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! Textbook of HUMAN VIROLOGY EDI TED B Y ROBERT B. BELSHE PSG PUBLISHING COMPAtiY, INC. LfT7ZETON. MASSACHUSET75 HASTER-1:5PP

Library of Congress Cataloging in Pubitcatton Data 4tain entry under title: Textbook of human virology. Bibliography: p. Includes index. 1. ViroloQr. :. Virus diseases. 1. Belshe. Robert B. QR360.TsS 1984 616.0194 83-2S0I8 t5B` 0-d8416-438-6 Published by: PSG Publishing Company, Inc. 545 Great R;,ad Littleton. Massachusetts 01460. C.S.A. Medicine is an ever-chan8tn8 science. As new research and clinical experience broaden our knoWledQe. changes in treatment and drug therapy are required. The authors and the publisher of this work ha~,e made every effort to ensure that the treatment and drug dosage schedules herein are accurate and in accord with the standards accepted at the time of publication. Readers are ad- %+sed, howe.er, to check the product information sheet included in the package ot` each drug they plan to ad- minister to be certain that changes ha.e not been made in the recommended dose or in the indications and con- traindicanons for administration. This recommendation is of particular importance in regard to new or infre- quently used drugs. Copyright O 1964 by PSG Publishing Company, Inc. All ristts reserved. No part of this publication may be reproduced or transmitted in any form or by any tneans, electronic or mechanical, including photocopy, recording, or any information storage or retrieval system, without permission in writing from the publisher. Printed in the United States of America International Standard Book Number: as8416-4s8-6 Library of Congress Catalog Card Number: s3-2sa18

CONTENTS 1 !r 3 6 Foreword xi Maurice A. Mufson Introduction usi Robert B. Belshe Structure and C7assi6cation of Viruses 1 Joseph L. Melnick Introduction to Methods for Characteriation of Viruses and Virat Macromolecules 29 James M. Wilhelm Replication of DNA Virscses 49 Terry W. Fenger Replication of RNA Viruses 79 Terry W. Fenger Immunology of Viral Infections 103 Gerald V. Quinnan, Jr. RNA Tumor Viruses 139 1 Rudiger Hehlmann Hartmut Schetters Volker Erfie Diagnostic Virology 179 Marilyn A. Menegus Aativirai Chemotherapy 193 Lee P. Van Voris Nosocomial Viral infectioas 231 William M. Valenti InAuensa Viruses 267 Lee P. Van Voris James F. Young Jack M. Bernstein William C. Graham Edwin L. Anderson Geoffrey J. Gorse Robert B. Belshe ParaisAuenzr Vimses 299 Peter F. Wright Mumps Vir.f 311 Mark D. Toipin Victoria Schauf Messia Virus 333 13 John F. Modlin ix .

x 14 Respiratory Syncytia) Virus 361 Robert B. Belshe Jack M. Bernstein Karen N. Dansby 15 16 17 Coronaviru~es 395 Maurice A. Mufson Rhinoviruses 391 Roland A. Levandowski Enteroviruses, including Polioviruses 407 Melinda Moore David M. Morens 18 Rsbies Virus iaS Patrick A. Robinson 19 Atettavitvses 513 C. J. Peters 20 Bunyaviruses, Phieboviruses and Related Viruses 547 C. J. Peters James W. LeDuc 21 Topviruees 599 Robert B. Craven 22 other Vira! Hemorrhagic Fevers and Colorado Tkk Fever 649 Kelly T. McKee, Jr C. J. Peters Robert B. Craven D. Bruce Francy 23 Robens Vws em Cuherine L. Lamprecht 7A Hep.tltb A Visti 707 Gert Frosaer 25 Hepattds s Yient 729 Larry I. Lutwick 26 Nori-A. No" Hepadtb 757 Stephen M. Feinstone lr ! Adeuo.ietutet 779 Sharon R. Snavely C.ltien Liu f+S Rotaviruees and Other Viruses Causing Gastroenteritis 795 Robert H. Yolken 29 Hetpes Simpkx Vlruxs d11 Richard C. Reichman 30 VatkeUa.Zoster Virus in9 Victoria Schauf Mark Tolpin 31 Epstein•Barr Virns g33 Gary R. Fleisher 32 Cytomeiabvintses n7 Sirus Naraqi 33 Poxviruses m Derrick Baxby 34 Human Papillotnaviruses 951 A. Bennett Jenson Wayne D. Lancaster 35 Human Poiyomaviruses 969 Thomas F. Hogan Billie L. Padgett Duard L. Walker 36 Virus-induced Subacute Spongiofotln Encephaiopatbks (Kuru and Creutziddt,iakob Disease) 997 Colin L. Masters 37 Ro.eou i.ta.tnm (Euariem Sttbitttm) 1011 Prudence Krieger 38 En-*em i.t.ctio..m (Fiftk DNes.e) 10]S Prudence Kriefer 39 mwmw Syadro.e ><Q1g Marian E. Melish Nyven J. Muchetu 40 ,:,aa syadmee io3 Frederick L. Ruben Liwt liiS

Ir CHAPTER 34 !Sl HISTORY 9S2 THE STRUCTL7tE AND BIOLOGY OF HPV 9S3 CLASSIF7CATION OF HPV TYPES 9S4 EPIDEMIOLOGY fS4 PATHOGENFSIS 954 TRANSMISSION 955 tNCUBATiON PERIOD ns HOST RESPONSE 9% CLINICAL SYNDROII(ES (COMMON) 956 CUTANEOUS 956 MUCOSAL !SI CLINICAL SYNDROMES (UNCOMMON) 9SS IMMUNOLOGIC RESPONSES 93g CELL-MEDIATED IMMUNITY 958 HUMORAL IMMUNITY !S! LABORATORY DtAGNO6IS OF INFF.Cl7ON 959 GENUS-SPECIFIC TESTS 961 TYPE-SPECIFIC TESTS !f3 TRF'.AY'11lErri !i4 VACCINATION !64 SUMMARY Human Papillomaviruses A. Bennett Jenson Robert J. Kurman Wayne D. Lancaster 951 The human (H) papillomaviruses (PV) cause a variety of cutaneous (plantar, common, and fiat or juvenile) warts'•' and proliferative squamous lesions of mucosal surfaces such as the oral cavity; .• larynx,'.: and anogenital areas'-' Al. though most lesions associated with HPV infec- tion appear to be benign and many spontaneously disappear, some cutaneous and mucosal papillo- mas undergo malignant transformation into in situ and invasive squamous carcinoma.'•t8- " The inability to propagate HPV in tissue culture" or transmit it to other animal species" has been the major impediment in characterizing the virus and studying its oncogenic potential. Recent advances in molecular virology, however, have led to the recognition that HPV displays a remarkable plur- ality with at least 16 different types (HPV-1 to HPV.16) distinguished serologically and/or by molecular hybridization techniques (Table 34-1). From these studies evidence is emerging that the type of HPV determines, in part, the clinical and pathological appearance, and natural fate of HPV-associated lesions. HPV are members of the A (PV) genus of the family Papovaviridae; the polyomaviruses consti- tute the B genus." The genera do not share any antigenic detetTninants" or polynucleotide sequence homology." The PVs have a larger ico- sahedral capsid (55 nm vs 45 nm) and a larger supercoiled, double-stranded DNA genome (5.0 x 10• dahons vs 3.3 x 10' daltons)." The genera also differ in biological properties.'• PV are species specific, producing hyperplasias/neo- plasias in natural hosts. In vitro infection is relatively quiescent without expression of late viral genes.'•-" In contrast, the polyomaviruses give rise to both productive and nonproductive in- fections in vitro but do not cause tumors in the natural host." HLSTORY Warts have created a mystique dating from antiquity since many undergo spontaneous regres- sion frequently attributed to an assortment of HWSTER-S-PP002745

l I 952 Tabk 34-1 Classification of Human Papillomavirus Types and Subtypes and Lesion with which They are Most Often Associated Type Lesion Reference la,b,c Plantar warts Gissmann et al" Heilman et all' 2a.b Common warts Heilman et all' Orth et all' 3 f7at warts Orth et al" 4 Plantar warts Heilman et all' Gissmann et al" sa,b.c Epiderrnodysplasia verruciformis (EV) Kremsdorf et al "' Ostrow et all' H Pfister, personal communication 6a,b Anogenital warts Gissmann and zur Hausen" de Villiers et a!" 6c,d,e Laryngeal papilloma. anogenital warts Gissmann et al" 7 Common warts of butchers Orth et al "' S EV Pfister et al "s 9 EV Kremsdorf et al iu 10 EV G Orth, personal communication I i Laryngeal papilloma. cervical dysptasia Gissmann et al°' Gissmann et•a!" 12 EV G Orth, personal communication 13 EV H Pfister, personat communication 14 EV G Orth, personal communication is EV G Orth, personal communication 16 Cervical carcinoma H zur Hausen. personal communication unconventional forms of treatment,'"13 including genital Sact condyiomas to human volunteers hypnosis and psychotherapy (reviewed by Bun- who developed typical cutaneous warts at the sites ney'). HPV was the ftrst tumor virus to be tratu- of inoculation was interpreted as indicating that micced experimentally from one host to another. s there was JW one type of human wart virus and This was accomplished in 1894 by L3cht,h" who A~'that the site olAftdon d~ p~erhaps, the genetic transmi:tte~ warts from his=other to ltimaeK by mak~ of~~ Oatient d~e~ttitted the clinical inoculation of •crude watt &ateriat. .Cia~O" iA 5-tppaFattCt. tYf cfitme4ua warts and mucosal pa- 1907 mid Serra'& oftPear later derttonstrsted thak.- pilloeais. 1-4o+Mrva, recognition that there were ~._ warts taDUid be fiat*xW b3!- cell-free filtrates ~_..dia~: papilloata~tts types and subtypes"'" wart maieaal. in i919, Wile and Kingreyn sue4- stimul#ted a new-t intermt in the role of these cessfuIIlr traasmitfed waRS through a succtssion _.Mptaqj="n '?iyp501ssiaslneoplasias arising in of hutnan volunteers using sterile extracu. E3ec-- OwmFoWspithdiut>t. tron microscopic studies by Strauss et al: !~ Melnick A a1,'' Bntitit~," and Alteiidz -et aN' confuined- a viral tttiofo:y for cutaneoua-warts. z~ THE Melnick,a' in 1962, RottQed the papillotnaviruses7n_ 81006 together with the polyotrtttvitwea in the fat3dty Pa- _-: 4iPV. =tr* rii>~t- `' `t»tnvdoped icosahedral povaviridae beause bot>!~e DNA ptmorvirttses'- eapsi~ ~~ in dit~er) with 72 capso- with sittn'tar uitrawucttuat features. Repotts meres" Theq o aot contaitt~lipids and are inac- (reviewed by Rowson and Mahy')of transmission of tivated by treatment with 0.4% formalin for 72 filtrates of warts, larMeal papillomas, and hours at 4•C" Both complete and empty par-

953 icles may be present.,' I The complete particles nave a sedimentation coefficient of 296 to 300 S and a buoyant density in CsC1 of 1.34 g/mL; empty particles have sedimentation coefficients of 168 to 172 S and a bouyant density of 1.29 g/mL (tubular capsids are frequently observed at this density). Molecular analysis of PV DNA was first deter- mined by Crawford and Crawford'0 and Craw- ford." " Using stringent hybridization techniques without the aid of various restriction endonucle- ases, it was concluded that although PV from the various species had similar structures and molecu- lar weights, there were no polynucleotide se- quences shared among the different genomes analyzed. The PV genome exists in virions and in infected cells in three forms (Fo); FoI is a cova- lently closed, circular, supercoiled molecule with a sedimentation coefficient of 23 S; FoII is an open, circular molecule with a sedimentation coefficient of 17 S and, Fo1II is a linear molecule with a sedi- mentation coefficient of 16 S u," AU forms appear to exist as nonintegrated, replicating plas- mids in both benign and malignant lesions."~" The molecular size of the genome based on agarose gel electrophoresis and contour length measure- ment of DNA molecules by electron microscopy reveals a molecular weight of approximately 5 x 10• daltons, corresponding to 8000 base pairs of genetic information, which is sufficient to code for 300,000 daltons of protein?'-" The guanine-plus- cytosine content of HPV DNA is 41 moi°1o,•' and nearest-neighbor analysis indicates a similarity to host species DNA" Two pairs of inverted repeti- tive (palindromic) sequences have been detected in the genome of HPV-I" the significance is unknown. Structural viral proteins constitute approxi- mately 88% of the mass of the PV virion," and up to 10 polypeptides have been resolved by sodium dodecyl sulfate polyacrylamide gel dectrophoresis. Each PV has a major capsid protein with a molec- ular weight of 54,000 to 63,000 daltons" "-" A variety of other polypeptides in the molecular weight range of 30,000 to 53,000 daltons are con- sistently resolved in most virus preparations. Al- though some may represent degradation products of the major capsid protein, others are most likely minor capsid proteins. Four low-molecular- weight polypeptides closely associated with viral DNA have been resolved and are similar to cellu- lar histones." At present nonstructural viral pro- teins and/or PV tumor antigens have not been identified in HPV-associated lesions using a variety of techniques. CLASSMCATION OF HPV TYPES The papillomaviruses are classified into types or subtypes on the basis of polynucleotide sequence homology." To be classified as a new PV type, a maximum of 5007o polynucleotide sequence ho- mology with other classified viruses should exist in conjunction with significant serological deviations in reciprocal assays. Those viruses with greater than 50°to but less than 100eto deoxyribonucleic acid (DNA) homology are subtypes. The closely related subtypes usually differ by having one or more distinct restriction endonuclease cleavage patteras. For example, HPV-6 and HPV-11 share about 2507o DNA sequence homology"•" and are thus considered different types; however, HPV types la and lb are subtypes since they are indis- tinguishable by hybridization and differ only with respect to a limited number of restriction sites." HPV DNA studies are dependent on extraction of nonintegrated supercoiled viral DNA from either purified virions or directly from HPV-asso- ciated lesions'-" The recoverability of virions appears to be dependent on both the type of HPV and the extent of differentiation of squamous epi- thelium as characterized by the degree of keratini- zation.30 PV structural antigens (and therefore virions) have not been found in lesions composed primarily of proliferating squamous epithelial cells with little or no differentiation or in squamous carcinomas regardless of the degree of differentia- tion (Jenson, unpublished data). Cutaneous warts, particularly plantar and common warts caused by HPV-1, contain the largest quantity of virions" whereas mucosal papillomas appear to contain the fewest viral particles. Recovery of viral DNA for purposes of classification can be accomplished by a variety of different approaches. One approach requires an abundance of HPV virions that are ex- tracted from the wart/papilloma and purified in CsCI equilibrium density gradients. The virions are ruptured by treatment with sodium dodecyl sulfate, deproteinized by phenol extraction, and supercoiled DNA subsequently isolated in CsCI-ethidium bromide equilibrium density gra- dients"•" Another method, particularly suitable if there are only small amounts of HPV particles, is extraction of supercoiled HPV DNA as a plas- mid from infected celLs"•"•"''° usually using modifications of the Hirt" differential salt extrac- tion technique. Early studies of endonuclease restriction pu- terns and physical maps of HPV DNA were limited to those viruses that produced large amounts of virions in cutaneous warts"•" How- - --tlmr- n_ P

954 ~s. HPV-S iid i~V~t have been frequently :w_ d ~idtffiobyca! studier, case reports, and = detected in pityriasis rosea-tike l,esions oa patients fe+r traaswlstion sttidies a¢wns humans.' For W year=:hgr-ieea known that cutaneous with epiderttiodysptisia vesrirciformis, a rare fa- .a& ,~,:_ milia~e#isorder, and in-immunosuppressed pa- warts ¢ould be traasmitted between individuals, tients. HPV-6 is the predominant virus associated either directly by skin contact, or indirectly from occasional mosaic plaatac warts and atftc '_al ~-- xlM[oa of_tlte,svailabk endeace that HPVs are warts. HPV-3 isdoiM aftnon exclusively ia 'lfat --tr~rt~u'3hibk, .- infectiotss Wnts comes from in common watts..*ii it.3tas al:o been found in "M11am1MM reassociation kiaetics" _ w*-nOw know t!~'most naturally occurring anti- Using molecularrb3+tfidizatioa techniques and - bodies are t7ps specific, reqtming the appropriate restriction easyme, diRst~on aaalysis. at least ii ~'.._ HPY type-speci8c anti,st for a positive reaction different types~of HPV bavar been clauified (Table : regii•dleia-of ,,,~e test. Ia- the past, most HPV an- 34-I): Tlwa vinues ace peefetentially, but not ex- ftea grep.is~ons have been obtained from pooled te%* speciSc clinical lesions. _erat4, which, in r+etrospecttPreclude interpreta- clusively, atsociad HP1%rpe 1 and 4_(HPV_.i_aad HPV.4) are asso- tioa_of some of the results. ciued mith pWttar waeta: I#PV-1 has also been ` ideati5ad..ia a small pe+oportioa of common and !A?HOGENFSIS anaseslital warts. HPV-2 is pfeCasttinantly found ever, with the development of molecular cloning with anogenital warts. HPV-7 is only associated technology, many new HPV types have been iden- with warts of meat handlers such as butchers, etc. tified from tissues containing small amounts of HPV-10, 12. 13, 14, and 15 have been detected viral DNA."'* Viral sequences are cleaved with a only in patients with epidermodysplasia verruci- battery of restriction enzymes of which one may formis. HPV-li is associated most commonly yield a single cleavage site. facilitating cloning of with largyngeal papillomas but, along with the entire viral genome. The vector systems cur- HPV-16, has been reported in cervical dysplasias rently in use are bacterial plasmids, particularly and cervical carcinoma. pBR3,1-1, and derivatives of bacteriophage lambda. The viral sequences to be cloned are ligated to the EPIDE!rtIOLOGY %ector and then used to transform competent bac- Accurate information on the prevalence of terial cells. Most vectors have selective markers HPV-associated lesions is not available because tt such as antibiotic resistance or metabolic pathway is based primarily on clinical observations and his- inactivation. Once a bacterial colony that contains tories of patients.'.'-" Detailed epidemiolog,c the proper insert of viral DNA is selected, vir- studies have not been performed. Laryngeal papil- tua4ly unlimited amounts of viral sequences can lomas occur predominantly in preschool children" be prepared from mass culture for detailed but exhibit a second lower peak in later life.'0 Ver- characterization."" rucae plana (flat or juvenile warts) occur primarily Preliminary identification andior classification in preschool and grade-school children. Common of DNA sequences extracted from biopsy material warts appear to occur most frequently in school- are accomplished by probing for HPV sequences age children and adolescents with the frequency using blotting methodologies such as described by of current HPV infection varying from S% to Southern." With this method the low-molecular- 13?7.. Piantar warts appear to be more common in weight DNA sequences are extracted from virions adolescents and young adults, probably as a result or tissues and cleaved using restriction enzyme en- of a high exposure in communal activities such as donucleases.43 The DNA fragments are separated bathing and swimming, where a combination of by gel electrophoresis and then transferred to a moisture and minor trauma to the feet play a role. nitrocellulose membrane and hybridization with a Anogenital warts are most often seen in young, radiolabeled PV probe can be performed under sexually promiscuous adults.' stringent (2S°C below the melting temperature of Epidemiologic studies of HPV-associated the DNA or Tm -2S°C) or relaxed (43°C below lesions must take into account that the spontan- the melting temperature of DNA or Tm -43°C) eous regression of warts, and probably mucosal conditions."-°'-" Under relaxed conditions. papillomas, is high, approaching 25074 to 35°7o in regions of HPV DNA homology with as much as the first six months and 359% to 70% within two 337% base mismatch can be detected. The percent years.?~v_ Assessment of antibody prevalence is -homology among the various HPVs, however, pebalWft most reliable measure for evaluating can only be accutatdy measured by DNA-DNA tlW,epideteti0W of HPV infections." However, I 0

955 clothing, jewelry, bathroom floors, etc. Warts and mucosal papillomas/condylomata, particu- larly those occurring at pressure points such as the sole of the foot or in loose traumatized tissue like the laryrtx, are likely to be multiple and recur after therapy. This is probably due either to auto- inoculation or seeding of HPV at the site of iatro- genic trauma. There is good evidence that infants may contract the HPV that causes juvenile laryn- geal papilloma as they pass through the birth canal of mothers who have genital condylomata, and, perhaps, cervical dysplasia.'•' Some cases of _#rai condylomata occur concurrently in individ- uals with genital condylomata.•" All of these ob- servations suggest that HPVs are the tra8stz>Wle agents that cause cutaneous and mucosal paj5il- lomZs in man. Two populations appear to be partictelarftore- disposed to HPV infections: 1) institunonalized individuals, and 2) immunosuppressed individ- uals. In one study over one quarter of patients in a mental institution had warts." This probably only reflects increased contact among individuals in close quarters, since the spontaneous regression rate was as high as other populations. The increased incidence and severity of warts in patients with naturally acquired and iatrogenic immunosup- pression undoubtedly reflects the role of the im- mune system in HPV infections.= '13-76 Although generalized warts have been seen in patients with agarnmaglobinemia, it appears to be more fre- quent in patients with decreased cell-mediated responses. Incubation Period The incubation period of warts is best assessed by reviewing data from experiments on the trans- mission of human warts.' The incubation period for most of the experiments was one to three months, but some incubation periods were as long as six to 20 months. The incubation period for genital warts has been estimated at two to three months with an infectivity rate of approximately bS47o." Host Response All three types of squamous epithelium, 1) cu- tane.ous (keratinized), 2) mucosa! (nonkeratinized), and 3) metaplastic, are susceptible to infection by HPV.' Generally, the various types of human warts and mucosal-.,papillomas are well-circum- scribed papillomatous growths that vary in size and color and tend to have a roughened horny surface but some HPV-associated lesions such as juvenile warts, cervical dysplasia, and pityriasis rosea-like lesions are flat and difficult to delineate precisely on visual examination.=•'• It is thought that the HPV genome is present in a stable form in the basal layer of the wart," and that early gene expression is associated with acan- thosis (increase in stratum spinosum or prickle cell layer). Vegetative viral DNA synthesis begins in the suprabasal cells of the prickle layer" and is followed by late gene expreuion (structural poly- peptides) and virion assembly occurring almost ex- clusively within nuclei of the granular layer of cells." The phenotypic expression (histopathologic Nwe«~ rsor~om. - - hoi+wn~ow ~ ° tlie4. o1n" Figure 34-1 This illustration depicts the hi:tolopc features of normal skin and the histaoat6biogic features of an adjacent papilloma (wan). in the normal itiitt, there is a basal layer of od(i,which under" divisdon to fotut a multipk cell layer of prickle cells. The number ofprictk cells determines the thiftness of the skin, which varies aecorditt; to location. As the prickle cells are pushed toward the surface, they flatten and develop cytoplauaic keratohyaline =ranules (Ranular cells). The Rattular cells then lose nudei, and the cytoplasm and keratohyatitte giranuks coalesce into a flat, acetlular keratinized layer. In the papilloma. there is a sinlle layer of basal celis but there is hyperplasia of prickle cells (acanthosis) and production of excess keratin (hyperkeratosis) which is associated with the formation of epithelial spikes (papillomatosis). Virus inclusions andlor expression of HPV structural and{ens usually appear in granular cells with degenerative cytoplasmic vacuolization (koilocytotic cells). Reprtnted by permission from Jenson et al.'4 ~~~~ ~~ -S, 0 Aw

956 features) of most cutaneous warts and mucosal papillomas are similar' (Figure 34-1). Productive HPV infection is manifested by proliferation of prickle cells (acanthosis), degenerative cytoplas- mic vacuolization (koilocytosis), nuclear altera- tions (wrinkling and pyknosis) of granular cells. and the production of excess keratin. The acan- thosis and hyperkeratosis are associated with the formation of epithAal spikes referred to as papillomatosis. The epithelial proliferation may also extend downward, resulting in accentuated rete pegs referred to as inverted papillomatosis. Inverted papillomatosis is a feature of all but the flat lesions such as juvenile warts, pityriasis-like lesions, and cervical dysplasia. Inverted papillo- matosis is frequently encountered in vulvar lesions such as bowenoid papulosis (dysplasia), where it may be°mistaken for stromal invasion. Another characteristic feature of PV-induced lesions is their vascularity. As the epithelial proliferation becomes more exuberant, capillaries from the underlying -1dermis or stroma are drawn into the lesion. This accounts for the vascularity of warts and the abnormal vascular patterns seen in cervical dysplasia when viewed through the colposcope. CLINICAL SYNDROMES (COMMON) Cutaneous' " (Table 34I ) Verruca vulgaris (HPV-2; occasionally HPV-1) is the most common (vulgar) of all the warts. It is sessile and exophytic with a crusty appearing pa- pillomatous surface. Common warts can occur singly but are frequently multiple. They are usu- ally located on the hand. Verruca also occur in the oral cavity but much less frequently than on the skin. They are most frequently seen in young chil- dren. Some verruca disappear, but many are treated. Nonetheless a small but significant per- centage will recur regardless of the form of thera- peutic intervention. Verrua platttarfs or plantar warts (HPV-1: HPV-4) art seen mainly in adolescents and young adults. They usually occur as a single lesion on the sole of the foot. Although clinically aggressive, these warts usually respond well to treatment. They ars not elevated above the surface of the skin but extend deep into the sole where they are frequently painful. Although many forms of ther- apy, including irradiation. have been used on these lesions, there are no reports of malignant transformation. Verrnca plana (HPV-3) are flat warts which usually appear over the face and those parts of the extremities other than the hands and feet. Thev are multiple. Since these warts usually appear in children, they are frequently called juvenile wans. Juvenile warts are usually asymptomatic. cause few cosmetic problems, and may persist for a number of years, only to spontaneously disappear within a few weeks of each other.'°-'1 Mucosal Oral cavity and larynx Focal epithelial hyper- plasia (HPV type unknown) occurs only in the oral cavity, appearing clinically to be flat or slightly elevated and either white or the color of the surrounding mucosa.' These lesions have been reported to occur primarily in natives of Green- land and North and South America. suggesting the influence of environmental andtor genetic fac- tors. In Greenland Eskimos, it has been observed primarily in adults, whereas in the southwest In- dians, it has been reported to occur primarily in children." These lesions are usually multiple and spontaneously disappear. Single oral papiIlomas (HPV type unknown) are the most common benign epithelial tumors of the oral cav%ty!' They are pedunculated with a fibrovascular stalk and usually have a rough papil- lary appearance to their surface. They can occur in any age group, are usually solitary, and rarely recur after surgical excision. Multiple papillomas (HPV type unknown) are clinically and pathologically similar to condylo- mata, which occur infrequently in the oral cavity.4 Laryngeal papillomas are associated with HPV-11 "•" and are the most common benign epithelial tumors of the larynx." The clinical pic- ture is that of small exophytic papillomas which can coalesce and appear very exuberant.' They occur more frequently in children than adults, are typically multiple, and frequently recur after surgical removal. Laryngeal papillomatosis is usu- ally considered a life-threatening condition in children because of the danger of airway obstruc- tion and suffocation; they frequently disappear after puberty. Occasionally papillomas may ez- tend down the trachea and into the bronchi. Ma- lignant transformation may occur after radiation therapy.,."-" Aaogtaftal Condyloma acuminata, so-called anogenital or venereal warts, are caused primarily by HPV-6u•"•" but also HPV-li 1!' -1, and -2!' and occur almost exclusively on mucosd surfaces of external genitalia and perianal areas.".« They are occasionally found in the oral cavity where MRSTER-S3PP