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PAPOVAVIRUS
PAPILLOMA
POLIOMA
VACUOLANTE DELLA SCIMMIA
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-Sono virus nudi piccoli con dimensioni di circa 50 nmcon capside icosaedrico
- Il genoma è formato da DNA bicatenario circolare e
spiralizzato
- La replicazione avviene nel nucleo
PAPOVAVIRUS
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2 generi
Papillomavirus
HPV (>70 tipi diversi)
Poliomavirus
Virus BK
Virus JCSV40 (virus vacuolante della scimmia)
che differiscono per dimensione, determinanti antigenici e
proprietà biologiche
Gli studi su questi virus si sono intensificati da quando si è visto
che il genoma di alcuni di questi è presente nel 93% di
carcinomi- cervice uterina
- ano-genitali
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I papovavirus codificano proteine che promuovono la crescita
cellulare
• Questo facilita il ciclo litico virale nelle cellule permissive.• Queste proteine possono però determinare anche trasformazione
oncogena in cellule non permissive.
I papillomavirus sono associati ai vari tipi di verruche cutanee
• mentre i virus del Polioma sono facilmente coltivabili
• i virus del Papilloma non sono coltivabili ma sono stati
individuati attraverso l’analisi del DNA virionico estratto.
Non è possibile propagare HPV su colture cellulari perché il
virus replica nell’epitelio squamoso stratificato (cellule
differenziate) la cui coltivazione in vitro è difficile.
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I Papillomavirus umani possiedono un esclusivo
tropismo per le cellule epiteliali dell’epidermide e
delle mucose, dovuto probabilmente alla presenza solo
in queste cellule di fattori cellulari necessari alla
trascrizione virale
• Epitelio squamoso della cute: verruche
• Membrane mucose: papillomi (genitali, orali,
congiuntivali)
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Electron micrograph of BPV-1 virion particles (55 nm in diameter)
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Il genoma del papillomavirus possiede
• due geni tardivi (L1 e L2) che codificano per proteine
strutturali
• sette/otto geni precoci che producono proteine non
strutturali, alcune delle quali (E6 ed E7) possono
promuovere l’inattivazione di due importanti proteine
cellulari (p53 e pRb) che presenziano al controllo del ciclo
cellulare.
Papillomavirus
Struttura del virione
52-55 nm diametro
8 kbp genoma
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Genomic map of HPV-16
Figure 66-2 Genomic map of HPV-16. The genome is a double-stranded circular DNA
molecule of 7904 base pairs. Transcription occurs in a clockwise manner; the only
transcriptional promoter presently mapped for HPV-16 is designated P97. The open reading
frames deduced from the DNA sequence are designed E1 to E7, L1, and L2.
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Il papillomavirus
• infetta le cellule dello strato basale dell’epitelio• si moltiplica e persiste durante il differenziamento
cheratinocitico delle cellule dallo strato spinoso, granuloso e
corneo.• Nelle cellule dello strato basale e spinoso non si trova il
virione ma solo il DNA libero nel nucleo
• le particelle virali si ritrovano nello strato granuloso e corneo
• alcune cellule ingrossate tra lo strato spinoso e granuloso, i
coilociti, sono altamente indicativi delle infezioni papillomatose.
.
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Replication cycle of a papillomavirus
Figure 65-6 Replication cycle of a papillomavirus. To establish a wart or papilloma, the virus must infect a basal
epithelial cell. Our knowledge is limited about the initial steps in the replication cycle such as attachment (1), uptake (2),
endocytosis (3), and transport to the nucleus and uncoating of the viral DNA (4). Early-region transcription (5),
translation of the early proteins (6), and steady-state viral DNA replication (7) all occur in the basal cell and in the
infected suprabasal epithelial cell. Events in the viral life cycle leading to the production of virion particles occur in the
differentiated keratinocyte: vegetative viral DNA replication (8), transcription of the late region (9), production of the
ca sid roteins L1 and L2 10 assembl of the virion articles 11 nuclear breakdown 12 and release of virus 13 .
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Carcinogenesi
I papillomavirus sono associati con lesioni proliferative.
Lesioni proliferative in genere benigne (verruche) della pelle e
delle mucose.
Tuttavia alcuni tipi di HPV (16 & 18) sono strettamente associati a
carcinomi che presentano DNA virale nelle cellule.
I geni di HPV rilevanti nel processo di trasformazione sono E6
(che lega p53) & E7 (che lega Rb ipofosforilata)
• Nell’infezione produttiva E6 & E7 favoriscono la sintesi di DNAvirale e il ciclo replicativo
• Nell’infezione non produttiva sono responsabili della
trasformazione oncogena.
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E6 & E7 alterano rispettivamente l’attività delle proteine p53 e Rb
(retinoblastoma) che hanno un’attività di controllo negativo dellacrescita cellulare.
Nelle cellule quiescenti Rb è presente in forma ipofosforilata e
viene fosforilata nella fase G1 del ciclo cellulare
Rb controlla un fattore di trascrizione E2F-1
Rb fosforilata non lega E2F-1p53 ha un ruolo chiave nell’arresto del ciclo cellulare in G1
Nel ciclo replicativo “normale” del virus la produzione di E6 e E7
è tenuta sotto controllo dal gene E2
Il gene E2 viene perso però durante l’integrazione del genoma di
HPV nel genoma cellulare
Produzione incontrollata di proteine E6 e E7.
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The level of p53 in primary cells is generally low
Stabile complesso non funzionale
degradazione
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E7 abrogates the cell cycle regulation mediated by pRB
(as well as the related proteins p107 and p130) by
complex formation.
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• Nelle verruche e nei condilomi (escrescenze benigne) il
genoma virale si trova in forma episomiale.
• Nel carcinoma della cervice uterina e in carcinomi squamosi
(un tumore che può svilupparsi in pazienti colpiti da una rara
malattia ereditaria, l’epidermodisplasia verruciforme), ilgenoma virale è stato ritrovato integrato nel DNA della cellula
tumorale.
La verruca è una proliferazione benigna autolimitante della pelle,
stimolata dal virus, che regredisce col tempo. Si manifesta in 3-4
mesi. L’infezione virale rimane localizzata, in genere regredisce
spontaneamente.
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Esempi dei tipi più comuni di papilloma associati a malattie
Verruche plantari tipi 1,2
Verruche comuni tipi 1,2
Verruche piane tipi 3,10
Condilomi acuminati tipi 6,11
Papillomi orali tipi 13,32
Papillomi laringei tipi 6,11
Carcinomi cervicali tipi 16,18
(genoma virale integrato sicuramente concausa del tumore)
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Sezione istologica di una verruca
cutanea.
Ispessimento dell’epidermide e
numerosi strati di cheratinociti
desquamanti.
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Papillomavirus
I papillomi sono ampiamente distribuiti nella specie umana
Le verruche ano-genitali sono a trasmissione sessuale, con
incidenza proporzionale al numero dei partner sessuali
La papillomatosi respiratoria ricorrente è causata dalla
trasmissione al tratto respiratorio di HPV6 e HPV11
Il rischio maggiore è per i bambini al disotto dei 5 anni e la
trasmissione avviene probabilmente durante il parto
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Papillomavirus
Manifestazioni cliniche
Verruche
Condilomi
Epidermodisplasia verruciforme
Papillomi
Replicazione virale e trasformazione cellulare
Cellule epiteliali squamose in differenziamento = infezione produttiva
stadi precoci
stadi tardivi
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PapillomavirusEpidemiologia
HPV può essere trasmesso per
• Contatto diretto e tramite piccole lacerazioni cutanee o delle mucose
(anche durante rapporti sessuali!!, parto)
• Contatto indiretto (con oggetti contaminati:pavimenti, asciugamani)
• Autoinoculazione
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Papillomavirus
Patogenesi
Ispessimento dell’epidermide
Ipercheratosi
Papillomatosi di grado variabile
Membrana basale intatta
Cofattori
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Patogenesi del cancro del collo
dell’utero
HPVinfection
PersistentHPV infection
Cellulardysregulation
High-gradeCIN
Invasivecancer
Immunologicfactors Co-carcinogens
Bosh FX, et al. Journal of Clinical Pathology, 2002,55: 244-265.
Papillomavirus
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Papillomavirus
Diagnosi
-No sierologica
-No isolamento colturale
- Clinica
- Colposcopia
- Citologica
- Istologica
- Immunocitochimica (group specific not type specific)
- PCR DNA (unica metodica in grado di tipizzare HPV)
- Microscopia elettronica
Si può differenziare tra infezioni oncogeniche e non oncogeniche da HPV
!! I virioni non sono presenti nel tessuto trasformato !!
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Major clinical association of genital tract and other mucosal
HPVs (from Fields et al.)
CLINICAL ASSOCIATION HPV TYPES
GENITAL TRACT
Subclinical infection All types
Exophytic condyloma - any site HPV 6 , 11
Flat condyloma - especially cervix HPV 6, 11,16, 18, 31, others
Bowenoid papulosis HPV 16 Giant condyloma HPV 6, 11
Cervical cancer
• Strong association HPV16, 18, 31, 45
• Moderate association HPV 33, 35, 39, 51, 52, 56, 58, 59, 68
•
Weak or no association HPV 6, 11, 26, 42, 43, 44, 53, 54, 55, 62
Vulvar cancer HPV 16
Penile cancer HPV 16
RESPIRATORY PAPILLOMAS HPV 6, 11
CONJUNCTIVAL PAPILLOMAS HPV 6, 11
ORAL CAVITY
Focal epithelial hyperplasia HPV 13, 32
Infection with genital tract HPVs HPV 6, 11, 16
Lesions on Lip HPV 2
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Papillomavirus
Terapia
Agenti c austic i
Crioterapia
Inib itori della sintesi di DNA
Terapia c hirurgica
!! Recidive !!
Phylogenetic tree of human and animal papillomaviruses
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Phylogenetic tree of human and animal papillomaviruses
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Raft cultures showing normal keratinocytes
(A) and keratinotcytes transfected with thefull-length HPV-16 genome (B).
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Cervical squamous carcinoma precursors
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Low-grade squamous intraepithelial lesions of
the cervix
E i f l f i l HPV
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Estimates of prevalence of genital tract HPV
infections and of HPV-associated diseases, inU.S. women.
Patterns of HPV type distribution within four
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yp
diagnostic categories
Figure 66-7 Patterns of HPV type distribution within four diagnostic categories: Neg, negative; Low,
low-risk HPVs (HPV-6, HPV-11, HPV-42, HPV-43, HPV-44); Unc, unclassified HPVs; Int,
intermediate-risk HPVs (HPV-31, HPV-33, HPV-35, HPV-51, HPV-52); High, high-risk HPVs (HPV-
16, HPV-18, HPV-45, HPV-56); LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade
squamous intraepithelial lesion.
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Ruolo clinico dell’ HPV Test
Prof. Cartesio Favalli
Dott. Marco CiottiVirologia Molecolare-PTV
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Histological classification:
CIN: cervical intraepithelial neoplasia
LSIL: low-grade squamous intraepithelial lesionsHSIL: high-grade squamous intraepithelial lesions
Tipizzazione HPV
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Tipizzazione HPV
PCR con primers contro la regione E6/E7 degli HPV a
Basso rischio (6,11) e Alto Rischio (16,18,31,33,35,45,52,58)
Innolipa : Ibridazione inversa
Riconosce14 HPV ad Alto Rischio e 11 HPV a Basso Rischio
Sequenziamento del frammento MY09/MY11
del gene capsidico L1
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Fig. 1. Age-standardized incidence and mortality rates for invasive cervical cancer in different regions of the world. Rates areper 100,000 women and are standardized according to the age distribution of the world population of 1960. Source of data:Globocan 2002
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Poliomavirus
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Infezioni benigne, asintomatiche, persistenti nell’ospite naturale
BKV
sintomi respiratori alla sieroconversione nell’immunocompetente
cistite o danno renale nel bambino immunocompromesso
JCV
Leucoencefalopatia Progressiva Multifocale (LPM)
nell’immunodeficienza
Poliomavirus
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Non inducono neoplasie in cellule dell’ospite in cui si replicano main cellule di altri animali non permissivi
Il virus si integra in siti multipli nei cromosomi ed esprime solo
alcuni geni precoci
Antigeni T (tumorali) ottenuti per splicing del RNA virale
T grande
T piccolo
T medio (espresso solo dal polioma) substrato per
Srctirosinochinasi
fosfatidinositol-3-chinasi
Viral DNA, minichromosomes, and virions.
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Figure 63-1 Viral DNA, minichromosomes, and virions.
A: Electron micrograph of supercoiled SV40 DNA molecules.
B: Electron micrograph of an SV40 minichromosome. Note that this particular
minichromosome displays a nucleosome-free region. About 20% of minichromosomes have a nucleosome-free region surrounding the regulatory
region at the origin of DNA replication.
C: Computer graphic representation of the structure of the SV40 virion. Note that
the shell is made up of 72 pentamers of VP1.
Mappa genomica dei papovavirus
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Polioma
Geni precoci (catena E early)
T-grande Ag (Tumor-Specific Trasplantation Antigen; TSTA)
Trascrizione tardiva (late)
VP1 – VP2 – VP3
Poliomavirus
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Antigene T grande è una proteina multifunzionale
Infezione produttiva
inizio della sintesi del DNA virale
repressione della trascrizione precocetrascrizione tardiva
Infezione non produttiva
inizio della trasformazione
mantenimento della trasformazione
Espressione di poliomavirus (SV40) nel
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p p ( )
ciclo litico e in quello trasformante