout the viral aetiology of herpes simplex, but wasimpressed by his observations and suggested thatposterior root ganglia were responsible for the com-mon forms of herpes simplex. Paine (1964) empha-sized that the surgical trigger only operated if thetrigeminal ganglion and the peripheral divisions ofthe fifth nerve were intact. Although Carton andKilbourne (1952) and Sabin (1975) used the evidenceto support the hypothesis of HSV latency or per-sistence at skin or mucous membrane level, mostcommentators have taken the opposite view andheld that neurosurgical experience pointed to viruslatency in the semilunar ganglion itself (Paine,1964; Klein, 1976; Bierman, 1976). However, arecent report of recurrent herpes simplex in patientswith total fifth nerve avulsion caused by severefacial injury, has cast doubt on this and the wholequestion must be left open (Hoyt and Billson,1976).Boyd (1976) has made the very pertinent observa-

tion that recurrent herpes simplex does not have thecharacteristic distribution which, in the manner ofzoster, can easily be associated with neurogenicdisease. This is clearly a serious objection to theposterior root ganglion model, nevertheless it isimportant to note that HSV disease can (albeitinfrequently) present in a zosteriform way, and whenit does the dermatomes of predilection are those oftrigeminal nerve and of the sacral nerves (herpesglutealis) (Slavin and Ferguson, 1950; Behrman andKnight, 1954; Longson, 1970). In this form of recur-rent herpes simplex, pain is a constant feature, andthere may be permanent sensory loss (Krohel,Richardson and Farrell, 1976). One wonders whythis form of the disease is not seen more fre-quently.The model based on the semilunar ganglion

hypothesis can be summarized as follows. Uponprimary infection, HSV multiplies in and around thesite of inoculation (mouth, eye or genitals) and dis-seminates elsewhere. It spreads along the localsensory nerve (Goodpasture, 1929; Johnson, 1964;Wildy, 1967; Cook and Stevens, 1973) to reach the

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posterior root ganglion. Here it establishes a life-long latent or persistent infection which survives,even when the primary infection has healed. Fol-lowing reactivation by surgical intervention, or byany one of the other well known 'triggers', the virustravels peripherally down the nerve, reaches theskin, where it produces a vesicular eruption. Hilland Blyth (1976) have argued about a possible'ganglion trigger' or 'a skin trigger' mechanism, butdo not disagree with the basic hypothesis. Thecharacteristic anatomical distribution of recrude-scences can be explained on the basis that they arelimited to the dermatomes innervated by neuroneswhich were originally selectively infected by virtueof the site of the primary infection.

It is necessary at this point briefly to digress anddescribe one or two aspects of laboratory techniques.The presence of a virus in a tissue can be determinedby methods which involve molecular (e.g. nucleicacid hybridization), immunological (e.g. immuno-fluorescence), ultramorphological or infectivity tech-niques. All have been used in the study of persistentor latent HSV infection, in both man and animals.A tissue acutely (or productively) infected by HSVreadily yields its virus if it is tested by any one ofthe four approaches. Most importantly, infectiousvirus will be easily recoverable, in 2-8 days, by asimple culture of homogenates obtained by grindingof the tissue. However, as infection subsides andthe tissue heals, the virus becomes progressively moreand more difficult to find and soon all tests arefound to be negative. The virus is now undetectableby electron microscopy, immunofluorescence, DNAhybridization or by the normal culture of homo-genized tissue extracts. If the virus is still presentin the tissue, it must be latent or masked andin a non-productive, or almost non-productive,state.

In recent years, a refinement in methodology hasled to the exciting revelation that latent HSV canbe unmasked and stimulated into a productiveinfection by explant culture, or co-cultivation, of afragment of the tissue which harbours it. A latentlyinfected tissue will resist all attempts to culture HSVfrom homogenized tissue extracts, but will yield toco-cultivation of its intact cells with a HSV-sensi-tive cell line, or to maintenance as an in vitro ex-plant. Using either of these techniques, infectiousvirus can be obtained from a latently infected tissuein 3-8 weeks (Stevens and Cook, 1971; Plummer,1973; Stevens, 1975; Baringer, 1975a).Although co-cultivation methods tell us nothing

about the state of the virus in HSV latency, it hasprovided virologists with a powerful tool for theinvestigation of the site of this latency. It has beenused to verify the suggestion that the trigeminal andother posterior root ganglia might harbour the

latent infection in m-in, and in elegant demon-strations of similar phenomena in experimentalanimals.

Laboratory evidence for HSV persistence in nervetissue in manHarvey Cushing's suggestion that the semilunar

ganglion might be the source of herpes simplex, wascorroborated by Howard's (1903) morbid anatomicalobservations of neuronal changes in the posteriorroot ganglia innervating areas of active herpessimplex in patients having died as a result ofpneumonia. It is a pity that this work has never beenconfirmed, but Baringer (1975a) has explainedperhaps why.this work has never been confirmed, but Baringer(1975a) has explained perhaps why.

Stimulated by the works of Plummer et al. (1970)and of Stevens and Cook (1971), various workershave used co-cultivation or explant culture techniqueto recover HSV from human posterior root ganglia,usually with conspicuous success (Bastian et al.,1972; Rodda, Jack and White, 1973; Plummer,1973; Baringer and Swoveland, 1973). Thus,Baringer (1975b) reported latent virus in 41%(31/76) of trigeminal ganglia, 11% (5/46) sacralganglia and 3°/O (1/34) of thoracic ganglia, all re-moved from unselected cadavers undergoing post-mortem less than 24 hr from the time of death.As Baringer (1975a) himself emphasized, there hasbeen little correlation between the presence of latentvirus in nerve tissue and any history of recurrentherpes simplex, but if Hill and Blyth (1976) are cor-rect in postulating a 'skin trigger' mechanism, this isperhaps not important. The chronic 'herpeticker'may be distinguished from his more fortunate fellowmen, not by differences at the seat of virus latency,but by differences operating at the periphery.

Experimental evidence for HSV persistence in nervetissueThe so called 'virological misadventure' which,

many years ago, incriminated HSV in the aetiologyof encephalitis lethargica (Van Rooyen and Rhodes,1948), was in fact a remarkable stimulus for muchimaginative experimental work, particularly inrabbits. Many of these experiments (Doerr andVochting, 1920; Goodpasture and Teague, 1923;Marinesco and Draganesco, 1923; Good andCampbell, 1948; Field, 1952; Schmidt and Ras-mussen, 1960) are directly relevant to the presentdiscussion and often go to show that there is littlenew in the world. The original articles, or thewritings of previous reviewers, should be consulted(Van Rooyen and Rhodes, 1948; Paine, 1964;Stevens, 1975; Baringer, 1975a; Wheeler, 1975;Epstein, 1976).

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FIG. 1. Diagrammatic representation of a myelinated sensory nerve, to show possible routesof virus spread to and from a dorsal root ganglion such as the trigeminal ganglion (adaptedfrom Baringer, 1975a).

Virus may be transported passively in the cytoplasm of the axon (D), or it may infect aSchwann cell and replicate in its nucleus (E). Therefrom it will spread from Schwann cell toSchwann cell until it infects a satellite cell before entering the neuronal soma (B). Anotherpathway may involve the perineural space (H) or supporting fibroblasts (F). The virus couldalso be spread via the perineural lymphatics (G) or blood vessels, either passively or by infectiveinvolvement of endothelial cells. (A) Satellite cell, (C) Neurone nucleus.

There have been repeated attempts to establishthe pathway(s) by which HSV might travel from thesite of primary inoculation, to its putative per-manent home in a posterior root ganglion (Johnson,1964; Wildy, 1967; Severin and White, 1968;Baringer and Griffith, 1970). It is established that inmice and rabbits, HSV spreads via peripheral nerves,probably to the exclusion of any other route. Withina nerve trunk it is not certain whether the virustravels through the axon, the perineural space, theperineural lymphatics or whether it 'leap frogs'from Schwann cell to Schwann cell to satellite cell(see Fig. 1). and the evidence is confusing becauseit appears to depend on the technical methods usedto reveal the virus (Johnson, 1965; Cook andStevens, 1973). Current opinion now favours viruscarriage by some form of transport mechanism(probably provided by the endoplasmic reticulum)within the axon itself (Hill, Field and Roome, 1972;Baringer and Swoveland, 1974). The evidence iscarefully argued by Stevens (1975) and by Baringer(1975a), but it is of more than passing interest tonote that HSV replicates exclusively in the nucleusof its host cell and, if it is carried in the axon of anerve cell, the relevant nucleus is in the neuronalsoma which (in the case of a sensory nerve) lies in

the posterior root ganglion - a long, long way fromthe site of virus inoculation. Notwithstanding thiswell established argument against the axonal trans-port of HSV, there is no a priori reason why thevirion should not join the movement of cell organelleswhich are known to travel up and down in an axonalflow of cytoplasm (Cook and Stevens, 1973).

Co-cultivation (or the culture of explants) ofposterior root ganglia from mice (Stevens and Cook,1971), rabbits (Baringer and Swoveland, 1974), Cebusmonkeys (Reeves et al., 1976) and guinea-pigs(Tenser and Hsiung, 1977), infected with HSV at aperipheral site many weeks or months before theextirpation of the specimen, has confirmed thepresence of latent virus in exactly the same way as inman. Similar results have been obtained in the caseof both trigeminal (Nesburn et al., 1976) and spinalganglia (Prince et al., 1975), and in the brain stem(Knotts, Cook and Stevens, 1973).The neurotropism of HSV would appear to

be substantial. Even if the virus is injected intra-venously, the virus appears to establish a latentinfection exclusively in nerve tissue. Followinginjection of HSV into the tail vein, Cook andStevens (1976) found that the viraemia producedwidespread dissemination of the virus, and many

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animals died. But, in survivors, once recovery wasestablished the only site for latency appeared to bethe spinal ganglia. Occasionally they demonstratedlatency in other areas of the CNS and autonomicnervous system, but they never revealed it in anyother type of tissue or organ.

Ganglia are of course complex anatomicalstructures, and none of the experiments describedin any way pinpoints the actual cell type involved inHSV latency - neurone, satellite cell, or fibroblast -but the evidence incriminating the nerve cell itself issubstantial. There is not only the obvious neuro-tropism of the virus, but there are the results ofultra-morphological studies of ganglia during theactive phase of the illness, before the establishmentof latency. In all cases, mature HSV virions arerevealed in neurones only. In contrast to this, virusreplication in Schwann and satellite cells appears tobe abortive, with evidence of a striking defect in theenvelopment of nucleocapsids, and a high propor-tion of empty particles (Hill, Field and Roome,1972; Hill and Field, 1973; Cook and Stevens,1973). This suggests that of all cells, neurones areselectively capable of supporting the assembly ofmature intact virions. Once latency has been estab-lished, and release of infectious virus has ceased,virus particles can no longer be seen in any cell.But, even in latently infected ganglia, careful elec-tron microscopic search will reveal occasionalneurones containing very scattered envelopedherpesvirus nucleocapsids (Baringer and Swoveland,1974). These neurones themselves are obviously nolonger latently infected, in that they are activelyproducing virus, but even so the nerve cells appear tobe the only cell type in the ganglion to contain anyevidence of such virus activity. In certain experi-mental situations, it is possible to re-activate HSVin latently infected ganglia. In one of these studies,Cook, Bastone and Stevens (1974) monitored theactual appearance of HSV antigens and of viralDNA, and concluded that both appeared in neuroneslong before any other cell type became involved.

On the experimental reactivation of herpes simplexVery occasionally, animals 'cured' from an

experimental herpetic infection, will spontaneouslyreactivate and shed virus, with or without clinicallesions or illness (Perdrau, 1938; Schmidt and Ras-mussen, 1960; Nesburn, Elliot and Leibowitz, 1967).In other situations, reactivations are not spon-taneous, but can be provoked by varied stimuli suchas anaphylactic shock (Good and Campbell, 1948),the injection of adrenaline (Schmidt and Rasmussen,1960; Laibson and Kibrick, 1966), steroids (Under-wood and Weed, 1974) or of prostaglandins (Blythet al., 1976), exposure to ultra-violet light (Blythet al. (1976), mechanical stimulation of the semilunar

ganglion (Nesburn et al., 1977) and epilation (Hurdand Robinson, 1977). The models will undoubtedlyserve for a better understanding of the nature ofHSV latency and reactivation, but do not for themoment shed very much more light on the mech-anisms involved. Three or four reports are howeverworthy of particular mention. These describe experi-ments in animals where it is known that the dorsalroot ganglia were latently infected by earlier peri-pheral inoculation of virus.

In mice, Stevens and Cook (1973) had been quiteunable to provoke recrudescence by a whole seriesof insults, including fever, steroids, cytophosph-amide, graft versus host reaction, etc., but two yearslater reported (Stevens, Cook and Jordan, 1975) thatwithin 24-48 hr, experimental Streptococcus pneu-moniae pneumonia led to the release of infectiousHSV from spinal ganglia and the appearance ofviral DNA in neurones. A few days later virusappeared in the roots and nerves associated withthese ganglia. The association of herpes febrilis withpneumococcal pneumonia in man is, of course, wellknown (Griesinger, 1857) and the mouse model isof interest, especially because Stevens and hiscolleagues claimed, on the basis of controlledexperiments, that the pneumococcus had had adistinct role in the phenomenon. Interestingly how-ever, in contrast to what happens in man, there wasno induction of skin lesions and no virus shedding orlatent virus at skin level. In this context, the 'skintrigger' theory proposed by Hill and Blyth (1976)is certainly most pertinent and will be discussedlater.

In man, pneumococcal pneumonia is a potenttrigger of recurrent herpes and so is trigeminalneurectomy. Similarly in rodents, virus reactivationis regularly induced by trauma to the mouse sciaticnerve (Walz, Price and Notkins, 1974) or to the fifthnerve in rabbits (Nesburn et al., 1976, 1977).In the latter case, the nerve pathway between tri-geminal ganglion and skin is not interrupted andmechanical stimulation, or stereotaxic manipulation,of the ganglion leads to HSV shedding within 48 hrfrom the eyes in 80%. of animals. The authors do notcomment about the clinical status of the affected eyesand it is not clear whether the rabbits developrecrudescent keratitis.A third very common cause of human cold sores is

ultra-violet light. Here again, there is an animalmodel (Blyth et al., 1976), but it may be asked how,if HSV is latent in nerve ganglia, can a non-pene-trating influence such as u.v. activate virus in sucha remote site? The Bristol workers have taken upthis question and in a carefully reasoned paper (Hilland Blyth, 1976) have put forward an interestinghypothesis. Briefly, this suggests that the ganglionis the site of a persistent infection, in which there

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is a production of mature intact virions, but withsuch a low frequency that they are either undetectable(Epstein, 1976) or rarely detectable (Baringer andSwoveland, 1974). As a result, virus travels downthe axon and reaches the skin in an almost con-tinuous stream. Microfoci of infected epidermalcells develop, but are usually eliminated by de-fence mechanisms and the lesions are abortive.However, under certain circumstances, a 'skintrigger' induces changes and allows the microfoci togrow into visible lesions, either by stimulating virusreplication or by a temporary suppression of localdefences.The alternative to the 'skin trigger' theory is the

'ganglion trigger', through which a truly latentinfection in a ganglion is stimulated to 'switch on'into a productive infection. There have been a numberof theories concerning the possible mechanisms whichwill maintain HSV latency and induce reversion to aproductive infection. The most attractive of theseincriminate immune mechanisms and ascribe a roleto HSV-specific immunoglobulins which, by bind-ing to specific sites on the virogenic, latently infectedneurone, will protect it from destruction by humoraland cellular defences (Lehner, Wilton and Shillitoe,1975). At the same time, virus replication in thenerve cell may well be 'switched off'. There isexperimental support for the suggestion that anti-HSV antibody attached to the outside of the cell,will inhibit virus multiplication (Costa, et al., 1977)and it is known that latently infected murine gangliawill promptly yield infectious virus, and its con-stituent neurones will synthetize viral DNA if theyare transplanted into the peritoneal cavity of non-immune mice (Stevens and Cook, 1974). The viruswill not however, be unmasked and latency will bepreserved if the graft is made into mice which havebeen previously immunized against HSV.The role of cellular immune mechanisms in HSV

disease is very confused and it is perhaps wise toagree with Klein, (1976) about the prematurity ofany conclusions. Recent contributions to the bodyof knowledge on this subject include Ennis andWells, 1974; Rouse and Babiuk, 1975; Thons et al.,1975; Russel, 1975; Rager-Zisman and Allison,1976. It is also interesting to note that there may bea genetic basis for suceptibility to recurrent herpessimplex (Russell and Schlaut, 1975; Zimmermanet al., 1977).One problem which will have to be faced before

the neuronal theory of HSV latency can be fullyaccepted, is the fate of the nerve cell(s) whichharbour(s) the infection. Except for very rareinstances (Krohel et al., 1976), there is no suggestionthat re-activation of HSV disease leads to thedestruction of nerve cells. It is exceedingly difficult tounderstand how this can be.

Oncogenic potential ofHS VIt is not the purpose of this review to discuss the

oncogenic properties of HSV, but it is impossible towrite about the question of persistence without abrief reference to the subject. Suffice it to say thatthe oncogenic role of the virus is as yet entirelyunproved, but remains possible. It is howeverestablished that HSV can transform cell culturesin vitro and that such transformed cells will, oninjection, induce malignant tumours in weanlinghamsters. Tumour cells obtained from the neo-plasm do not yield infectious virus, but do carryvirus footprints in the form of HSV specific antigensand nucleic acid. Tumour-bearing animals developspecific anti-HSV antibodies. There is thus persistenceof the HSV genome in the cells and the model istherefore directly relevant to the present review.Contributions by Roizman and Frenkel, 1975 andRapp and Reed, 1976, are of interest.

ConclusionsHerpesvirus simplex is the type species of one of

the largest group of all animal viruses. At least fourmembers of the group are human 'pathogens' andthese four are perhaps the most ubiquitous of allviruses which can infect man. Once one of these fouragents enters its human host, it establishes aninfection which, in all probability, will never belost and which the patient will take with him to thegrave. There is hardly an adult in the world who isnot chronically infected with all four of these viruses.One of the four (and perhaps as many as three) isclosely linked with malignant disease, a second is thecause of the most widespread form of communicablecongenital crippling, a third is the commonest causeof sporadic fatal encephalitis in the temperate world,and a further two or three have fearsome significancein the area of graft surgery and the management ofimmuno-compromized patients. It is hardly sur-prising that there are now determined efforts tocontrol these infections by prophylactic vaccinationand by anti-viral chemotherapy. However, it isprobably illusory to expect success in this field beforethere is a fuller understanding of the natural historyof the herpesviruses. There are many reasons tobelieve that all the agents of the group share someidentical, and many similar properties. Recentachievements in the elucidation of persistence ininfections caused by the virus of herpes simplexcannot fail but to improve our knowledge of theproperties of the whole group and eventually yielda significant improvement in the control of herpeticdiseases in general. Similarly, the elegant and pains-taking work undertaken in recent years will surelyprove to be a milestone in our knowledge of thepathogenesis of neurotropic virus infections.

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