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Oncogenic viruses

These slides provide an overview of the role of


oncogenic viruses in cancer progression
Dr. Momna Hejmadi, University of Bath
N.B. ome images used in these slides are from the
te!t"oo#s listed and are not covered under the
$reative $ommons license as yet
This resource created "y Dr. Momna Hejmadi, University of Bath, %&'&, is
licensed under the $reative $ommons (ttri"ution)Non)$ommercial)hare (li#e
%.& U*+ ,ngland - .ales /icense.
To view a copy of this license, visit
http+00creativecommons.org0licenses0"y)nc)sa0%.&0u#0

1ncogenic viruses
1ncogenic viruses
Key Concepts

Normal cells infected with certain


viruses can "e transformed into
cancer cells due to e!pression or
activation of viral oncogenes

Transformation can result in


integration of viral genes or genomes
into the host genome

Figure 3.1; 3.2 The Biology of Cancer ( Garland Science 2007)
1909, Peyton Rou dico!er arco"a#inducing agent in
c$ic%en
2s cancer infectious3
2s cancer infectious3

&o$anne Fi'iger
(
Paraite caued to"ac$ cancer
(
192) *o'el Pri+e
(
,icredited -or%

Figure 3.7a The Biology of Cancer ( Garland Science 2007)
Normal cells infected with certain viruses
Normal cells infected with certain viruses
can "e transformed
can "e transformed

Tumour virus implicated as
Tumour virus implicated as
aetiological agents for every 1 in
aetiological agents for every 1 in
6 human cancers!!
6 human cancers!!

Family Example Tumour type
! !
" "
.er/e!iridae
Human Herpes V8
#$$%&'
Epstein()arr virus
#E)%'
*aposi4s
sarcoma
Hodg#in4s
lymphoma
! !
" "
Pa/o!a!iridae
human papilloma
virus #$*%'
$ervical
carcinoma
! !
" "
.e/adna!iridae
hepatitis ) virus(
#$)%'
/iver
carcinoma
R*0 Flaviviridae
$epatitis C virus
$C%5
R*0 Retroviridae
Human T-cell
lymphotropic virus
(HTLV type I)
1#cell leu%ae"ia

1verview of viral replication
1verview of viral replication

6enome replication
6enome replication
DNA viruses RNA viruses

How does tumourigenicity occur3
How does tumourigenicity occur3
7iral genomes show the presence of several human
gene homologues 8cellular proto)oncogenes5
2nfective viruses 9#idnap4 proto)oncogenes which are
then transformed into oncogenes
e.g. c)src0v)src : v)myc0c)myc : v2/;0 2/; 8interleu#in ;5

v-myc and c-myc ("yc oncogene)
How does tumourigenicity occur3
How does tumourigenicity occur3

.u"an /a/illo"a !iru (.P2)
.u"an /a/illo"a !iru (.P2)
Dede (tree man)

Human papilloma virus 8H<75
Human papilloma virus 8H<75
90% of 90% of cervical cancers cervical cancers contain HPV DNA. contain HPV DNA.
t!"es (HPV#$%& HPV#$'& HPV#($& and HPV#)) accounts t!"es (HPV#$%& HPV#$'& HPV#($& and HPV#)) accounts
for * '0% of HPV#"ositive cancers. for * '0% of HPV#"ositive cancers.
HPV#$% + $' most common t!"e of HPV found in *,0% of HPV#$% + $' most common t!"e of HPV found in *,0% of
cervical carcinomas. cervical carcinomas.
HPV#%&$$ - common in .enital /arts HPV#%&$$ - common in .enital /arts
Copyright 1998 - 2000 David Reznik, D.D.S. All Right Reerved
non(enveloped
viruses composed
of a dou+le(
stranded, closed
circular !"
genome-
$*% is genetically
sta+le

H<7 infection to cervical
H<7 infection to cervical
carcinoma
carcinoma
$&000&000 females
$00&000 females
'000 females
$%00 females

HPV life c!cle
HPV life c!cle
(
3n4ection eta'li$ed in 'aal e/it$elial layer -$ere !iral
geno"e "aintained a an e/io"e
(
2iral re/lication occur in u/ra'aal layer
(
3n4ection are t$ere4ore long lating

2ntegration into the host genome
2ntegration into the host genome

HPV $% "roduces onl! ei.0t "roteins
HPV $% "roduces onl! ei.0t "roteins
1$ Re"lication of viral DNA2 maintenance of viral
e"isome2 essential for viral re"lication and
control of .ene transcri"tion
13 1ssential for viral re"lication2
re"ression of 1% and 1,
1 4orms filamentous c!to"lasmic net/or5s
1) Prevents acidification of endosomes2
interaction /it0 1"idermal 6ro/t0 4actor
(164) 7Platelet#Derived 6ro/t0 4actor
(PD64)
89R :ri.in of DNA re"lication2 re.ulation of HPV
.ene e;"ression
Protein 4unction
8$ <a=or ca"sid "rotein in t0e virus "article2 >! itself& 8$ can
assem>le into ca"somers and t0en form virus#li5e "articles
(V8Ps)
83 <inor ca"sid "rotein in t0e virus "article2 83 >inds to DNA
1% Destruction of ")( tumor su""ressor "rotein
1, ?nactivation of Retino>lastoma tumor su""ressor "rotein (R>)

$ervical carcinoma progression
$ervical carcinoma progression

,; and ,= proteins inactivate tumour suppressor
,; and ,= proteins inactivate tumour suppressor
proteins p>? and p@B
proteins p>? and p@B
1ran4or"ing acti!ity o4 .P21) lin%ed to 1% and 1, /rotein
1% and 1, inter4ere -it$ tu"our u//reor acti!ity

2nactivation of p@B "y ,=
2nactivation of p@B "y ,=

(
Pre!entati!e 4or cer!ical cancer in c$ildren
aged 9516 year and -o"en 4ro" 1)#2)
year
(
nearly 100 /ercent e44ecti!e in /re!enting
/recancerou cer!ical leion,
/recancerou !aginal and !ul!ar leion
and genital -art caued 'y in4ection -it$
t$e .P2 ty/e ), 11, 1) or 17 in -o"en
'et-een t$e age o4 1) and 2).
6ardasil 6ardasil
@ @
(<erc5)- (<erc5)-
Auadrivalent recom>inant vaccine a.ainst HPV t!"es %& $$& $% Auadrivalent recom>inant vaccine a.ainst HPV t!"es %& $$& $%
and $' and $'

.eading
8$a/ter (9 Biolo.! of 9ancer >! RA Weinberg
(dditional reading
(
:ncogenic !irue 'y Dennis J McCance
---.el.net
(
.o- -ill .P2 !accine a44ect cer!ical cancer;
Roden R, <u 18 Nat Rev Cancer. 200)
:ct;)(10)9763#)3
(
1$e 'iological /ro/ertie o4 =) and =7
onco/rotein 4ro" $u"an /a/illo"a!irue. Virus
Genes. (2009) :ct 17. 'y G$ittoni R et al.

1$e 4ollo-ing lide are 4or
general interet only
and
/ro!ide ot$er e>a"/le o4 ,*0 ?
R*0 !irue in oncogenei

Flaviviridae
8hepatitis C virus
$C%5

Retroviridae
Human T-cell lymphotropic
virus (HTLV type I)
RNA viruses
RNA viruses

@N( viruses
@N( viruses

Unsta"le @N(
genome

prone to
mutations

6enerates
genetic diversity
and escape
antiviral therapy

$an "e
oncogenic
8e.g.hepatitis $
virus H$75

Figure 3.17 The Biology of Cancer ( Garland Science 2007)
@etroviral replication
@etroviral replication

Human 2mmunodeAciency 7irus H27

H27 life cycle
See ani"ation at $tt/9??---.roc$e#$i!.co"?$o"e?$o"e.c4"

H27 genome
3 structural genes
gag 8group speciAc
antigen5 encodes matri!,
capsid, nucleocapsid
proteins
pol 8polymerase5 encodes
reverse transcriptase,
integrase, protease
env 8envelope5 encodes
surface - transmem"rane
proteins
6 regulatory genes
rev 8regulatory virus
protein5
tat 8transactivator5
nef 8negative regulatory
factor5
vif, vpr, vpu, env
8envelope5 encodes surface
- transmem"rane protein

8oure o4 .32 in4ection

"ntiretroviral or anti $/%
therapy
(ll approved anti)H27 drugs attempt to "loc# viral replication
within cells "y inhi"iting either @T or H27 protease.
Nucleoside analogues mimic H27 nucleosides preventing DN(
strand completion e.g. Bidovudine 8(BT5, dd2, dd$, tavudine
Non nucleoside @T inhi"itors 8NN@T25 e.g Delavirdine and
Nevirapine
<rotease inhi"itors "loc# active, catalytic site of H27 protease
Multidrug therapy
H((@T 8highly active antiretroviral therapy5 usually consists
of triple therapy including
0 % nucleoside analogues C ' protease inhi"itor
0 ' non nucleoside @T inhi"itor C '8%5 prot. inhi"itor

Flaviviridae
8hepatitis C virus
$C%5

Retroviridae
Human T-cell lymphotropic
virus (HTLV type I)
RNA viruses
RNA viruses

hepatitis $ virus
hepatitis $ virus
$C%
$C%
(Dects ?E of glo"al population
2nfects primarily hepatocytes
>&)F&E of infected individuals go on to develop hepatocellular
carcinoma 8H$$5
(t least ; genotypes #nown

.hat causes hepatocellular
.hat causes hepatocellular
carcinoma3
carcinoma3

HB7 and H$7 co)infection3

HB7 integrates into genome and produces a


protein H"!, involved in H$$

H$7 does not integrate into the genome "ut


can interact with host proteins and cause an
inGammatory response, which can
transform cells
e.g. H$7 proteins N? and N>( can disrupt
transcription factors leading to proliferation
and inhi"ition of apoptosis

$C% life cycle
$C% life cycle

Human Herpes Virus 8
Human Herpes Virus 8
8
8
$$%&' or
$$%&' or
aposi!s sarcoma associated virus "HV
aposi!s sarcoma associated virus "HV
Herpes virus family
Type ' ) causes
9cold sores4 on lips
8HI&E of
population5

Type % ) se!ually
transmitted disease
that causes Jcold
soresJ on the
genitals 8H %>E of
U adults5.

Human Herpes Virus 8
Human Herpes Virus 8
(
(
$$%&' a-1-a
$$%&' a-1-a
*aposi4s
*aposi4s
sarcoma associated virus
sarcoma associated virus
..27 ende"ic region
..27 ende"ic region

*aposi4s sarcoma
*aposi4s sarcoma

HH7F and transformation
HH7F and transformation
(
@ot /eo/le in4ected -it$ ..27 do not get AS
(
3""unou//reed indi!idual are uce/ti'le
(
2iral $o"ologue o4 e!eral $u"an /rotein (e.g. !#cyc, !3B))

Herpesviridae

Human Herpes Virus


(HH7F5 a.#.a *aposi4s
sarcoma associated
virus

,pstein)Barr virus
8,B75
DNA viruses
DNA viruses

E)%( Epstein )arr %irus
E)%( Epstein )arr %irus
most potent transforming agent,
widespread in all human populations
usually carried as an asymptomatic persistent
infection (latent).
virus sometimes associated with the
pathogenesis of certain types of lymphoid and
epithelial cancers, including
Burkitts lymphoma (BL),
Hodgkin disease and
Nasopharyngeal carcinoma (NPC).

Bur#itt4s Bur#itt4s
lymphoma lymphoma
Nasopharyngeal Nasopharyngeal
carcinoma carcinoma
Hodg#in4s Hodg#in4s
lymphoma lymphoma
C0#60D o4 /atient
are
=E2 ero/oiti!e
*P8 tiue tained 4or t$e
/reence o4 =E2 late
antigen.

,B7 genome and host cell transformation
,B7 genome and host cell transformation
=E2#encoded nuclear antigen 2 (=E*02)
latent "e"'rane /rotein 1 (B@P1)
"i"ic 8,C0 rece/tor
B@P2 "i"ic t$e E cell rece/tor

in vivo
in vivo
interactions "etween ,B7 and host
interactions "etween ,B7 and host
cells
cells

aetiolo.! of several different l!m"0oid and


e"it0elial mali.nancies.

1BV#encoded latent .enes induce B#cell


transformation in vitro >! alterin. cellular .ene
transcri"tion and constitutivel! activatin. 5e!
cell#si.nallin. "at0/a!s.

1BV e;"loits t0e "0!siolo.! of normal B#cell


differentiation to "ersist /it0in t0e memor!#B#
cell "ool of t0e immunocom"etent 0ost.
ummary of ,B7
ummary of ,B7