醫(yī)學(xué)微生物學(xué)資料：Human Papillomavirus

1、Human Papillomavirus 人乳頭瘤病毒 YTaxonomy of papillomavirusesHand wartsGenital wartsMucosal cancer associated Cutaneous, Mostly asymptomaticMain referencesOther referencesFrame-work based learning INTRODUCTION AND CLASSIFICATIONVIROLOGYEPIDEMIOLOGYPATHOGENESISIMMUNITYPAPILLOMAVIRUS DISEASEMANIFESTATIONS

2、DIAGNOSISTREATMENT AND PREVENTIONDNA virusesParvoviruses Papillomaviruses Adenoviruses Polymaviruses Herpesviruses Poxviruses Hepadnaviruses B19 virusJC virus; BK virusHuman papillomavirusAdenovirus Herpes simplex virusVaricella zoster virusCytomegalovirusHuman herpesvirus-6 and 7Epstein-Barr virusK

3、arposi sarcoma herpesvirus/human herpesvirus-8Variola (smallpox) virusMonkey pox virusMolluscum contagiosum virusHepatitis B virusINTRODUCTION AND CLASSIFICATION VIRUS SIZEHUMAN SUBTYPESTRANSMISSIONDISEASETREATMENTPREVENTIONPapilloma 55 nmHPV-13, 10Close contact, occupational exposure, public shower

4、/swimming poolSkin wartsTopical cytotoxins or surgical removalPapilloma 55 nmHPV-6, 11Close contact, sexual contactOral, laryngeal papillomatosis Genital warts (condylomata accuminata)Treatment of laryngeal lesions is complex, variedVaccinePapilloma 55 nmHPV-16, 18 (several others are also increasin

5、gly implicated)SexualCervical, other neoplasiasMay be removed by electrocauteryVaccinePolyoma 45 nmBKVRespiratory or oral (?)Hemorrhagic cystitis in transplant recipients; postrenal transplantation nephropathyCidofovir may be used, but is not provenPolyoma 45 nmJCVRespiratory/oral (?)Progressive mul

6、tifocal encephalopathy (PML)Reduce immune suppressionCharacteristics of Papilloma and Polyoma VirusesHarald zur Hausen(1936 )Epidermodysplasia verruciformis疣狀表皮發(fā)育不良VirologySmall (55 nm ) , Naked capsid (unenveloped), Double -stranded, circular DNA virus，2 structural proteinsHighly tropic forepitheli

7、al cells of the skin and mucous membranesElectron micrograph of humanpapillomavirus(HPV) particles (300 000). 72 L1 pentamers72 L1 pentamers+ 72 L2Papillomavirus virion HPV16 L1 VLPNormal epitheliumHPV infected epitheliumHuman papillomavirus life cycleSchematic of DNA genome of HPV16Map of the human

8、 papillomavirusgenome (HPV-6, 7902 base pairs) PAPILLOMAVIRUS DISEASEGenital Warts (Condyloma acuminata)Common wartsAnogenital cancer More than 100 genotypes Low- riskHigh- risk oncogenic typesHuman papillomavirus(HPV)EPIDEMIOLOGYMost common sexually transmitted infectionMajor cause of cervical canc

9、ers in womenHPV types 6 and 11 common; rarely lead to malignancyTypes 16, 18, 31, 45, and 56 associated with dysplasia and malignancyCommon warts Anogenital warts From where do these bad guys come?Direct contatIndirect contactAnnual number of cases worldwide660 millionThe role of men as carriers of

10、HPV High prevalence of HPV DNA in normal skin from healthy adultsImmunosuppressed patients experience an increased incidencePATHOGENESISReplication in squamous epitheliumViral genomes carry their own transforming genes, E6 and E7E6 degrades p53 and E7 interacts with pRB to abrogate cell cycleHPV is

11、the major cause of cervical cancerMechanism of oncogenicitySchematic representation of a skin wart (papilloma)Cytology LSILHSILHistology CIN1CIN2CIN3Normal Very mild/mild dysplasiaModerate dysplasiaSevere dysplasiaIn situ carcinomaInvasive carcinomaVirus production,HPV infection No virus productionH

12、igh E6 and E7Viral DNAIntegration Microinvasive carcinomaTransmission occurs by close contactMicrolesions faciliate infection HPV 16 and 18 : high cancer riskViral early proteins E6 and E7PATHOGENESISRelationship among cervical humanpapillomavirus(HPV) infection, precancer, and cancerIMMUNITYMost wa

13、rts are benign and do not progress to malignancy. Both cell-mediated immunity and antibody are induced by viral infectionImmunosuppressed patients：higher risk Persistent HPV infection can be associated with carcinoma of the uterine cervix and penis.A 25-year-old woman presents to her gynecologist wi

14、th complaints of itching, burning ,and tenderness in the genital area. The patient is sexually active but with no history of sexually transmitted disease. Physical examination is significant for flesh-colored exophytic papules on the labia and vulva. A Pap smear is performed to check for cervical ab

15、normalitiesMANIFESTATIONSOral or laryngeal papillomatosis in infants infected during deliveryAnal carcinoma due to HPV may be increasingWarts(Reproduced with permission from Willey JM:Prescott, Harley, & Kleins Microbiology,7thedition. McGraw-Hill, 2008.)Common wartsFlat wartsPlantar warts Perianal

16、condylomata acuminataExternal genital HPV infectioncondylomata acuminatascattered acetowhite stainingDIAGNOSISCervical cytology ：by the Papanicolaou(Pap)smear PCR or DNA hybridizationAbnormal Pap smear：koliocytotic cellTREATMENT AND PREVENTIONCryosurgery ,Application of caustic agents, Electrodesicc

17、ation , Surgical exision, Ablation with a laser Topical antimetabolites : 5-fluorouracil TREATMENT AND PREVENTIONRecurrences are commonRemoval of warts by cryosurgery or other methodsCondom usageCervical Pap smears should be done regularlyVaccines Two recombinant vaccines,Cervarix(HPV 16 and 18), Ga

18、rdasil(HPV types 6, 11, 16, and 18), Vaccine should be given at the onset of sexual activityGardasil Cervarix Manufacturer Merk GlaxoSmiththKlineVLP typesHPV6, 20gHPV11, 40gHPV16, 40gHPV18, 20gHPV16, 20gHPV18, 20gProducer cellsSaccharomyces cerevisiaeSpodopterafrugiperda SF9Trichoplusia ni Hi 5Adjuv

19、ant 225g aluminum hydroxyphosphate sulfate 500g aluminum hydrooxide, 50g 3-O-deacylated-4-monophosphoryl lipid AInjection schedule 0,2, 6 mo0,1,6 moHPV,human papillomavirus; VLP, virus-like particle Comparison of commercial HPV VLP vaccines討論及FBL學(xué)習(xí)實踐1 自由選擇以下模擬行業(yè)2 根據(jù)所選行業(yè)，以個人為單位構(gòu)建相應(yīng)的學(xué)習(xí)框架，并說明其理由。公司或企業(yè)工

20、作人員：疫苗研發(fā)提供消毒技術(shù)/消毒劑治療藥物研發(fā) 診斷試劑研發(fā)醫(yī)生：內(nèi)科外科傳染科婦科兒科全科醫(yī)生/家庭醫(yī)生疾病預(yù)防控制中心（CDC）工作人員Introduction Clinical description Virology Pathogenesis Epidemiology and transmission Diagnosis Prophylactic vaccines Preclinical development Current vaccines Formulation Immunogenicity Efficacy Immunogenicity bridging trials Mechanism of protection Duration of protection Indica