Human papillomaviruses (HPV) are common human pathogens and are classified into more than 80 different types. These viruses produce benign warts in many cases and aggressive squamous cell carcinomas in other cases.
Objective:
The goal of this review is to update the reader on the epidemiology, pathogenesis, and therapy of HPV infections. Nonanogenital warts are transmitted by skin-to-skin contact while anogenital warts are usually transmitted sexually. Both types of warts produce much morbidity but rarely undergo malignant transformation. They are commonly treated with surgical or cytodestructive therapy, but immunomodulatory agents, such as imiquimod, have been proven to be very effective in anogenital warts and are being evaluated in nonanogenital warts. Other types of HPV have marked oncogenic potential such that over 99% of all cervical cancers and over 50% of other anogenital cancers are due to infection with oncogenic HPV. Many cofactors, such as cigarette smoking, genetics, and helper viruses, have potential roles in HPV oncogenesis, but their relative contributions are poorly understood. Other control measures for warts and HPV-associated cancers are under study, but the greatest future potential may be from the development of prophylactic and therapeutic vaccines.
Conclusions:
Infection with HPV is very prevalent as are the clinical manifestations of this family of pathogens. Improved therapies for warts (e.g., imiquimod) have recently become available. Vaccines for HPV offer hope for future interventions for warts as well as for prevention of anogenital malignancies.
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References
1.
zur HausenH. Papillomavirus infections—a major cause of human cancers. Biochim Biophys Acta1996; 1288:F55–F78.
2.
MajewskiSJablonskaS. Human papillomavirus-associated tumors of the skin and mucosa. J Am Acad Dermatol1997; 36:659–685.
3.
VillaLL. Human papillomaviruses and cervical cancer. Adv Cancer Res1997;71:321–341.
4.
ScurryJWellsM. Viruses in anogenital cancer. Epithelial Cell Biol1992; 1:138–145.
5.
Van RanstMKaplanJBBurkRD. Phylogenetic classification of human papillomaviruses: Correlation with clinical manisfestation. J Gen Virol1992; 73:2653–2660.
6.
McKaigRGBaricRSOlshanAF. Human papillomavirus and head and neck cancer: Epidemiology and molecular biology. Head Neck1998; 20:250–265.
7.
KarciogluZAIssaTM. Human papilloma virus in neoplastic and non-neoplastic external eye. Br J Ophthalmol1997; 81:595–598.
8.
BuchwaldCFranzmannMBJacobsenGK. Carcinomas occurring in papillomas of the nasal septum associated with human papilloma virus (HPV). Rhinology1997; 35:74–78.
9.
KiviatNBKoutskyLACritchlowCW. Prevalence and cytologic manifestations of human papilloma virus (HPV) types 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, and 56 among 500 consecutive women. Int J Gynecol Pathol1992; 11:197–203.
10.
zur HausenH. Human papillomaviruses in the pathogenesis of anogenital cancer. Virology1991; 184:9–13.
11.
SchneiderA. Pathogenesis of genital HPV infection. Genitourin Med1993; 69:165–173.
MajewskiSJablonskaS. Epidermodysplasia verruciformis as a model of human papillomavirus-induced genetic cancers: The role of local immunosurveillance. Am J Med Sci1992; 304:174–179.
14.
DaymanGLStewartMGWeberRS. Human papillomavirus in laryngeal and hypopharyngeal carcinomas. Relationship to survival. Arch Otolaryngol Head Neck Surg1994; 120:743–748.
15.
GomezMADrutRLojoMM. Detection of human papillomavirus in juvenile laryngeal papillomatosis using polymerase chain reaction. Medicina1995; 55:213–217.
16.
ChangFSyrjanenSKellokoskiJ. Human papillomavirus (HPV) infections and their associations with oral disease. J Oral Pathol Med1991;20:305–317.
17.
SnijdersPJvan den BruleAJCMeijerCJLM. Papillomaviruses and cancer of the upper digestive and respiratory tracts. In: zur HausenH, ed. Human pathogenic papillomaviruses. Berlin: Springer-Verlag, 1994, pp 177–198.
18.
MillerCSWhiteDK. Human papillomavirus expression in oral mucosa, premalignant conditions, and squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontr1996; 82:57–68.
19.
SteinbergBMAubornKJ. Papillomaviruses in head and neck disease: Pathophysiology and possible regulation. J Cell Biochem1993; 17F: 155–164.
20.
BrownDRFifeKH. Human papillomavirus infections of the genital tract. Med Clin North Am1990; 74:1455–1485.
21.
CampionMJ. Clinical manifestations and natural history of genital human papillomavirus infection. Dermatol Clin1991; 9:235–249.
22.
DoorbarJGallimorePH. Identification of proteins encoded by the LI and L2 open reading frames of human papillomavirus la. J Virol1987; 61:2793–2799.
23.
ChowLTBrokerTR. Papillomavirus DNA replication. Intervirology1994; 37:150–158.
24.
MansurCPAndrophyEJ. Cellular tranformation by papillomavirus oncoproteins. Biochim Biophys Acta1993; 1155:323–345.
25.
BanksLMatlashewskiG. Cell transformation and the HPV E5 gene. Papillomavirus Rep1993; 4:1–4.
26.
HudsonJBBedellMAMcCanceDJ. Immortalization and altered differentiation of human keratinocytes in vitro by the E6 and E7 open reading frames of human papillomavirus type 18. J Virol1990; 64:519–526.
27.
DoorbarJElySSterlingJ. Specific interaction between HPV-16 E1-E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network. Nature1991; 352:824–827.
28.
TurekLP. The structure, function, and regulation of papillomaviral genes in infection and cervical cancer. Adv Virus Res1994; 44:305–356.
29.
BernardH-UAptD. Transcriptional control and cell type specificity of HPV gene expression. Arch Dermatol1994; 130:210–215.
30.
DesaintesCDemeretC. Control of papillomavirus replication and transcription. Sem Cancer Biol1997; 7:339–347.
31.
Hoppe-SeylerFButzK. Cellular control of human papillomavirus oncogene transcription. Mol Carcinog1994; 10:134–141.
32.
StubenrauchFMalejczykJFuchsPG. Late promoter of human papillomavirus type 8 and its regulation. J Virol1992; 66:3485–3493.
33.
HigginsGDUzelinDMPhillipsGE. Transcription patterns of human papillomavirus type 16 in genital intraepithelial neoplasia: Evidence for promoter usage within the E7 open reading frame during epithelial differentiation. J Gen Virol1992; 73:2047–2057.
34.
McBrideAARomanczukHHowleyPM. The papillomavirus E2 regulatory proteins. J Biol Chem1991; 266:18411–18414.
35.
ChooKBPanCCHanSH. Integration of human papillomavirus type 16 into cellular DNA of cervical carcinoma: Preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames. Virology1987; 161:259–261.
36.
ShirasawaHTornitaYSekiyaS. Integration and transcription of human papillomavirus type 16 and 18 sequences in cell lines derived from cervical carcinomas. J Gen Virol1987; 68:583–591.
37.
CooperKMcGeeJO. Human papillomavirus, integration and cervical carcinogenesis: A clinicopathological perspective. Mol Pathol1997; 50:1–3.
38.
MohrIJClarkRSunS. Targeting the El replication protein to the papillomavirus origin of replication by complex formation with the E2 transactivator. Science1990; 250:1694–1699.
39.
HamJDostatniNGauthierJ-M. The papillomavirus E2 protein: A factor with many talents. Trends Biochem Sci1991; 16:440–444.
40.
DemeterLMStolerMHBrokerTR. Induction of proliferating cell nuclear antigen in differentiated keratinocytes of human papillomavirus-infected lesions. Hum Pathol1994; 25:343–348.
41.
JonesKTSharpeGR. Proliferating cell nuclear antigen decreases in normal human keratinocytes with differentiation stimuli but not in an HPV immortalised cell line. Acta Dermatol Venereol1994; 74:241–244.
42.
ChengSSchmidt-GrimmingerD-CMurantT. Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev1995; 9:2335–2349.
43.
LaiminsLA. Regulation of transcription and replication by human papillomaviruses. In: McCanceDJ, ed. Human Tumor Viruses. Washington, DC: American Society for Microbiology, 1998, pp 201–223.
44.
UstavEUstavMSzymanskiP. The bovine papillomavirus origin of replication requires a binding site for the E2 transcriptional activator. Proc Natl Acad Sci USA1993; 90:898–902.
45.
EnzenauerCMengusGLavigneA. Interaction of human papillomavirus 8 regulatory proteins E2, E6 and E7 with components of the TFIID complex. Intervirology1998; 41:80–90.
46.
GoodwinECNaegerLKBreidingDE. Transactivation-competent bovine papillomavirus E2 protein is specifically required for efficient repression of human papillomavirus oncogene expression and for acute growth inhibition of cervical carcinoma cell lines. J Virol1998; 72:3925–3934.
47.
FavreMRamozNOrthG. Human papillomaviruses: General features. Clin Dermatol1997; 15:181–198.
48.
SyrjanenKJ. Spontaneous evolution of intraepithelial lesions according to the grade and type of the implicated human papillomavirus (HPV). Eur J Obstet Gynecol Reprod Biol1996; 65:45–53.
SouthernSAHerringtonCS. Molecular events in uterine cervical cancer. Sex Transm Infect1998; 74:101–109.
51.
ShrirasawaHTornitaYKubotaK. Transcriptional differences of the human papillomavirus type 16 genome between precancerous lesions and invasive carcinomas. J Virol1988; 62:1022–1027.
52.
JohnssonMABlomfieldPIBevanIS. Analysis of human papillomavirus type E6-E7 transcription in cervical carcinomas and normal cervical epithelium using the polymerase chain reaction. J Gen Virol1990; 71:1473–1479.
53.
SyrjanenK. Anogenital human papilloma virus and the problem of persistence. Eur J Dermatol1998; 8:5–7; discussion 20–22.
54.
BoschFXManosMMMunozN. Prevalence of human papillomavirus in cervical cancer: A worldwide perspective. International Biological Study on Cervical Cancer (IBSCC) Study Group (see comments). J Natl Cancer Inst1995; 87:796–802.
55.
RiouGFavreMJeannelD. Association between poor prognosis in early-stage invasive cervical carcinomas and non-detection of HPV DNA. Lancet1990; 335:1171–1174.
56.
ResnickRMCornelissenMTEWrightDK. Detection and typing of human papillomavirus in archival cervical cancer specimens by DNA amplification with consensus primers. J N Cancer Inst1990; 82:1477–1484.
57.
ArendsMJBuckleyCHWellsM. Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol1998; 51:96–103.
58.
SchiffmanMHBrintonLA. The epidemiology of cervical carcinogenesis. Cancer1995; 76:1888–1901.
59.
BarbosaMS. The oncogenic role of human papillomavirus proteins. Crit Rev Oncog1996; 7:1–18.
60.
CannizzaroLADurstMMendezMJ. Regional chromosome localization of human papillomavirus integration sites near fragile sites, oncogenes, and cancer chromosome breakpoints. Cancer Genet Cytogenet1988; 33:93–98.
61.
ChuTYShenCYLeeHS. Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: A local field effect of genomic instability and clonal evolution. Genes Chromosomes Cancer1999; 24:127–134.
62.
ParkJSunDGenestDR. Coexistence of low and high grade squamous intraepithelial lesions of the cervix: Morphologic progression or multiple papillomaviruses?Gynecol Oncol1998; 70:386–391.
63.
KalantariMKarlsenFJohanssonB. Human papillomavirus findings in relation to cervical intraepithelial neoplasia grade: A study on 476 Stockholm women, using PCR for detection and typing of HPV. Hum Pathol1997; 28:899–904.
64.
StopplerHStopplerMCSchlegelR. Transforming proteins of the papillomaviruses. Intervirology1994; 37:168–179.
65.
GissmannnL. Papillomaviruses and human oncogenesis. Curr Opin Genet Dev1992; 2:97–102.
66.
HowleyPMScheffnerMHuigbretseJ. Oncoproteins encoded by the cancer-associated human papillomaviruses target the products of the retinoblastoma and p53 tumor suppressor genes. Cold Spring Harb Symp Quant Biol1991; LVL:149–155.
67.
DonehowerLABradleyA. The tumor suppressor p53. Biochim Biophys Acta1993; 1155:181–205.
68.
MungerKPhelpsWC. The human papillomavirus E7 protein as a transforming and transactivating factor. Biochim Biophys Acta1993; 1155:111–123.
69.
JonesDLMungerK. Interactions of the human papillomavirus E7 protein with cell cycle regulators. Sem Cancer Biol1997; 7:327–337.
70.
HubbertNLSedmanSASchillerJT. Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. J Virol1992; 66:6237–6241.
71.
WernessBALevineAJHowleyPM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science1990; 248:76–79.
72.
ButzKShahabeddinLGeisenC. Functional p53 protein in human papillomavirus-positive cancer cells. Oncogene1995; 10:927–936.
73.
LevineAJ. The p53 tumor suppressor gene and product. Biol Chem Hoppe Seyler1993; 374:227–235.
74.
SelterHMontenarhM. The emerging picture of p53. Int J Biochem1994; 26:145–154.
75.
GartelALTynerAL. Transcriptional regulation of the p21 ((WAF1/CIP1)) gene. Exp Cell Res1999; 246:280–289.
76.
WagaSHannonGJBeachD. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature1994; 369:574–578.
77.
ShackelfordREKaufmannWKPaulesRS. Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environ Health Perspect1999; 107:5–24.
78.
GreenblattMSBennettWPHollsteinM. Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res1994; 54:4855–4878.
79.
PaquetteRLLeeYYWilczynskiSP. Mutations of p53 and human papillomavirus infection in cervical carcinoma. Cancer1993; 72:1272–1280.
80.
HellandAKarlsenFDueEU. Mutations in the TP53 gene and protein expression of p53, mdm2 and p21/WAF-l in primary cervical carcinomas with no or low human papillomavirus load. Br J Cancer1998; 78:69–72.
81.
MinB-MBaekJ-HShinK-H. Inactivation of the p53 gene by either mutation or HPV infection is extremely frequent in human oral squamous cell carcinoma cell lines. Eur J Cancer1994; 30B:338–345.
82.
ScheffnerMWernessBAHuigbretseJM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell1990; 63:1129–1136.
83.
PenhallowJSteingrimsdottirHElaminF. p53 alterations and HPV infections are common in oral SCC: P53 gene mutations correlate with the absence of HPV16-E6 DNA. Int J Oncol1998; 12:59–68.
84.
ScheffnerMMungerKByrneJC. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci USA1991; 88:5523–5527.
85.
DesaintesCHallezSDetremmerieO. Wild-type p53 down-regulates transcription from oncogenic human papillomavirus promoters through the epithelial specific enhancer. Oncogene1995; 10:2155–2161.
86.
KurvinenKSyrjanenKSyrjanenS. p53 and bcl-2 proteins as prognostic markers in human papillomavirus-associated cervical lesions. J Clin Oncol1996; 14:2120–2130.
87.
PillaiMRHalabiSMcKalipA. The presence of human papillomavirus-16/18 E6, p53, and bcl-2 protein in cervicovaginal smears from patients with invasive cervical cancer. Cancer Epidemiol Biomarkers Prev1996; 5:329–335.
88.
MiwaKMiyamotoSKatoH. The role of p53 inactivation in human cervical cell carcinoma development. Br J Cancer1995; 71:219–226.
89.
NganHYSStanleyMLiuSS. HPV and p53 in cervical cancer. Genitourin Med1994; 70:167–170.
90.
SheetsEEYehJ. The role of apoptosis in gynaecological malignancies. Ann Med1997; 29:121–126.
91.
SlebosRJCLeeMHPlunkettBS. p53-dependent Gl arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein. Proc Natl Acad Sci USA1994; 91:5320–5324.
92.
DemersGWFosterSAHalbertCL. Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. Proc Natl Acad Sci USA1994; 91:4382–4386.
93.
KessisTDSlebosRJNelsonWG. Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. Proc Natl Acad Sci USA1993; 90:3988–3992.
94.
AlfandariJMagalShnitman SJackmanA. HPV16 E6 oncoprotein inhibits apoptosis induced during serum-calcium differentiation of foreskin human keratinocytes. Virology1999; 257:383–396.
95.
PillaiRMNairPNairKM. Decreased programmed cell death in the uterine cervix associated with high risk human papillomavirus infection (in Process Citation). Pathol Oncol Res1999; 5:95–103.
96.
FuruyaHYabushitaHNoguchiM. Apoptosis and cell growth fraction in normal, dysplastic and neoplastic squamous epithelium of uterine cervix. Nippon Rinsho1996; 54:1916–1921.
97.
MythilyDVKrishnaSTergaonkarV. Pleiotropic effects of human papillomavirus type 16 E6 oncogene expression in human epithelial cell lines. J Gen Virol1999; 80:1707–1713.
98.
LiuYTergaonkarVKrishnaS. Human papillomavirus type 16 E6-enhanced susceptibility of L929 cells to tumor necrosis factor alpha correlates with increased accumulation of reactive oxygen species. J Biol Chem1999; 274:24819–24827.
99.
KilicGCardilloMOzdemirliM. Human papillomavirus 18 oncoproteins E6 and E7 enhance irradiation- and chemotherapeutic agent-induced apoptosis in p53 and Rb mutated cervical cancer cell lines. Eur J Gynaecol Oncol1999; 20:167–171.
100.
StoreyAThomasMKalitaA. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature1998; 393:229–234.
101.
RosenthalANRyanAAl-JehaniRM. p53 codon 72 polymorphism and risk of cervical cancer in UK. Lancet1998; 352:871–872.
102.
HellandALangerodAJohnsenH. p53 polymorphism and risk of cervical cancer. Nature1998; 396:530–531.
103.
StoreyAThomasMKalitaA. p53 polymorphism and risk of cervical cancer. Nature1998; 396:531–532.
104.
JosefssonAMMagnussonPKEYlitaloN. p53 polymorphism and risk of cervical cancer. Nature1998; 396:531.
105.
DiPaoloJAPopescuNCWoodworthCD. Papillomaviruses and potential copathogens. Toxicol Lett1996; 88:1–7.
106.
GallowayDAMcDougallJK. The disruption of cell cycle checkpoints by papillomavirus oncoproteins contributes to anogenital neoplasia. Sem Cancer Biol1996; 7:309–315.
107.
HashidaTYasumotoS. Induction of chromosome abnormalities in mouse and human epidermal keratinocytes by the human papillomavirus type 16 E7 oncogene. J Gen Virol1991; 72:1569–1577.
108.
YinXYGroveLDattaNS. C-myc overexpression and p53 loss cooperate to promote genomic instability. Oncogene1999; 18:1177–1184.
109.
HeselmeyerKMacvilleMSchrockE. Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q. Genes Chromosomes Cancer1997; 19:233–240.
110.
DaviesRHicksRCrookT. Human papillomavirus type 16 E7 associates with a histone H1 kinase and with p107 through sequences necessary for transformation. J Virol1993; 67:2521–2528.
111.
LudlowJWSkuseGR. Viral oncoprotein binding to pRB, p107, p130, and p300. Virus Res1995; 35:113–121.
112.
LeCouterJEKablarBWhytePF. Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. Development1998; 125:4669–4679.
113.
BowmanTSymondsHGuL. Tissue-specific inactivation of p53 tumor suppression in the mouse. Genes Dev1996; 10:826–835.
114.
GranaXGarrigaJMayolX. Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth. Oncogene1998; 17:3365–3383.
115.
WeinbergRA. The retinoblastoma protein and cell cycle control. Cell1995; 81:323–330.
116.
HartwellLHKastanMB. Cell cycle control and cancer. Science1994; 266:1821–1828.
117.
FarnhamPJSlanskyJEKollmarR. The role of E2F in the mammalian cell cycle. Biochim Biophys Acta1993; 1155:125–131.
118.
NevinsJR. E2F: A link between the RB tumor suppressor protein and viral oncoproteins. Science1992; 258:424–429.
119.
HelinK. Regulation of cell proliferation by the E2F transcription factors. Curr Opin Genet Dev1998; 8:28–35.
120.
ImaiYMatsushimaYSugimuraT. Purification and characterization of human papillomavirus type 16 E7 protein with preferential binding capacity to the underphosphorylated form of retinoblastoma gene product. J Virol1991; 65:4966–4972.
121.
McIntyreMCRueschMNLaiminsLA. Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a complex with cdk2 and p107. Virology1996; 215:73–82.
122.
ZerfassKSchulzeASpitkovskyD. Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J Virol1995; 69:6389–6399.
123.
AntinoreMJBirrerMJPatelD. The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors. EMBO J1996; 18:1950–1960.
124.
SteeleCCowsertLMShillitoeEJ. Effects of human papillomavirus type 18-specific antisense oligonucleotides on the transformed phenotype of human carcinoma cell lines. Cancer Res1993; 53:2330–2337.
125.
DurstMBoschFXGlitzD. Inverse relationship between human papillomavirus (HPV) type 16 early gene expression and cell differentiation in nude mouse epithelial cysts and tumors induced by HPV-positive human cell lines. J Virol1991; 65:796–804.
126.
NairSANairMBJayaprakashPG. Ras and c-myc oncoproteins during tumor progression in the uterine cervix. Tumori1998; 84:583–588.
127.
IwasakaTYokoyamaMOh-UchidaM. Detection of human papillomavirus genome and analysis of expression of c-myc and Ha-ras oncogenes in invasive cervical carcinomas. Gynecol Oncol1992; 46:298–303.
128.
BreitburdFRamozNSalmonJ. HLA control in the progression of human papillomavirus infections. Sem Cancer Biol1997; 7:359–371.
129.
GlewSSConnorMESnijdersPJF. HLA expression in pre-invasive cervical neoplasia in relation to human papilloma virus infection. Eur Cancer1993; 29A:1963–1970.
130.
CrommeFVMeijerCJLMSnijdersPJF. Analysis of MHC class I and II expression in relation to presence of HPV genotypes in premalignant and malignant cervical lesions. Br J Cancer1993; 67:1372–1380.
131.
CrommeFVSnijdersPJvan de BruleAJ. MHC class I expression in HPV 16 positive cervical carcinomas is post-transcriptionally controlled and independent from c-myc overexpression. Oncogene1993; 8:2969–2975.
132.
KeatingPJCrommeFVDuggan-KeenM. Frequency of down-regulation of individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1 expression. Oncogene1995; 10:405–411.
133.
McFaddenGKaneK. How DNA viruses perturb functional MHC expression to alter immune recognition. Adv Cancer Res1994;63:117–209.
134.
BartolomewJSGlenvilleSSarkarS. Integration of high-risk human papillomavirus DNA is linked to the downregulation of class I human leukocyte antigens by steroid hormones in cervical tumor cells. Cancer Res1997; 57:937–942.
135.
SoodAKPanJBiroPA. Structure and polymorphism of class I MHC antigen mRNA. Immunogenetics1985; 22:101–121.
136.
ErlichHABugawanTL. HLA class II gene polymorphism: DNA typing, evolution, and relationship to disease susceptibility. In: ErlichHA, ed. PCR technology. New York: Stockton Press, 1989, pp 193–208.
137.
SanjeeviCBHjelstromPHallmansG. Different HLA-DR-DQ haplotypes are associated with cervical intraepithelial neoplasia among human papillomavirus type-16 seropositive and seronegative Swedish women. Int J Cancer1996; 68:409–414.
138.
BoschFXManosMMMunozN. Prevalence of human papillomavirus in cervical cancer: A worldwide perspective. J Natl Cancer Inst1995; 87:796–802.
139.
LorinczATReidRJensonAB. Human papillomavirus infection of the cervix: Relative risk associations of 15 common anogenital types. Obstet Gynecol1992; 79:328–337.
140.
SandPBowenLBuschkeS. Evaluation of male consorts of women with genital human papillomavirus infection. Obstet Gynecol1986; 68:679–681.
141.
DalingJRShermanKJWeissNS. Risk factors for condyloma acuminatum in women. Sex Transm Dis1986; 13:16–18.
142.
KoutskyLAGallowayDAHolmesKK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev1988; 10:122–163.
143.
TrofatterKF. Diagnosis of human papillomavirus genital tract infection. Am J Med1997; 102(5A):21–27.
144.
MitchellHDrakeMMedleyG. Prospective evaluation of risk of cervical cancer after cytological evidence of human papillomavirus infection. Lancet1986; 1:573–575.
145.
LombardIVincent-SalomonAValidireP. Human papillomavirus genotype as a major determinant of the course of cervical cancer. J Clin Oncol1998; 16:2613–2619.
146.
DalingJRShermanKJHislopTG. Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol1992; 135:180–189.
147.
LangleyPTyringSKSmithM. The cost effectiveness of patient applied vs provider administered intervention strategies for the treatment of external genital warts. Am J Managed Care1999; 5:69–77.
148.
FerenczyAMitaoMNagaiN. Latent papillomavirus and recurring genital warts. N Engl J Med1985; 313:784–788.
149.
KhawajaHT. Podophyllin versus scissor excision in the treatment of perianal condylomata acuminata a prospective study. Br J Surg1989; 76:1067–1068.
150.
StoneKMBeckerTMHadguA. Treatment of external genital warts: A randomized clinical trial comparing podophyllin, cryotherapy, and electrodesiccation. Genitourin Med1990; 66:16–19.
151.
FerenczyABehelakYHaberG. Treating vaginal and external anogenital condylomas with electrosurgery vs CO2 laser ablation. J Gynecol Surg1995; 11:41–50.
152.
FerenczyABergeronCRichartRM. Human papillomavirus DNA in CO2 laser-generated plume of smoke and its consequences to the surgeon. Obstet Gynecol1990; 75:114–118.
153.
AbdullahANWalzmanMWadeA. Treatment of external genital warts comparing cryotherapy (liquid nitrogen) and trichloroacetic acid. Sex Transm Dis1993; 20:344–345.
154.
PrideGL. Treatment of large lower genital tract condylomata acuminata with topical 5-fluorouracil. J Reprod Med1990; 35:384–387.
155.
SwinehartJMSperlingMPhillipsS. Intralesional fluorouracil/epinephrine injectable gel for treatment of condylomata acuminata. Arch Dermatol1997; 133:67–73.
156.
GodleyMJBradbeerCSGellanM. Cryotherapy compared with trichloroacetic acid in treating genital warts. Genitourin Med1987; 63:390–392.
157.
EdwardsAAtma-RamAThinRN. Podophyllotoxin 0.5% v podophyllin 20% to treat penile warts. Genitourin Med1988; 64:263–265.
158.
PetersenCSWeismannK. Quercetin and kaempherol: An argument against the use of podophyllin?Genitourin Med1995; 71:92–93.
159.
FrazerPALaceyCJM. Podophyllotoxin is superior to podophyllin in the treatment of genital warts. J Eur Acad Venereol1993; 2:328–334.
160.
TyringSKEdwardsLFriedmanDJ. Safety and efficacy of 05% podofilox gel in the treatment of external genital and/or perianal warts: A double-blind, vehicle controlled study. Arch Dermatol1998; 134:33–38.
161.
ShelleyWBShelleyED. Intralesional bleomycin sulphate therapy for warts. Arch Dermatol1991; 127:234–236.
162.
RogozinskiTGeizerJMCzarnetzkiBM. Acitretin in the treatment and prevention of viral, premalignant and malignant skin lesions. J Dermatol Treat1989; 1:91–93.
163.
EurardSVershooreuMTouraineJL. Topical retinoids for warts and keratoses in transplant recipients. Lancet1992; 340:48–49.
164.
NaylorMFNeidnerKHYarboroughGK. Contact immunotherapy of resistant warts. J Am Acad Dermatol1988; 19:679–683.
165.
LeeANMallorySB. Contact immunotherapy with squaric acid dibutylester for the treatment of recalcitrant warts. J Am Acad Dermatol1999; 41:595–599.
166.
GlassATSolomonBA. Cimetidine therapy for recalcitrant warts in adults. Arch Dermatol1996; 132:680–682.
167.
YilmazEAlpsoyEBasaranE. Cimetidine therapy for warts; A placebo controlled double blind study. J Am Acad Dermatol1996; 34:1005–1007.
168.
ColemanNBirleyHDLRentonAM. Immunological events in regressing genital warts. Am J Clin Pathol1994; 102:768–774.
169.
IsaacsALindemannJ. Virus interference I: The interferon. Proc R Soc Ser B1957; 147:258–267.
170.
RockleyPFTyringSK. Interferons alpha, beta, and gamma therapy of anogenital human papillomavirus infections. Pharmacol Therapeut1995; 65(2):265–287.
RusconiSAgarossiARavasiL. Serum 2″-5″-oligoadenylate synthetase levels and clinical response to interferon-beta therapy in women with genital human papillomavirus infection. J Infect Dis1994; 169:1112–1115.
173.
GrasseggerARollinger-HolzingerIZeigerBWH. Spontaneous or interferon-gamma-induced T-cell infiltration, HLA-DR and ICAM-1 expression in genitoanal warts are associated with TH1 or mixed TH1/TH2 cytokine mRNA expression profiles. Arch Dermatol Res1997; 289:243–250.
174.
AranyITyringSK. Activation of local cell-mediated immunity in interferon-responsive patients with human papillomavirus-associated lesions. J Interferon Cytokine Res1996; 16:453–460.
175.
TurekLPByrneJCLowyDR. Interferon induces morphologic reversion with elimination of extrachromosomal viral genomes in bovine papillomavirus-transformed mouse cells. Proc Natl Acad Sci1982; 79:7914–7918.
176.
FinterNB. An overview of Wellferon (interferon alpha-nl): The product. Med Clin North Am1986; 70((suppl)):13–18.
177.
IkicDOrescaninMKrusicJ. Preliminary study of the effect of human leukocyte interferon on condyloma acuminata in women. Proc Symp Clin Use Interferon Yugoslav Acad Sci Arts1975; 223–225.
178.
ArmstrongDKBMawRDDinsmoreWW. A randomized, double-blind, parallel group study to compare subcutaneous interferon alpha-2a plus podophyllin with placebo plus podophyllin in the treatment of primary condyloma acuminata. Genitourin Med1994; 70:389–393.
179.
DdcDBosnicNSmerdelS. Double blind clinical study with human leukocyte interferon in the therapy of condyloma acuminata. Proc Symp Clin Use Interferon Yugoslav Acad Sci Arts1975; 299–233.
180.
VesterinenEMeyerBCantellK. Treatment of vaginal flat condyloma with interferon cream. Lancet1984; 1:157.
181.
KeaySTengNEisenbergM. Topical interferon for treating condyloma acuminata in women. J Infect Dis1988; 158:934–939.
182.
SyedTALundinSCheemaKM. Human leukocyte interferon alpha in cream, for the treatment of genital warts in Asian women: A placebo-controlled double-blind study. Clin Investig1994; 72:870–873.
183.
SyedTACheemaKMKhayyamiM. Human leukocyte interferon-alpha versus podophyllotoxin in cream for the treatment of genital warts in males: A placebo-controlled double-blind comparative study. Dermatology1995; 191:129–132.
184.
SyedTAKhayyamiMKrizD. Management of genital warts in women with human leukocyte interferon-alpha versus podophyllotoxin in cream: A placebo-controlled, double-blind comparative study. J Mol Med1995; 73:255–258.
185.
CirelliRTyringSK. Interferons in human papillomavirus infections. Antiviral Res1994; 24:191–204.
186.
GeffenJRKleinRJFriedman-KienAE. Intralesional administration of large doses of human leukocyte interferon for the treatment of condyloma acuminata. J Infect Dis1984; 150:612–615.
187.
Friedman-KienAEEronLJConantM. Natural interferon-alpha for treatment of condylomata acuminata. J Am Med Assoc1988; 259:533–538.
188.
Friedman-KienAE. Management of condyloma acuminata with Alferon N injection, interferon alpha-n3 (human leukocyte derived). Am J Obstet Gynecol1995; 172(4, Pt2):1359–1368.
189.
EronLJudsonFTuckerS. Interferon therapy for condyloma acuminata. N Engl J Med1986; 15:1059–1064.
190.
VanceJCBartBJHansenRC. Intralesional recombinant alpha-2 interferon for the treatment of patients with condyloma acuminatum-verruca plantaris. Arch Dermatol1986; 122:272–277.
191.
VanceJCBartBJBartB. Effectiveness of intralesional human recombinant alpha-2b interferon (intron-A) for the treatment of patients with condyloma acuminatum. Clin Res1986; 34:993A.
192.
HatchKDBartBJHansenRC. Evaluation of interferon alpha2 in the treatment of condyloma acuminatum. Colposc Gynecol Laser Surg1988; 4:187–196.
193.
BootJMBlogBStolzE. Intralesional interferon alpha-2b treatment of condyloma acuminata previously resistant to podophyllum resin application. Genitourin Med1989; 65:50–53.
194.
ScottGMCsonkaGW. Effect of injections of small doses of human fibroblast interferon into genital warts. A pilot study. Br J Vener Dis1979; 55:442–445.
195.
MarcoviciRPeretzBAPaldiE. Human fibroblast interferon therapy in patients with condyloma acuminata. Isr J Med Sci1983; 19:104.
196.
MonsonegoJCessotGInceSE. Randomised double-blind trial of recombinant interferon-beta for condyloma acuminatum. Genitourin Med1996; 72:111–114.
197.
BornsteinJPascalBZarfatiD. Recombinant human interferon-beta for condyloma acuminata: A randomized, double-blind, placebo-controlled study of intralesional therapy. Int J STD AIDS1997; 8:614–621.
198.
DinsmoreWJordanJO'MahonyC. Recombinant human interferon-beta in the treatment of condyloma acuminata. Int J STD AIDS1997; 8:622–628.
199.
ReichmanRCOakesDBonnezW. Treatment of condyloma acuminatum with three different interferons administered intralesionally: A double-blind, placebo-controlled trial. Ann Intern Med1988; 108:675–679.
200.
EinhornNLingPStranderH. Systemic interferon-alpha treatment of human condyloma acuminata. Acta Obstet Gynecol Scand1983; 62:285–287.
201.
TrofatterKFEnglishPCHughesCE. Human lymphoblastoid interferon in primary therapy of two children with condyloma acuminata. Obstet Gynecol1986; 67:137–140.
202.
GallSAHughesCETrofatterK. Interferon for the therapy of condyloma acuminata. Am J Obstet Gynecol1985; 153:157–163.
203.
OlsenEATrofatterKFGallSA. Human lymphoblastoid alpha-interferon in the treatment of refractory condyloma acuminata. Clin Res1985; 33:673A.
204.
ReichmanRCMichaJPWeckPK. Interferon alpha-nl for refractory genital warts: Efficacy and tolerance of low dose systemic therapy. Antiviral Res1988; 10:41–57.
205.
WeckPKBuddinDAWhisnantJK. Interferons in the treatment of genital human papillomavirus infections. Am J Med1988; 85(suppl 2A):159–164.
206.
GrossGIkenbergHRoussakiA. Systemic treatment of condylomata acuminata with recombinant interferon-alpha-2a: Low-dose superior to high-dose regimen. Chemotherapy1986; 32:537–541.
207.
GrossGRoussakiASchopfE. Successful treatment of condyloma acuminata and bowenoid papulosis with subcutaneous injections of low-dosage recombinant interferon-alpha. Arch Dermatol1986; 122:749–750.
208.
Condylomata International Collaborative Study Group. Recurrent condylomata acuminata treated with recombinant interferon-alpha-2a. J Am Med Assoc1991; 265:2684–2687.
209.
Condylomata International Collaborative Study Group. Recurrent condylomata acuminata treated with recombinant interferon-alpha-2a. Acta Derm Venereol1993; 73:223–226.
SchonfeldANitkeSSchattnerA. Intramuscular human interferon-beta injections in treatment of condyloma acuminata. Lancet1984; 1:1038–1042.
212.
OlmosLVilataJPichardoRidriguez A. Double-blind, randomized clinical trial on the effect of interferon-beta in the treatment of condyloma acuminata. Intl J STD AIDS1994; 5(3):182–185.
213.
KirbyPWellsDKiviatN. A phase I trial of intramuscular recombinant human gamma interferon for refractory genital warts. J Infect Dis1986; 86:485.
214.
GrossGRoussakiABrzoskaJ. Low doses of systemically administered recombinant interferon gamma effective in the treatment of genital warts. J Invest Dermatol1988; 90:242.
215.
KirbyPKKiviatNBeckmanA. Tolerance and efficacy of recombinant human gamma interferon in the treatment of refractory genital warts. Am J Med1988; 85:183–188.
216.
ZouboulisCStadlerRBcenbergH. Short-term systemic recombinant interferon-gamma treatment is ineffective in recalcitrant condyloma acuminata. J Am Acad Dermatol1991; 24:302–303.
217.
SchneiderAPapendickUGissmanL. Interferon treatment of human genital papillomavirus infection: Importance of viral type. Intl J Cancer1987; 40:610–614.
218.
FierlbeckGRassnerG. Treatment of condyloma acuminata with systemically administered recombinant gamma interferon. Z Hautki1987; 62:1280–1287.
219.
TiedemannKHErnstTM. Combination therapy of recurrent condylomata acuminata with electrocautery and alpha-2 interferon. AKT Dermatol1988; 14:200–204.
220.
ArmstrongDKBMawRDDinsmoreWW. Combined therapy trial with interferon alpha-2 a and ablative therapy in the treatment of anogenital warts. Genitourin Med1996; 72:103–107.
221.
VanceJCDavisD. Interferon alpha-2b injections used as an adjuvant therapy to carbon dioxide laser vaporization of recalcitrant anogenital condyloma acuminata. J Invest Dermatol1990; 95:146S–148S.
222.
HohenleutnerULandthalerMBraun-FalcoO. Post-operative adjuvante therapie mit interferon-alfa-2b nach laserchirurgie von condylomata acuminata. Hautarzt1990; 41:545–548.
PetersonCSBjerringPLarsenJ. Systemic interferon alpha-2b increases the cure rate in laser-treated patients with multiple persistent genital warts: A placebo-controlled study. Genitourin Med1991; 67:99–102.
225.
DavisBENobleMJ. Initial experience with combined interferon alpha-2b and carbon dioxide laser for the treatment of condyloma acuminata. J Urol1992; 147:627–629.
226.
ReidRGreenbergMDPizzutiDJ. Superficial laser vulvectomy V. Surgical debulking is enhanced by adjuvant systemic interferon. Am J Obstet Gynecol1992; 166:815–820.
227.
Condylomata International Collaborative Study Group. Randomized placebo-controlled double-blind combined therapy with laser surgery and systemic IFN-alpha 2a in the treatment of anogenital condylomata acuminatum. J Infect Dis1993; 167:824–829.
228.
NieminenPMarkkuALehtinenM. Treatment of genital HPV infection with carbon dioxide laser and systemic interferon alpha-2b. Sex Transm Dis1994; 21(2):65–69.
229.
GrossGRoussakiABaurS. Systemically administered interferon alpha-2a prevents recurrence of condylomata acuminata following CO2-Iaser ablation. The influence of the cyclic low-dose therapy regimen. Results of a multicentre double-blind placebo-controlled clinical trial. Genitourin Med1996; 72(1):71.
230.
HandleyJMHornerTMawRD. Subcutaneous interferon alpha-2a combined with cryotherapy versus cryotherapy alone in the treatment of primary anogenital warts: A randomized observer blind placebo-controlled study. Genitourin Med1991; 67:297–302.
231.
EronLJAlderMBO'RourkeJM. Recurrence of condyloma acuminata following cryotherapy is not prevented by systemically administered interferon. Genitourin Med1993; 69:91–93.
232.
DouglasJMEronLJJudsonFN. A randomized trial of combination therapy with intralesional interferon alpha-2b and podophyllin versus podophyllin alone for the therapy of anogenital warts. J Infect Dis1990; 162:52–59.
233.
MillerRLImbertsonLMReiterMJ. Inhibition of herpes simplex virus infection in a guinea pig model by S-26308. ASM, Interscience Conference on Antimicrobial Agents and Chemotherapy. Minneapolis, MN1985; 235.
234.
HarrisonCJJenskiLVoychehovskiI. Modification of immunological responses and clinical disease during R-837 treatment of genital HSV-2 infection. Antiviral Res1988; 10:209–224.
235.
BernsteinDIHarrisonCJ. Effects of the immunomodulating agent R-837 on the acute and latent herpes simplex virus type 2 infections. Antimicrob Agents Chemother1989; 33:1511–1515.
236.
HarrisonCJStanberryLRBernsteinDI. Effects of cytokines and R-837, a cytokine inducer, on UV-irradiadon augmented recurrent genital herpes in guinea pigs. Antiviral Res1991; 15:315–322.
237.
ChenMGriffithBPLuciaHL. Efficacy of S-26308 against guinea pig cytomegalovirus. Antimicrob Agents Chemother1988; 32:678–683.
238.
KendeMLuptonHWCanonicoPG. Treatment of experimental viral infections with immunomodulators. Adv Biosci1988; 68:51.
239.
MillerRLImbertsonLMReiterMJ. Interferon induction by antiviral S-26308 in guinea pigs. ASM, Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA1986; 168.
240.
SidkyYABordenECWeeksCE. Inhibition of murine tumor growth by an interferon inducing imidazoquinolone. Cancer Res1992;52:3528–3533.
241.
WeeksCEReiterMJ. Antiviral/immunomodulator R-837 induces alpha interferon in mice. Presented at the International Dermatology Symposium, Berlin, Germany.
ReiterMJTestermanTLMillerRL. Cytokine induction in mice by the immunomodulator imiquimod. J Leukoc Biol1994; 55:234–240.
244.
WagnerTLHortonVLCarlsonGL. Induction of cytokines in cynomolgus monkeys by the immune response modifiers, imiquimod, S-27609, and S-28463. Cytokine1997; 9(11):837–845.
245.
WeeksCEGibsonJ. Induction of interferon and other cytokines by imiquimod and its hydroxylated metabolite R-842 in human blood cells in vitro. J Interferon Res1993; 14:93–97.
246.
GibsonSJImbertsonLMWagnerTL. Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609. J Interferon Cytokine Res1995; 15:537–545.
247.
MegyeriKAuWCRosztoczyI. Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. Mol Cell Biol 1995; 15(4):2207–2218. Erratum. Mol Cell Biol1995; 15(5):2905
248.
TestermanTLGersterJFImbertsonLM. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol1995; 58:365–372.
249.
KonoTKondoSPastoreS. Effects of a novel topical immunomodulator, imiquimod, on keratinocyte cytokine gene expression. Lymphokine Cytokine Res1994; 13(2):71–76.
250.
BordenEWittPKvamD. An effective oral inducer of interferons in humans. J Interferon Rest1991; 11:S92.
251.
ImbertsonLMWeeksCAdamsN. Induction of antiviral activity and cytokines by oral imiquimod in healthy volunteers. J Interferon Res1992; 12:S127.
252.
TyringSKAranyIStanleyMA. Molecular study of condylomata acuminata clearance during treatment with imiquimod: A randomized, double-blind, vehicle-controlled study. J Infect Dis1998; 178:551–555.
BeutnerKRSpotswoodLSHoughamAJ. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol1998; 38:230–239.
255.
BeutnerKRTyringSKTrofatterKF. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother1998; 42(4):789–794.
256.
GreenbergMDRutledgeLHReidR. A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women. Obstet Gynecol1991; 77:735–739.
257.
LalezariJPStaggRJJaffeMS. A preclinical and clinical overview of the nuecleotide-based antiviral agent cidofovir (HPMPC). Antiviral chemotherapy 4: New directions for clinical application and research. Adv Exp Med Biol1996; 394:105–115.
258.
TyringSKDouglasJCoreyL. A phase I/II study of cidofovirgel for refractory condyloma acuminatum in patients with HIV infection (poster 296). Presented at the 55th Annual Meeting of Dermatology, San Francisco, CA, March 21–26, 1997.
259.
ZabawskiEJCockrellCJ. Topical and intralesional cidofovir: A review of pharmacology and therapeutc effects. J Am Acad Dermatol1998; 34:741–745.
260.
KimbauerRTaubJGreenstoneXX. Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into virus-like particles. J Virol1993; 67:6929–6936.
261.
ChristensenNDReedCACladelNM. Immunization with virus-like particles induces long-term protection of rabbits against challenge with cottontail rabbit papillomavirus. J Virol1996; 70:960–965.
HinesJFGhimS-JChristensenND. Role of conformational epitopes expressed by human papillomavirus major capsid proteins in the serologic detection of infection and prophylactic vaccination. Gynecol Oncol1994; 55:13–20.
