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    HPV Murray

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    Mikael Reynardi Sutanto

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    © All Rights Reserved
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    41 Papillomaviruses and Polyomaviruses A47-year-old divorced, sexually active womanis seen for a routine gynecologic exam. She is a pack-a-day smoker. A Papanicolaou (Pap) smear is performed, and the report indicates high-grade squamous intraepithelial lesion (SIL) corresponding to a mod- erate dysplasia and cervical intraepithelial neoplasia (CIN) score of 2. Polymerase chain reaction (PCR) analysis indicates that cells in the lesion are infected with human papillomavirus 16 (HPV-16). 1. What properties of HPV-16 promote the development of, cervical cancer? How is the virus transmnitted? ‘What is the nature of the immune response to the virus? How can transmission and disease be prevented? ‘42-year-old man comes tohis physician 9 months after alung transplant, complaining that he has dou- ble vision, difficulty speaking, feels that his muscles do not work right, has difficulty with balance, has tingling of his hands and feet, and keeps forgetting ‘Summaries Clinically Significant Organisms raruiomavnuses Thgge Weds Hvar tloopes cn ance, pret Matgy Veen and Disease "Spalted capa ONA genre aero aici ecmindtyca eee ect eeptnea ces fie senor re eee fer ry tered cate elmer pe De crnecoe steer ge ee ar Renuer ames peas ir ls brine ent FP shaie fem immune j ‘responses and persists. ei ae sicce a pioeeeeey a Vastra eae + Gta gper RPV va eolae eater ees aud inlephepngel cnc Epldensiny en era Tov Coty cried doa iene: psp beige Diagnosis 35,45, 52,and 58 igger Words and spreaés by vi arly inte asymptomatic ‘anal or ryngelpaailomae ype: 6 lungs sna) (AN, Cervical ntraeothlal neoposi CT, computerized tomography, HU. ‘ha reaction PM, progressive mulifca uxcencephal yl Ware common; STD = Asymptomatic transmission found \Worlide,no seasonalinedence = PCR genome analysis of cervical swabs and issue specimens ‘Treatment, Prevention, and Control * Vaccine for HPV types 611, 16.18.31 = JCV: PML, opportunistic disease abnor imal olgadendrocytes, demyelination BK virus: Kidney; MCPyV: Mel ell y, Virulence, and Disease 1 Small naked capsid, ONA genome Dantgen inactivates p53 and RB to promote cll growth 1 Virus infects tonsils and lymphocytes, mia tne kine 1 Virus ubiquitous and infections are things. A month later, he has difficulty speaking and needs assistance with normal daily functions. His mental and physical functions become progressively worse. He is treated with cidofovir, and his immu- nosuppressive therapy is eased, but his disease pro- gresses to paralysis and he dies. A biopsy of the brain, shows lesions with sites of demyelination, astrocyto- sis with atypical nuclei, and many histiocytes. PCR analysis demonstrates the presence of JC polyomavi- mus in the lesion, confirming a diagnosis of progres- sive multifocal leukoencephalopathy (PML). 5. What properties of JC virus (JCV) promote the develop- ment of PML? 6. Why is this disease also prevalent in individuals with, acquired immunodeficiency syndrome (AIDS)? Who else is at risk for this disease and why? Answers to these questions are available on student Consult.com, 1 Iniowmunocempremised people, Jc is activated, spreads tothe brain, and causes Pl whichis 3 conventional Slow virus disease In PMLJCV partly transforms trocjes and kil oligodendrocytes, ‘Causing choracteristilesans and ses of demyelination = PML esions are eemyetinated wth urusuallarge astrocytes andl ligoden- ‘rool cele with very lage nucl, = Bkvrs is benign but may ause kidney disease in immanocompromised patents 5 = Transmitted by inhalation or contact ‘with contaminsteg water or salva = Ubiquitous: mmunceompremised people at risk or PL by SCV ane Kidney damage by 3K virus = Found worldwide, no seazonal incidence Diagnesis JC Presence of PCRamplfied val DNA in cerearospnalfudand MAL or CT vidence of lesions Treatment, = Nomodes of contro! jevention, and Contr 1 Virus establishes persistent and latent Infection n organs such as kidneys and alors CW ICs, magnen resonance maging: PCR polymerase lly vanemies doen an 412 SECTIONS + Viology ‘What used to be called the papovavirus family (Papova- viridae) has been divided into two families, Papillomaviti dae and Polyomaviridae (Table 41.1). These viruses are capable of causing lytic, chronic, latent, and transforming, infections, depending on the host cell. HPVs cause warts, and several genotypes are associated with human cancer (eg., cervical carcinoma), BK virus (BKV) and JCV. members of the Polyomaviridae, usually cause asymp- tomatic infection but are associated with renal disease and PML, respectively, in itnmunosuppressed people. Simian virus 40 (SV40) is the prototype polyomavirus, ‘The papillomaviruses and polyomaviruses are small nonenveloped, icosahedral capsid viruses with double stranded circular deoxyribonucleic acid (DNA) genomes (Box 41.1), They encode proteins that promote cell growth, ‘The promotion of cell growth facilitates lytic viral repli- cation in a permissive cell type but may oncogenically transform a cell that is nonpermissive. The polyoma: viruses, especially SV40, have been studied extensively as ‘model oncogenic viruses, Human Papilloma STRUCTURE AND REPLICATION ruses HPVs are distinguished and typed by DNA sequence homol- ogy. At least 100 types have been identified and classified into HPV can be distinguished further as cutaneous HY or "Von the basis ofthesancoptbletasce Witun themacosa IDV theresa group associated with cervical, penile. anal, and laryngeal cancer. Viruses in a group cause similar types of warts, ‘The icosahedral capsid of HPV is 50 to 35 nm in diam. eter and consists of two structural proteins that form 72 capsomeres (Fig. 41.1), The HPV genome is circular and has approximately 8000 base pairs. The HPV DNA encodes depending on the virus, and An upstream regulatory region contains the control sequences, for transcription, the shared N-terminal sequence for the carly proteins, and the origin of replication. All the genes are located on one strand (the plus strand) (Fig. 4.2) the replication cycle of HPV is linked to the life cycle of the keratinocyte and epliialcell ofthe skin and mucosa ‘The virus accesses the basal cell layer through breaks in the hin (ie, 113) The Lt protan of HPV ie the viral ata nent protein and nites epiation by TABLE41.1 Human Papillomaviruses and Polyomaviruses and Their Diseases Views Disease Papillomavirus Warts, condyiomas,papllmas cervical penile, Poloravinas ax virus Renal disease” sCvine Progressive multifocal leukoencephalopathy* Merkel cellvirus Merkel cell carcinoma 1370 atesentin $878 of hese exrcinomas nimmuncsuopressed pater sk genet "Daca ‘Proteelveans and other receptors to trigger endows, from the cell surface. The early genes of the vi Tate cell growth, which facilitates replication of the viral genome by the host cell DNA polymerase when the cells divide al DNA target induced increase in cell number catises th nd the “prickle cell layer (stratum spinosum) t n (wart, cone yloma, or papilloma). As the basal cell diflerentiates, the specific nuclear factors expressed in the different layers and types of skin and mucosa promote transcription of different viral genes. Expression of the viral genes correlates with, the expression of specific keratins, The late genes encoding the structural proteins are expressed only the and the ‘As the infected skin cell matures and works its way to the surface, the virus matures and cells ofthe upper layer and takes up to 3 weeks, PATHOGENESIS Papilomaviruses infect and replicate in the squamous ep- thalam ofan cmbranes (geaital to inde epithe. Drolferation, The HPV types are very tssue Speci, aug diferent diseate presentations, The wart develops Dpecause of virus ‘and thickening ‘of the basal and prickle Lavers ( 1), as well as the stratum granalosum, Koilocytes, characteristic of papillomavirus infection, are with lear les around Ie sally takes 310° forthe wart to develop (Fig, 41.4). The viral infection remains local and generally regresses spon taneously but ean recur: The HPV pathogenic mechanisms are summarized in Box 41.2 Innate and cell-mediated immunity are important for control and resolution of HPV infections. HPV can sup> from protective immune responses. In adi- tion to very low levels of antigen expression (except in the BOX 41.1 Unique Properties of Polyomaviruses and Papillomaviruses lomavirus: HPV types 1 t0 100+ (as determined by geno- ‘ype: types defined by DNA homology, tissue tropism, and asso ation wth oncogenes) Polyomavirus: 5V40, JC virus, BK virus KI, WU, Merkel ell poly ‘omavirus (MCPyV) ‘Small icosahedral capsid virion Double-stranded circular DNA genome replicated and as: ‘embled in nucleus Viruses have define tissue ropisms determined by receptor Interactions and transcriptional machinery of cll Viruses encode proteins that promote cell growth by binding to cellular growth-suppressor proteins p53 and pIOSRB (p105 retinoblastoma gene produc) polyoma Tantigen binds to 'p105R8 and p53; high-risk papillomavirus E6 protein binds to p53, activates telomerase, and suppresses apoptosis, and E7 protein binds te p10SRB_ Viruses can eauze lytic infections in permizsve cells but cause abortive, persistent, or atent infections or immertalize (transform) nonpermissive cells a3 41 Papilomaviruses and Peyoraviuses Computer reconstruction af eoclectron micrographs ofhuman papillomavirus (HPV) Left View ofthe surface of HPV shows 72 capsomeres aranged in an ieosadetahedron.Athe capsomeres appear to form a regular five-point star shape. Right, Computer cross-section of the apse shows the interaction of te capsomeres and channels nthe capi (ro Ea papllomaviuses. Analysis by cyoeecron microscoay andl thee-dm ‘Genome i doublesranded ercult metecul. 1 protein binds DNA a rand poms vial DNA replication and hhashetease acti ike T antigen of SV40). €2 poten Binds NA Tes and activates Wal mRNA Sythe TE ancopiaehn actvates he FCT receptor fo promote row Ef dsrpiseyocerains io promote release Egand E7 of highs sans, eg. HPV-16 and HPV-18, can become immoraizng goes and are assoialea wth human cervical ance: 17 and L2 gene products are ate strctral (capsid) proteins Esancer intl, ral ONA Tsaseplenel Melo sean pronating reat fos Be) = Fig. 412 Genome of human papillomavirus tye 16 (Hv-16) ‘Genomic DNA is normaly a double-stranded ercular molecule, but isshown herein alineat form. £5, Oncogene poten that enhances el ‘growth by stabilang and activating the epidermal growth factor recep~ {oF oncogene protein that binas ps3 and promatesits degradation, £7, oncogene protein that binds pIOSRB (a105 retinoblastoma gene product; EGF, epidermal growth factor LI, major capsid protein: L2, Iino capsid protein: LCR {URN long controlregion upstream regu tory reginl or origin of replication (Courtesy Tom 2raver altmore) terminally differentiated skin cel) the kerati- nocyte isan immunologically privileged site for replication Inflammatory responses are required to activate protective extolytic responses and promote resolution of wats. Inmt- OI veroca huve QUE uns core ams ctions. Antibody to the xluced by vaccina- ‘vagina and elsewhere and can ton is secreted in sonal mage recon Newsom, WN, Con, Ne, era, 19 fn. Biophys. 5,14 Keratnizaton 7 etease Replication Comeun Release ranulosum Maturation g futons spnesum Genome ° replication Infection Basal Cell protteraton keratinocytes ‘© Mature veton {Viral ONA Fig. 41.3 Development of papilloma (war). Human papilomavius Infection promotes the outgrowth of the basal ayer, Inereasing the number of price cell of the stratum spinesum {acanthos). These ‘Changes case the skint thicken ane promote the production of kes tin (hyperkeratosis), causing epithetal spikes to frm (papillomatosis, Vitus is produced inthe granular cals dosete the ral keratin ayer High-risk HPV types (¢-g., HPV-16, HPV-18; ‘Table 41,2) can initiate the development of cervical carci- noma and oropharyngeal, esophageal, penile, and anal cancers. Viral DNA is found in benign and malignant tumors, especially mucosal papillomas. Almost all cer- vical carcinomas coutain integrated HW DNA with 70% from HPV-16 or HPY-18. Breaking of the circular genome within the BI or B2 genes to promote integration causes these genes to be inactivated, pre venting viral replication without preventing expression of other HPV genes, including the ES, 26, and E7 genes (ig. 41.5). The E5, Bo, and 7 proteins of HPV-16 and HPV-18 have been identified as oncogenes. ‘The E5 414 SECTIONS + Veology Fig. 41.4 DNA probe analysis ofa human papillomavirus induced ‘anogentalcondyloma, A biotn-abeled DNA probe wa: localized by horseradish peronideseconjugated avidin conversion of substrate to 23 chromogen precptte Dark taining is seen over the nucle’ of ko ‘jtticcalls (vom abe, R298) Textoost a umanvrles, secon Mosey, Stu NO}. protein enhances cell growth by stabilizing the epidermal growth factor receptor to make the cell more sensitive to growth signals, whereas the E6 and E7 proteins sl event ncn of the alr grow spores (transformation-suppressor} proteins, p53, and the p105, retinoblastoma gene product (RB). E6 binds the p53 protein and targets it for degradation, and E7 binds and inactivates p105, Enhanced cell growth and inactiva- tion of p53 makes the cell more susceptible to mutation, chromosomal aberrations, or the action of a cofactor and promotes the development of cancer EPIDEMIOLOGY HPV resists inactivation and can be transmitted on fomites, such as the surfaces of countertops or farniture, bathroom, floors, a + 3] Amptomatie shedding may ion. HPV infection is acquiced (1) by promote direct contact through in the skin or mucosa, (2)duxing selina (3) while an ang through an infected birth canal. ‘Common, plantar, and flat warts are most common in steams aa ‘ecu i 2 only infects Tis possibly the most preva- lent sexual transmitted mfection in the word. wih cer tain HPV types common among sexually active men and women, Atleast 79 million people in the United States are infected with HPV, with approximately 14 million new ano- genital cases per year including HPV-16 and HPV-18. are present in oropharyngeal, penile, cervical, vaginal, and anal cancers. According to the Centers for Disease Control, and Prevention, oropharyngeal squamous cell carcinoma is, HPV-16 an 1 em. Other high-risk gen- olypes are more prevalent in different socioethnic groups. ‘Types 33, 35, 58, and 68 are common high-risk HPV types BOX41.2 Disease Mechanisms of Papillomaviruses and Polyomaviruses ao Vis aged coe contact nines te pte cls ce seer eee ee eee ee o nal oer ited eee Peete MeVoteton chen frm spnes nd pes ee ee ee ee Eevee Dern HV pes present neat inte tumor ce ae Polyomaviruses JCV and BKV) ‘Vitus is acquired through the respiratory or oral route, infects tonsils and lymphocytes, and spreads by viremia tothe kidneys carlin if. Virus is Ubiquitous, and infections are asymptomatic Virus establishes persistent and latent infection in organs such as the kidneys and lungs In immunecompromised people, JCV i activated, spreads to ‘the brain, and causes PML, which isa conventional slow virus disease In PML, JCV partialy transforms astrocytes and kills oligodendro- ‘ytes causing characters Iesions and sites of demyelination. PML lesions are demyelinated with unusual large astrocytes and ‘oligodendroglia ells with very large ne. KY is benign but may cause kidney disease in immunacompro: mised patients. 0, B¢ virus APY, hurmanpapilomav us JC, JC vs ‘ultfocal ukoencepmolooatry for African American women. Other high-risk strains are Used in Table 1.2; Cervical cancer the gezond lending cause of cancer death in women (=14,000 eases ai deaths per year in the United States) Approximately 5% of all Pap smears contain HPV- infected cells, and 10% of women inf th the high- risk HPV types Which is a precancerous state. Multiple sexual partners, smoking, a family history of cervical cancer, and immunosuppression ae the maj infection and progression to cancer. C8 Facters HPV-6 and HPV-11 ard low-risk HPV types for cervical carcinoma but cause condylonsa acusninatum and oral and laryngeal papillomas. CLINICAL SYNDROMES: ‘The clinical syndromes and the IIPV types that cause them are summarized in Table 41.2 Warts A wart is skin that ir ume Mos people wnsTPY into ave the common types of the virus QIPV.1 through IV) ‘which infect keratinized surfaces, usually on the hands and {eet (Fig, 41,6). Initial infection occurs in childhood or early 41+ Papllomaviruses and Polomavirses 415 TABLEAT.2 Clinical Syndromes Associated with BOX 413 Epidemiology of Polyomaviruses Papilomaviruses and Papillomaviruses HUMAN PAPILLOMAVIRUS TYPES Disease/Viral Factors eee el Srvicome __Common Lesscemen ps vias srerant to acivaton ‘uTANEOUSSTRORONES (ReneS Skin Warts Aemmetomn shel i Bet ae) frees Gonmonwat A762 (| Papas rect contac semicon emily transi ee Mena ee ene al aN Meee ee eee erste SaT720 9.128 ear ee aca eet pe 37 Oe Rey Mucosal stwoRoMEs Who tsatnise? Benign Head and Neck Tum< Papillomavirus: warts are common; sexually active people at risk ana peo a econ ileal ae oem aed | ee Sepptons

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