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BACTERIOLOGICAL REVIEWSVol. 28, No. 4, p. 472-479 December, 1964Copyright @ 1964 American Society for Microbiology

Printed in U.S.A.

LATENT HERPES SIMPLEX INFECTION IN 7MAN1

THOMAS F. PAINE, JR.

Department of Medicine, Nashville General Hospital, and Department of Medicine, Vanderbilt UniversitySchool of Medicine, Nashville, Tennessee

INTRODUCTION.................................................................................. 472EXPERIMENTAL INFECTION OF ANIMALS WITH HUMAN HERPES SIMPLEX VIRUS.................. 472LATENT HERPETIC EXPERIMENTAL INFECTIONS IN ANIMALS ..................................... 474EVIDENCE FOR LATENT HERPESVIRUS IN NERVOUS TISSUE IN MAN............................. 474EVIDENCE FOR LATENT HERPESVIRUS OUTSIDE OF THE NERVOUS SYSTEM IN MAN................. 476CONCLUSIONS................................................................................... 476LITERATURE CITED.................................................................. 477

INTRODUCTION

The biology of experimental herpes simplexinfections of chick embryo cells and tissue culturecells has been clarified greatly over the past fewyears by the clear-cut work of Scott and associ-ates (45, 46), Stoker and colleagues (50, 51), andothers. Indeed, the detailed knowledge of the"growth curve" of herpesvirus in infected cells,from their absorption and temporary disappear-ance from view, to the appearance of new virusparticles in the cell nucleus, then in the cyto-plasm, and again into the medium, might leadone to believe that the secrets between this virusand man are now understood. But, wait! There isstill an intriguing mystery regarding this virus-amystery which might have been foretold in theseancient words:

There be four things which are little upon theearth but they are exceeding wise;

The ants are a people not strong, yet they preparetheir meat in the summer;

The conies are but a feeble folk, yet make theytheir houses in the rocks;

The locusts have no king, yet go they forth allof them by bands;

The spider taketh hold with her hands, and is inkings' palaces (Proverbs 30:24-28)

And the herpes virus labors not, yet lives warmand rent-free. . .. might be added to these wordsfrom the Proverbs. All these little creatures have

1 A contribution to the Symposium on "CurrentProgress in Virus Diseases" presented as part ofthe program for the Centennial of the BostonCity Hospital, 1 June 1964, with Maxwell Finlandserving as Consultant Editor, and John H. Dingleand Herbert R. Morgan as moderators.

in common a superb adaptation to a hostileworld and have outlived empires and the bronto-saurus. It is the living in, with only occasionalclues to its presence, of the herpesvirus's residencein man which is a great mystery. The mystery isincreased by the involvement of a certain ana-tomical site-the lips, cornea, or genitalia-yearafter year in recurrent herpes, suggesting thatthe virus has picked a certain cell or group ofcells for its permanent abode. How the virusarrived there and what cells contain it duringlatency is unknown.

EXPERIMENTAL INFECTION OF ANIMALS WITHHUMAN HERPES SIMPLEX VIRUS

Interest in the pathogenesis of herpes infectionwas stimulated by the observation that an agentfrom human herpetic lesions could produce in-fection in the eye of the rabbit after inoculationof the scarified cornea (26, 35). In some instances,the corneal infection was followed by a herpeticencephalitis (16). Although the route of invasionof the central nervous system was unknown, boththe blood stream (15) and the optic nerve (34)were suggested as avenues. Subsequent studiesby Goodpasture showed that superficial inocu-lation of the herpes virus led to herpetic en-cephalitis by passage of the virus along thenerves; nevertheless, infection of the centralnervous system also could be produced by intra-venous injection of the agent (20, 24, 25). Hiselegant experiments bear closer investigation.Doerr and V6chting (16) had observed thatrabbits which developed encephalitis after uni-lateral corneal inoculation of herpesvirus showeda curious drawing of the head towards the affectedside. Goodpasture found that this neurologicalphenomenon was associated with unilateral

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lesions in the pons and medulla which corre-sponded to the central distribution of the sensoryfibers of the fifth cranial nerve on the inoculatedside (25). A reproduction of one of Goodpasture'sillustrations (Fig. 1) shows the grossly hemor-rhagic lesions in such an experimentally infectedrabbit. In this instance, the location of thelesions has been accentuated by the intravenousinjection of trypan blue before death of the

I.

FIG. 1. Brain of rabbit previously inoculated on

right cornea with virus of herpes febrilis, showingdistribution of area stained by intravenous injectionof trypan blue. Area of staining is unilateral on

right side, beginning in intradural part of sensoryportion of fifth cranial nerve and following the dis-tribution of these fibers through pons and medulla(reproduced from J. Med. Res. 44:206, 1923).

animal (37). Microscopically, acute inflammationwith necrosis and infiltration with polymorpho-nuclear and mononuclear cells was observed,limited to the side of the pons and medullacorresponding to the gross lesions. Herpeticintranuclear inclusion bodies were seen in glialand ganglion type cells in such lesions.Goodpasture demonstrated passage of herpes-

virus to the central nervous system in rabbits via

the three principal nervous pathways (25). Toillustrate transmission along sensory nerves, heinoculated the virus upon the right cornea; the

virus passed along sensory fibers of the rightfifth cranial nerve, producing local unilaterallesion in pons and medulla (right side) whichcorresponded to the distribution of sensory fibersof this nerve. Another experiment showed passagealong motor nerves. In this experiment, he foundthat virus inoculated into the right massetermuscle causes an encephalitis localized in ponsand medulla, with infection in and destruction ofganglion cells in the motor nucleus of the rightfifth cranial nerve. To show passage alongsympathetic nerve fibers, virus was inoculatedinto the left ovary, producing complete paralysisof the caudal half of the body, and acute herpeticmyelitis of the midthoracic segment of the spinalcord. These experiments led Goodpasture to con-clude that the virus of herpes labialis, wheninoculated into rabbits in the different sitesmentioned, could reach the central nervoussystem via sensory, motor, or sympathetic nerves.The initial injury in the brain or spinal cordarose at the point where the nerves which supplythe peripherally inoculated area entered thecentral nervous system. After entry into thebrain, the virus might then spread, producing ageneralized encephalitis. That the virus traveledvia the peripheral nerves was further supportedby studies showing that the lumbar spinal cordmyelitis produced by inoculation of the agentinto a leg muscle supplied by the sciatic nervedid not occur if the sciatic nerve was severedbefore inoculation. Goodpasture also noted thatherpes strains varied in neurotropic virulence andthat rabbits varied in their natural resistance toinvasion of the central nervous system by thisvirus (22).The neurotropism of herpesvirus was later con-

firmed in the chick embryo by Anderson (1)and in the mouse by Slavin and Berry (47).Goodpasture (25) postulated that transmissionof virus along the peripheral nerves occurredwithin the axons. Viral involvement of someneuroglial cells outside of the axis cylinders butstill inside the myelin sheath was interpreted asresulting from escape of virus in places along theaxons. A recent study by Johnson (30) with theuse of a fluorescent-antibody staining techniquein experimentally infected suckling mice providedgood evidence that the herpesvirus is transmittedin peripheral nerves through infected Schwanncells and perineural fibroblasts rather than in theaxis cylinders. Invasion of the sensory ganglia

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seemed to take place when the level of advancinginfection in the neuroglial cells reached theganglia. Axonal spread in addition to spread ofthe virus through the neuroglial cells was notentirely excluded, since the serum-conjugate sys-tem used in the indirect fluorescent-antibodystaining technique failed to stain herpetic ma-terial in the nuclei of cells (33, 42, 43) and mayhave failed to stain a form of the virus presentin the axons.The natural spread of herpesvirus among

rabbits provides another clue regarding theneurotropism of this agent. Goodpasture (21)placed normal rabbits in cages with rabbitsshedding purulent material from experimentalherpetic keratitis. The majority of normal rabbitsexposed developed herpetic encephalitis. Theearliest inflammatory lesions in the centralnervous system of the exposed animals werefound to involve the origins of the sensory di-visions of the fifth and the ninth cranial nerves,indicating a primary infection of cells in themucosa of the mouth, nose, or throat, followedby spread through the sensory nerves from theinfected tissue to the central nervous system.

Generalized herpetic infections with widespreadinvolvement of many organ systems can be pro-duced in experimental animals, particularly in theyoung (1, 30, 47), and have been observed inyoung children (3). In this respect, the herpesvirus is no different from many other infectiousagents which ordinarily infect one organ systembut occasionally produce overwhelming systemicinfections. In summing up the evidence fromexperimental herpes infections in animals, itseems safe to conclude that, after superficialinoculation in animals, the human herpes simplexvirus shows a remarkable preference for nervoustissue as a place for growth and infection.

LATENT HERPETIC EXPERIMENTAL INFECTIONSIN ANIMALS

Since the latent state of the herpesvirus inhumans was recognized, several attempts havebeen made to produce latent infections in experi-mental animals. Good and Campbell (19) re-ported the activation of herpes infection inrabbits 1 to 3 months after inoculation by pro-ducing an anaphylactic reaction with egg white.The original inoculation of virus was made intothe quadriceps muscle. Activation of herpeticinfection took the form of an acute myelitis and

encephalitis appearing about 5 days after theanaphylactic reaction. Although antibody meas-urements in the rabbits were not mentioned, it isreasonable to assume the presence of antibodies1 to 3 months after viral inoculation. The anti-bodies apparently did not interfere with the de-velopment of the encephalitis, suggesting that theherpes organisms may well have been present ina latent state in cells free from the inhibitingeffect of antibodies. Schmidt and Rasmussen (44)activated herpes infections in rabbits by the useof adrenaline as long as 5 months after inocu-lation. These authors injected herpesvirus di-rectly into the brains of rabbits immunizedagainst herpes. There seems little question butthat the virus existed quietly in the centralnervous system until activated and an en-cephalitis was produced. Again, although anti-body measurements were not mentioned, anti-bodies were certainly present and did notinterfere with the development of an encephalitis.Others (2) have described the reactivation ofherpesvirus in healed corneal lesions in rabbitsby means of a locally induced Arthus reaction;in these animals, the herpesvirus may have beenlatent in the corneal epithelial cells, althoughlatency in the peripheral nerves innervating thecorneas was not excluded.The few reports on latent herpes infections in

experimental animals contain some evidence thatnervous tissue may harbor the latent herpesvirus.More detailed work along this line will be neces-sary to determine whether prolonged latency canbe produced in animals and what tissues serve asa residence of the virus during latency.

EVIDENCE FOR LATENT HERPESVIRUS INNERVOUS TISSUE IN MAN

Most adults harbor herpes simplex virus (8).The oropharynx is considered the usual place ofprimary infection (8, 14), with no immediateindication of involvement of nerves supplyingthis area. Latency, as indicated by recurringvesicles on the lips, usually shows no evidence ofa distribution corresponding to peripheral nervefibers. There is, however, evidence linking theherpesvirus to nervous tissue in man. Earlyreports by Cushing (11, 12, 13) concerning thesurgical treatment of trigeminal neuralgia offeredthe first clues. His observations, coupled withlater experience with herpes activation by surgeryfor tic douloureux, have shown that: (i) labial

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and facial herpetic lesions appear postoperativelyin a high percentage of patients undergoingposterior root section of the fifth cranial nerve-ashigh as 93% in one series reported by Carton (9);(ii) the herpetic lesions occur on the same side onwhich the fifth nerve root is sectioned (9);(iii) the herpetic lesions appear usually in theskin or mucosal innervation areas of the secondand the third divisions of the sectioned fifthnerve (10); (iv) herpetic lesions do not appearafter interruption of the peripheral divisions ofthe fifth cranial nerve (9); (v) interruption of thesecond and third peripheral divisions of thetrigeminal nerve before subsequent root sectionprevents the appearance of herpetic lesionswhich usually follow such a procedure (9); and(vi) destruction of the Gasserian ganglion, by theinjection of alcohol into the ganglion, usually isnot followed by the appearance of herpeticlesions (9). These observations show that dis-turbing the posterior sensory root of the fifthcranial nerve by operation results in the appear-ance of herpetic vesicles in the areas innervatedby the second and third peripheral divisions ofthe nerve in a highly significant number ofpatients, provided the ganglion has not beendestroyed and the peripheral divisions are intact.

Other significant observations linking pe-ripheral nerves with herpes simplex virus havebeen summarized and substantiated by Slavinand Ferguson (48). Some patients with recurringherpetic vesicles show a distribution of lesionscorresponding to peripheral nerves. These pa-tients may have involvement of the trigeminalarea as well as other dermatomes in a zoster-likefashion. Recurring neuralgic pain in the inner-vation pattern of the involved area may be notedprior to the appearance of the vesicles, and mayindicate a posterior root involvement by thevirus. Herpes simplex virus was clearly isolatedby Slavin and Ferguson (48) from the vesicles ofa series of patients with recurring zosteriformlesions. It is of interest that Teague and Good-pasture (52) reported the production of zosteri-form lesions in rabbits and guinea pigs withhuman herpes simplex virus by irritating theskin with coal tar and inoculating the virusnearby. These studies indicated a centripetalspread of the virus from the inoculated site viaperipheral nerves to the sensory ganglia, followedby a centrifugal spread of the agent with the

appearance of vesicles in the area of the irritatedskin.

Since Goodpasture's early postulate (23) sug-gesting the Gasserian ganglion as a likely site forthe residence of latent herpesvirus, this ana-tomical structure has been the prime suspect forharboring the virus. The few reported (7, 10, 18,41) unsuccessful attempts to isolate virus fromGasserian ganglion removed at operation by nomeans eliminate this structure as a storage sitefor the agent. The herpesvirus particle is nowknown to consist of a core imbedded in a shelland surrounded by an envelope (56). Perhaps thecore of the virus is present during latency butlacks the shell or envelope to make it a completeinfective unit (36). Electron microscopic evidencesuggests that there is a structural difference be-tween intranuclear and intracytoplasmic herpesparticles (38). Herriott has suggested that theherpesvirus may exist as a free deoxyribonucleicacid (27). Thus, the latent virus may be presentin neural tissue in a form similar to that existingduring the eclipse phase (46) in tissue culturewhen active virus temporarily can not be isolated.

Other clues linking herpes and the fifth cranialnerve in man are not very definitive. Howard(28, 29) noted gross and microscopic inflamma-tory changes in the Gasserian ganglia in autopsystudies on two patients with labial herpetic-likelesions; one patient had succumbed with bacterialpneumonia and the other with typhoid andstaphylococcal pneumonia. Inflammatory infil-trations in the Gasserian ganglion in threepatients were described by Freeman, as quotedby Richter (41). Behrman and Knight (4) dis-cussed three patients in whom recurrent neuralgiaof branches of the trigeminal nerve was followedby the appearance of herpetic-like lesions inareas innervated by the involved nerve branches;this repetitive association suggested a relationshipbetween the recurrent neuralgia of the trigeminalnerve and the herpes virus. Another clue sug-gesting nervous tissue latency was the appearanceof herpetic lesions almost entirely in areas inner-vated by the second and third divisions of thetrigeminal nerve (32) in a high percentage ofadult patients given fever therapy when thismethod of treatment was in vogue. The oc-casional recurrence of herpes simplex vesicles ina zoster-like distribution and the high rate ofactivation of herpesvirus by operations on theposterior sensory root of the fifth cranial nerve

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in patients with trigeminal neuralgia suggestthat the herpesvirus may be present in its latentstate in nervous tissue. The virus could be presentin neurones or in neuroglial cells in the sensoryganglia or in peripheral nerves in Schwann orother cells within the myelin sheath. Definiteproof awaits isolation of the virus from thesestructures or demonstration of the latent formin situ.

EVIDENCE FOR LATENT HERPESVIRUS OUTSIDEOF THE NERVOUS SYSTEM IN MAN

The commonly recurring epithelial herpeticvesicles, with no apparent relationship to pe-ripheral nerves, may indicate a superficial resi-dence of the herpesvirus between attacks. Thelatent virus could be present in the basal germi-native layer of epithelial cells, with the viralnucleic acid being passed down to later gener-ations of germinative epithelial cells, as in thetransfer of bacteriophage nucleic acid to newgenerations of bacterial cells. Indeed, the sheddingof herpesvirus in the saliva for several weeksafter primary infection and the occasional findingof the virus in the saliva of apparently normaladults (6) might be taken as evidence for a super-ficial residence of the virus. However, it isequally reasonable to believe that the latent viruslives in superficial nerve endings, spreading tothe epithelial cells when activated. Epithelialtissues, including the mucous membranes andcornea, contain a rich variety of sensory nerves;these include networks of free sensory nerveendings, corpuscles of Vater-Pacini, nonencapsu-lated nerve glomeruli, genital corpuscles, andMeissner's corpuscles (5). One report, however,states that areas of facial skin subject to re-current herpes did not continue to manifestherpetic lesions if transplanted to another site onthe body (49).The presence of residual islands of latent

herpesvirus in the skin and mucosa has beensuggested as an explanation for the appearance ofherpetic vesicles in the distribution of the secondand third peripheral divisions of the trigeminalnerve after posterior sensory root section of allthree branches. This view has been advanced onthe thesis that if herpesvirus were activated whileresiding in the Gasserian ganglion it shouldspread to all peripheral branches of the fifthnerve (10). However, the latent herpesvirus maybe associated only with the neurones innervating

the site of original infection, a phenomenon notedby Goodpasture (21) in his study of the naturalspread of herpes infection in caged rabbits. Theoral cavity in man, innervated by the maxillaryand mandibular branches of the fifth cranialnerve, is the usual site of primary infection.Further, there is no reason to believe thatcommon neurones in the Gasserian ganglionserve all three peripheral branches of the tri-geminal nerve. In man's embryological develop-ment, the fifth nerve results from fusion of thesensory ganglia of two nerves, the ophthalmic,emerging in front of the second myotome, andthe maxillo-mandibularis, emerging behind thesecond myotome (31). Thus, while occupying acommon structure, the Gasserian ganglion, theneurones innervating the ophthalmic division areprobably quite distinct from those innervatingthe maxillary and mandibular divisions.

CONCLUSIONS

The life-long secret residence of the herpesvirusin man is still unknown. Clinical evidence sug-gests that the site relates to the point of primaryinfection, usually the mouth or lips. Experimentalstudies in animals and activation of latent in-fections in man after operation for trigeminalneuralgia indicate a distinct neurotropism of theherpes simplex virus. Although the original in-fection in epithelial cells may lead to depositionof viral nucleic acid in the basal germinativelayer of these cells, the definite neurotropism ofthe virus suggests that primary infection of manresults in invasion of superficial nerve endings,and thereafter the viral nucleic acid remains inneural tissue. Peripheral nerve cells are remark-able in their size and make-up, having nucleisituated near the central nervous system whiletheir cytoplasm extends many inches or evenfeet distant from their nuclei. Viral nucleic acidtaking refuge in nervous tissue would find asecure residence. These cells are not undergoingconstant new cell formation; thus, the risk ofbeing misplaced or lost while being transferredto daughter cells, as in an epithelial cell residence,is decreased. Perhaps it is a coincidence, butthere is a similarity in time of transmission ofherpesvirus from the cornea to the brain of arabbit (72 to 96 hr; 25) and the time requiredfor the expression of peripheral herpes in manfollowing posterior sensory root section in casesof trigeminal neuralgia (48 to 96 hr; 10). Cen-

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trifugal spread of the virus along nerves was earlydemonstrated by Teague and Goodpasture (52),and in the case of man this time could representthe period needed for migration of the viralnucleic acid from a central location in the nerveto the peripheral nerve endings in the epithelium.Nerve cell nuclei would be likely structures tosynthesize new infective virus particles from thelatent state. The participation of nuclei of tissueculture cells in production of herpesvirus hasbeen demonstrated clearly (33, 38, 39, 40, 42,43). Synthesized virus might travel centrifugallyin nerves in a manner first suggested by Weiss(53, 54), who proposed that the axon material ofthe nerve was produced in the region of thenucleus and moved away from the nucleus intothe peripheral nerves. A recent note (55) confirmsthis hypothesis and offers visual proof of aconstant movement of axonal material and ofmitochondria from the nucleus of the nerve intothe peripheral axon. Droz and Leblond (17),using tritium-labeled leucine, demonstrated thesynthesis of new protein in the rat sciatic nervecell nucleus and showed a centrifugal progressionof the labeled protein in the axon of the nerve inradioautographic studies. The rate of progressionof the labeled protein was not fast enough toaccount for the appearance of herpetic vesicles inthe skin after section of the posterior sensory rootof the trigeminal nerve if the virus had to progressfrom the Gasserian ganglion at the same rate asthe labeled protein. However, under differentcircumstances virus particles might move in theaxon at a different rate of speed. Weiss (55)recently described visible peristaltic waves oc-curring in myelinated sensory nerves in vitro.The rate of peristaltic activity in nerve fibersprobably depends upon the metabolic situation inthe nerve. An increased speed of centrifugalaxonal flow could result if nerve fiber peristalsisincreased because of metabolic changes in thefifth cranial nerve from the "irritation" of thesectioning of its posterior sensory root.Based on presently available information, the

following hypothesis for the pathogenesis oflatency of herpes simplex virus in man is sug-gested. (i) Primary infection probably involvessensory nerve endings in addition to epithelialcells. (ii) The virus travels centripetally insensory nerves through contiguous endoneuralsupporting cells, particularly the Schwann cells.(iii) Ganglionic nerve cell nuclei are invaded when

the centrally moving infection of the neuroglialcells reaches the level of the ganglia. (iv) Thenoninfective core of the herpesvirus may remainin its latent state in the sensory ganglia, usuallythe Gasserian ganglia. (v) On activation of theherpesvirus, new infective virus particles may besynthesized in the nerve cell nucleus and releasedinto the cytoplasm of the nerve. (vi) By meansof an axonal flow due to nerve fiber peristalsis,the infective virus particles move in a centrifugaldirection down the axon of the peripheral nerveuntil epithelial cells are reached, where thecharacteristic vesicles are produced.

LITERATURE CITED

1. ANDERSON, K. 1940. Pathogenesis of herpessimplex infection in chick embryos. Am. J.Pathol. 16:137-155.

2. ANDERSON, W. A., B. MARGRUDER, AND E. D.KILBOURNE. 1961. Induced reactivation ofherpes simplex virus in healed rabbit corneallesions. Proc. Soc. Exptl. Biol. Med. 107:628-632.

3. BECKER, W., W. DE T. NAUDE, A. Kipps, ANDD. MCKENZIE. 1963. Virus studies in dis-seminated herpes simplex infections. Asso-ciation with malnutrition in children. S.African Med. J. 37:74-76.

4. BEHRMAN, S., AND G. KNIGHT. 1954. Herpessimplex associated with trigeminal neural-gia. Neurology 4:525-530.

5. BLOOM, W., AND D. W. FAWCETT. 1962. Atextbook of histology, 8th ed., p. 234-237.W. B. Saunders Co., Philadelphia.

6. BUDDINGH, G. J., D. I. SCHRUM, J. C. LANIER,AND D. J. GUIDRY. 1953. Studies of the nat-ural history of herpes simplex infections.Pediatrics 11:595-610.

7. BURNET, F. M., AND D. LUSH. 1939. Herpessimplex. Studies on the antibody contentof human sera. Lancet 1:629-631.

8. BURNET, F. M., AND S. W. WILLIAMS. 1939.Herpes simplex: a new point of view. Med.J. Australia 1:637-642.

9. CARTON, C. A. 1953. Effect of previous sensoryloss on the appearance of herpes simplexfollowing trigeminal sensory root section.J. Neurosurg. 10:463-468.

10. CARTON, C. A., AND E. D. KILBOURNE. 1952.Activation of latent herpes simplex bytrigeminal sensory-root section. New Engl.J. Med. 246:172-176.

11. CUSHING, H. 1904. Perineal zoster, with notesupon cutaneous segmentation postaxial tothe lower limb. Am. J. Med. Sci. 127:375-391.

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12. CUSHING, H. 1904. Perineal zoster. JohnsHopkins Hosp. Bull. 15:172.

13. CUSHING, H. 1905. The surgical aspects ofmajor neuralgia of the trigeminal nerve. Areport of twenty cases of operation on thegasserian ganglion, with anatomic and phys-iologic notes on the consequences of itsremoval. J. Am. Med. Assoc. 44:773-779,860-865, 920-929, 1002-1008, 1088-1093.

14. DODD, K., L. M. JOHNSTON, AND G. J. BUD-DINGH. 1938. Herpetic stomatitis. J. Pediat.12:95-102.

15. DOERR, R., AND A. SCHNABEL. 1921. Das Virusdes Herpes febrilis und seine Beziehungenzum Virus der Encephalitis epidemica(lethargica). Z. Hyg. Infektionskrankh.94:29-81.

16. DOERR, R., AND K. VOCHTING. 1920. .Ptudessur le virus de l'herpes febrile. Rev. Gen.Ophthalmol. 34:409-421.

17. DROZ, B., AND C. P. LEBLOND. 1962. Migra-tion of proteins along the axons of thesciatic nerve. Science 137:1047-1048.

18. ELLISON, S. A., C. A. CARTON, AND H. M.ROSE. 1959. Studies of recurrent herpessimplex infections following section of thetrigeminal nerve. J. Infect. Diseases 105:161-167.

19. GOOD, R. A., AND B. CAMPBELL. 1948. Theprecipitation of latent herpes simplex en-cephalitis by anaphylactic shock. Proc. Soc.Exptl. Biol. Med. 68:82-87.

20. GOODPASTURE, E. W. 1925. The axis-cylindersof peripheral nerves as portals of entry tothe central nervous system for the virus ofherpes simplex in experimentally infectedrabbits. Am. J. Pathol. 1:11-28.

21. GOODPASTURE, E. W. 1925. The pathways ofinfection of the central nervous system inherpetic encephalitis of rabbits contractedby contact; with a comparative commenton medullary lesions in a case of humanpoliomyelitis. Am. J. Pathol. 1:29-46.

22. GOODPASTURE, E. W. 1925. Certain factorsdetermining the incidence and severity ofherpetic encephalitis in rabbits. Am. J.Pathol. 1:47-55.

23. GOODPASTURE, E. W. 1929. Herpetic infection,with especial reference to involvement ofthe nervous system. Medicine 8:223-243.

24. GOODPASTURE, E. W., AND 0. TEAGUE. 1923.The transmission of the virus of herpesfebrilis along sensory nerves with resultingunilateral lesions in the central nervoussystem in the rabbit. Proc. Soc. Exptl. Biol.Med. 20:545-547.

25. GOODPASTURE, E. W., AND 0. TEAGUE. 1923.

Transmission of the virus of herpes febrilisalong nerves in experimentally infectedrabbits. J. Med. Res. 44:139-184.

26. GRtTER, W. 1920. Experimentelle und Kin-ische Untersuchungen uiber den Sog. Herpescorneae. Klin. Monatsbl. Augenheilk. 65:398-399.

27. HERRIOTT, R. M. 1961. Infectious nucleicacids, a new dimension in virology. Science134:256-260.

28. HOWARD, W. T. 1902. The pathology of labialand nasal herpes and of herpes of the bodyoccurring in acute croupous pneumonia andtheir relation to the so-called herpes zoster.Trans. Assoc. Am. Physicians 17:189-207.

29. HOWARD, W. T. 1905. Further observationson the relation of lesions of the gasserianand posterior root ganglia to herpes, oc-curring in pneumonia and cerebrospinalmeningitis. Trans. Assoc. Am. Physicians20:165-172.

30. JOHNSON, R. T. 1964. The pathogenesis ofherpes virus encephalitis. I. Virus pathwaysto the nervous system of suckling micedemonstrated by fluorescent antibodystaining. J. Exptl. Med. 119:343-356.

31. KAPPERS, C. U. A., G. C. HUBER, AND E. C.CROSBY. 1960. The comparative anatomyof the nervous system of vertebrates, in-cluding man, vol. 1, p. 381. Hafner Pub-lishing Co., New York.

32. KEDDIE, F. M., R. B. REES, JR., AND N. N.EPSTEIN. 1941. Herpes simplex followingartificial fever therapy. J. Am. Med. Assoc.117:1327-1330.

33. LEBRUN, J. 1956. Cellular localization ofherpes simplex virus by means of fluorescentantibody. Virology 2:496-510.

34. LEVADITI, C., AND P. HARVIER. 1920. .tudeexp6rimentale de l'encephalite dite 1 thar-gique. Ann. Inst. Pasteur 34:911-972.

35. LOWENSTEIN, A. 1919. Aetiologische Unter-suchungen uber den fieberhaften Herpes.Muench. Med. Wochschr. 66:769-770.

36. LWOFF, A., T. F. ANDERSON, AND F. JACOB.1959. Remarques sur les caract6ristiques dela particule virale infectieuse. Ann. Inst.Pasteur 97:281-289.

37. MCCLELLAN, R. H., AND E. W. GOODPASTURE.1923. A method of demonstrating experi-mental gross lesions in the central nervoussystem. J. Med. Res. 44:201-206.

38. MORGAN, C., S. A. ELLISON, H. M. ROSE, AND

D. H. MOORE. 1954. Structure and develop-ment of viruses as observed in the electronmicroscope. J. Exptl. Med. 100:195-202.

39. MORGAN, C., E. P. JONES, M. HOLDEN, AND

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H. M. ROSE. 1958. Intranuclear crystals ofherpes simplex virus observed with theelectron microscope. Virology 5:568-571.

40. NEWTON, A., AND M. G. P. STOKER. 1958.Changes in nucleic acid content of HeLacells infected with herpes virus. Virology5:549-560.

41. RICHTER, R. B. 1944. Observations bearingon the presence of latent herpes simplexvirus in the human gasserian ganglion. J.Nervous Mental Disease 99:356-358.

42. ROIZMAN, B. 1961. Virus infection of cells inmitosis. 1. Observations on the recruitmentof cells in karyokinesis into giant cells in-duced by herpes simplex virus and bearingon the site of virus antigen formation. Virol-ogy 13:387-401.

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