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Nat Rev Microbiol. Author manuscript; available in PMC 2019 November 01.
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Published in final edited form as:

Nat Rev Microbiol. 2018 November ; 16(11): 684–698. doi:10.1038/s41579-018-0064-6.

Molecular mechanisms of viral oncogenesis in humans

Nathan A. Krump and Jianxin You*
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA.

Abstract
Viral infection is a major contributor to the global cancer burden. Recent advances have revealed
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that seven known oncogenic viruses promote tumorigenesis through shared host cell targets and
pathways. A comprehensive understanding of the principles of viral oncogenesis may enable the
identification of unknown infectious aetiologies of cancer and the development of therapeutic or
preventive strategies for virus-associated cancers. In this Review, we discuss the molecular
mechanisms of viral oncogenesis in humans. We highlight recent advances in understanding how
viral manipulation of host cellular signalling, DNA damage responses, immunity and microRNA
targets promotes the initiation and development of cancer.

When normal cell growth control mechanisms are disrupted, some cells may exhibit
uncontrolled proliferation and cease to perform their tissue-specific functions, leading to the
development of cancer. Infection by oncogenic viruses is thought to cause ~15–20% of all
human cancers1.
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The seven known human oncogenic viruses are Epstein–Barr virus (EBV), hepatitis B virus
(HBV), human T-lymphotropic virus 1 (HTLV-1), human papillomaviruses (HPVs), hepatitis
C virus (HCV), Kaposi sarcoma-associated herpesvirus (KSHV; also known as human
herpesvirus 8 (HHV-8)) and Merkel cell polyomavirus (MCPyV) (Table 1 and reviewed in
ref.2). EBV and KSHV are large DNA viruses that can cause solid tumours and lymphoid
malignancies3,4 (Table 1). HPV and MCPyV (box 1) have smaller DNA genomes than EBV
and KSHV. Whereas oncogenic HPVs establish persistent infections in mucosal epithelia5,
MCPyV infects and likely persists latently in dermal fibroblasts6. These small DNA
oncogenic viruses promote tumorigenesis using relatively few multifunctional
oncoproteins7,8. HCV, a positive-sense, single-stranded RNA virus, and HBV, a small DNA
virus, both infect hepatocytes and cause chronic liver inflammation, liver cirrhosis and
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*
[email protected].
Author contributions
N.A.K. and J.Y. researched data for the article, substantially contributed to discussion of content, wrote the article and reviewed and
edited the manuscript before submission.
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Microbiology thanks D. Galloway and other anonymous reviewers for their contributions to the peer review of this
work.
 Krump and You Page 2

hepatocellular carcinoma (HCC)9,10. Lastly, HTLV-1 is a human oncogenic retrovirus that

infects T cells and can cause adult T cell lymphoma11.
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Human oncogenic viruses have diverse genomes, cellular tropisms, cancer pathologies and
disease prevalence (Table 1). However, they share many features that can lead to cancer in
humans. They are transmitted between humans and can establish chronic infections that last
for years without obvious symptoms. Throughout these prolonged periods, oncogenic
viruses co-opt cellular processes for replication and undermine immune recognition. They
derail conserved signalling pathways that control cell cycle progression and apoptosis (box
2) to support their propagation. Although tumorigenesis is a unifying pathological feature
for oncogenic viruses, it is neither evolutionarily advantageous for the virus nor required for
virus propagation. Many of the properties that are shared among the seven oncogenic viruses
are also common to other viruses. To identify what makes these seven unique, we must
examine the specific mechanisms by which they alter the cellular environment.
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Major discoveries in recent years have revealed similar oncogenic mechanisms among these
divergent viruses. Advances in omics technologies have resolved a network of genetic and
functional changes induced by oncogenic virus infection. In this Review, we discuss recent
insights that explain how oncogenic viral factors modulate host cell processes and cellular
microenvironments to promote cellular transformation and metastasis. Identifying
commonalities among these events may lead to new approaches for preventing and treating
cancers caused by viruses.

Targeting tumour suppressor pathways

The activation of tumour suppressor pathways is crucial to defence against cellular
transformation that can occur when cells are infected by oncogenic viruses. The resulting
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cellular responses, including cell cycle arrest, apoptosis and senescence, can inhibit virus
replication, repair DNA damage and prevent cancer development12. Cellular tumour antigen
p53 and retinoblastoma protein (prb) are at the heart of the two major tumour suppressor
pathways, which function to repress tumorigenesis by tightly regulating cell cycle
progression, stimulating cellular DNA damage response and inducing apoptosis after
irreversible cell damage12. Nearly all the oncogenic viruses encode oncoproteins that
dysregulate the p53 and pRB pathways; however, the mechanisms that they employ are
distinct2. Viral oncoproteins inhibit the function of p53 and pRB by inducing their
degradation, inactivation, repression or dissociation from cognate functional partners
(reviewed in refS2,13,14).

Dysregulating the tumour suppressor activities of p53 and pRB can benefit virus
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propagation. For example, the oncoproteins encoded by small DNA oncogenic viruses (for
example, HPV) and large oncogenic herpesviruses (for example, EBV and KSHV) can
inactivate the function of pRB and p53 to drive the cell into S phase (that is, the phase of
DNA synthesis), granting the virus access to the cellular replication machinery and
nucleotides for viral DNA synthesis13. In addition, both HTLV-1 oncoproteins transactivator
from X-gene region (Tax) and basic zipper factor (HBZ) can inhibit p53 function through
various mechanisms that predispose cells to oncogenesis15. The p53 and pRB pathways are

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also frequently dysregulated in HBV-associated HCC; the viral HBV-X protein (HBx) forms
a complex with p53 and inhibits its DNA binding and transcription factor functions16.
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Elimination of virally infected cells through apoptosis represents a principle host defence
mechanism against viral infection. Inhibition of apoptotic signalling by oncogenic viruses
therefore permits viral replication and propagation before the death of the host cell2. Nearly
all oncogenic viruses have evolved complex apoptosis evasion strategies that target the p53
and pRB pathways to evade host responses to infection and to establish a persistent
infection16–20. Targeting of cell cycle checkpoints and apoptosis pathways by viruses places
host cells at risk of cellular genomic instability and chromosome abnormality2.
Compounding genetic mutations that are acquired by cells in this deteriorating environment
could ultimately lead to cancer.

Targeting host signalling pathways

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Cellular proliferation is regulated by tightly controlled signalling pathways (box 2).

Evidence from recent studies has revealed common strategies that are used by oncogenic
viruses to subvert these pathways in a manner that promotes viral infection and occasional
cellular transformation (box 2; FIG. 1).

PI3K–AKT–mTOR signalling.
The phosphatidylinositol 3-kinase–AKT–mechanistic target of rapamycin (PI3K–AKT–
mTOR) pathway is a major eukaryotic nutrient-sensing pathway that coordinates
macromolecule synthesis and metabolism in response to nutrient abundance (box 2; FIG.
1a). It has an important role in the regulation of cellular growth, cell cycle progression,
proliferation, survival, quiescence and longevity by coordinating growth stimuli and
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regulating downstream effectors, including AKT and mTOR. Dysregulation of the PI3K axis
can disrupt normal cellular growth control and result in the survival and proliferation of
tumour cells21. Some oncogenic viruses, including HPV, EBV, HTLV-1, KSHV and MCPyV,
have evolved mechanisms to engage this pathway in the absence of necessary growth factors
and when nutrient levels are low (FIG. 1a).

Activation of PI3K–AKT–mTOR signalling may benefit viral infection by promoting cell

proliferation22,23 and inhibiting autophagy, which can impede viral replication24. The most
extensively studied case is that of HPV, in which each of the viral oncoproteins E5, E6 and
E7 either directly or indirectly target the pathway and promote cell division, predisposing
infected cells to tumour initiation and progression25 (FIG. 1a). The EBV latent membrane
protein 2A (LMP2A) induces AKT phosphorylation and activates the PI3K–AKT pathway26
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(FIG. 1a). This contributes to an anti-apoptotic function that prevents the removal of
damaged cells and provides a selective advantage for LMP2A-expressing B cells during the
development of EBV-associated malignancies26. LMP2A-mediated activation of the PI3K–
AKT pathway also inhibits epithelial cell differentiation in EBV-infected cells, suggesting
that the same mechanism contributes to progression of EBV-related carcinomas and
lymphomas27. HTLV-1 modulates AKT in CD4+ T cells, promoting a long latent phase28.
The HTLV-1 Tax oncoprotein was found to activate the AKT pathway and induce AKT-
dependent inactivation of the fork-head box protein O3 (FOXO3), which causes depletion of

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CD4+ T cells through induction of pro-apoptotic and anti-proliferative target genes28 (FIG.
1a). Inhibition of FOXO3 therefore promotes the survival and proliferation of CD4+ T cells
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that maintain the capacity to spread infectious HTLV-1 particles28. This Tax protein function
enables the long-term maintenance of infected CD4+ T cells during the early phase of
HTLV-1 pathogenesis28.

The importance of mTOR signalling in KSHV biology was highlighted by the observation
that the mTOR inhibitor rapamycin — but not other immunosuppressants — promotes
tumour regression in transplant patients affected by KSHV-induced Kaposi sarcoma29. It
was later discovered that expression of KSHV ORF45, a lytic gene expressed in infected
lymphatic endothelial cells, selectively upregulates mTOR signalling30 (FIG. 1a). The
dependence of KSHV-infected cells on the mTOR signalling pathway for their survival
explained their sensitivity to rapamycin-induced apoptosis. Expression of the KSHV G
protein-coupled receptor (vGPCR) in a mouse allograft model is sufficient to induce
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sarcomagenesis through the activation of AKT phosphorylation31. The role of AKT in

human Kaposi sarcomagenesis was supported by the observation of robust AKT activation
in Kaposi sarcoma biopsy samples taken from individuals with AIDS31. In B cells, the K1
protein of KSHV activates AKT signalling to inhibit apoptosis (FIG. 1a), suggesting that this
is a mechanism to protect virus-infected cells from premature cell death during KSHV-
induced oncogenesis32. By comparison, the small T oncoprotein of MCPyV targets the
PI3K–AKT–mTOR signalling pathway further downstream (FIG. 1a). It promotes the hyper-
phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), a
crucial target of mTOR complex 1 (mTORC1), leading to hyperactivated cap-dependent
translation of cellular proteins and cellular transformation33. Infection by each of these
evolutionarily distinct viruses leads to a state of anabolism that is caused by targeting
mTOR, which ordinarily responds to a network of signals such as amino acid availability
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and environmental stress.

MAPK signalling.
Mitogen-activated protein kinase (MAPK) pathways regulate the transcription of genes that
control cell proliferation and the antiviral immune response34 (box 2). They are involved in
the life cycle and propagation of several oncogenic viruses, such as HCV, HPV and MCPyV,
by promoting viral assembly, production and release (FIG. 1b). For example, the activity of
MAPK-regulated cytosolic phospholipase A2 (PLA2G4A) contributes to the assembly of
infectious HCV particles35. Arachidonic acid, the cleavage product of PLA2G4A-catalysed
lipolysis, restores the production of infectious HCV particles in the absence of PLA2G4A35.
This suggests that PLA2G4A-mediated lipolysis provides a membrane environment for
efficient incorporation of core proteins into the lipid envelope of nascent viral particles35.
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MAPK signalling also enhances non-enveloped virus production, as evidenced by increased

HPV virion production upon induction of extracellular-signal-regulated kinase 1 (ERK1)
and ERK2 in HPV-infected cells36. In agreement with this finding, inhibition of
MAPK/ERK kinase 1 (MeK1) and MEK2 with a cancer drug (trametinib) drastically limits
MCPyV infection by blocking MCPyV transcription and/or replication in infected cells,
suggesting that activation of the MAPK pathway is needed to support these events in the

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MCPyV life cycle6. However, whether MAPK pathways also have a role in the development
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of MCPyV-associated Merkel cell carcinoma (MCC) is unknown.

Oncogenic viruses often manipulate MAPK pathways to promote host cell proliferation, but
this process could incidentally give rise to invasive cells that contribute to metastasis. During
the switch from the latent to the lytic phase of EBV infection, the p38 MAPK pathway has a
crucial role in protecting host cells from apoptosis and in inducing viral reactivation37. The
EBV LMP1 that is induced during the latent–lytic transition has been proposed to prevent
apoptosis and mediate reactivation, although this hypothesis has not been tested
experimentally37. LMP1 expression in epithelial cells activates the ERK–MAPK pathway,
promoting cell motility and metastasis38 (FIG. 1b). In this way, LMP1 may contribute to cell
invasion in EBV-associated nasopharyngeal carcinoma38.

The molecular mechanism by which KSHV activates MAPK pathways is better understood
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than in EBV infection39. The KSHV kaposin B protein binds to and activates an effector of
the p38 MAPK signalling pathway, MK2 kinase (MK2K), which then stabilizes pro-
inflammatory and pro-survival cytokine mRNAs39 (FIG. 1b). The increased cytokine
production could promote the growth and survival of tumour cells in KSHV-associated
oncogenesis39. As another example, the HBV HBx protein activates the ERK pathway and
induces the expression of a master regulator of tumour metastasis, FOXM1 (ref.40) (FIG.
1b). FOXM1 contributes to HBV-induced hepatocarcinogenesis by transactivating the
expression of MMP7, RHOC and ROCK1, which promote hepatoma cell invasion and
metastasis40. Enhanced invasiveness, dysregulated cell division and elevated cytokine
production via hyperactive MAPK signalling may provide the optimal environment for virus
propagation, but it also drives cancer pathology and resistance to treatment.
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Notch signalling.
Depending on the cellular environment and tissue context, perturbations in the Notch
signalling pathway can either promote or suppress tumorigenesis41 (box 2). A role for Notch
signalling was found in the development of chronic lymphocytic leukaemia, B cell
malignancies and breast cancer42. By contrast, Notch signalling has a tumour suppressor
function in skin epithelia and pancreatic cells41. Unlike the pathways explored in the
previous sections that are largely upregulated in all cancers, the divergent association of
Notch signalling with different cancers is reflected in the variety of approaches through
which viruses exploit this pathway (FIG. 1c).

In a systematic analysis of the host interactome and transcriptome networks that are
perturbed by oncogenic virus proteins, Notch signalling was identified as a key pathway that
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is targeted by EBV, HPV and MCPyV oncoproteins, highlighting its importance in viral
tumorigenesis43. HPV E6 oncoproteins repress Notch signalling and promote viral
persistence in basal epithelial cells. Mastermind-like protein 1 (MAML1) and several other
components of the Notch transcription complex are targeted by β-genus HPV E6 proteins to
repress Notch transcriptional activation44 (FIG. 1c). E6 proteins of other cutaneous HPVs,
such as HPV-8, use a similar strategy to suppress Notch-dependent transcription of the
HES1 transcriptional repressor45,46, halting keratinocyte differentiation, a disruption that has
been linked to the function of HPV in promoting cell proliferation and oncogenesis45,46.

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EBV also interferes with Notch signalling to provide a cellular environment for long-term
infection47. Epstein–Barr nuclear antigen 2 (EBNA2) and activated Notch both compete for
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recombining binding protein suppressor of hairless (RBP-Jκ)47, and therefore, activated

Notch limits EBNA2-mediated transcription of EBV genes involved in the transformation of
infected B cells. Constitutive Notch signalling in the lymphoid microenvironment may lead
to EBV latency by downregulating the transcription-promoting function of EBNA247.

HBV and KSHV also activate Notch signalling. The HBV HBx protein stimulates the
expression of neurogenic locus Notch homologue protein 1 (NOTCH1), which promotes the
proliferation of HCC cells and may thus contribute to the oncogenic mechanism of HBV-
associated HCC48 (FIG. 1c). Elevated levels of activated Notch proteins are frequently
observed in KSHV-associated Kaposi sarcoma lesions49. KSHV proteins, including viral
FLICE inhibitory protein (vFLIP), vGPCR, latency-associated nuclear antigen (LANA),
replication and transcription activator (RTA) and viral interleukin-6 (vIL-6), can induce the
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expression of core Notch receptors and ligands that activate the pathway50,51 (FIG. 1c).
Stimulation of Notch signalling by these viral proteins appears to suppress the expression of
cell cycle-associated genes in neighbouring uninfected cells, inhibiting their proliferation
and potentially providing a growth and survival advantage to infected cells during Kaposi
sarcoma pathogenesis50,51. Notch pathway activation induced by vFLIP and vGPCR also
results in transcriptional reprogramming of the infected lymphatic endothelial cells to
mesenchymal cells through a process called endothelial-to-mesenchymal transition. The
growth and migration of infected cells promote viral spread and contribute to Kaposi
sarcoma invasiveness52. KSHV LANA competitively inhibits the interaction between the
intracellular domain of NOTCH1 (ICN) and an E3 ubiquitin ligase, F-box/WD repeat-
containing protein 7 (SEL10; also known as FBXW7), thereby preventing proteasomal
degradation of ICN53 (FIG. 1c). Stabilized ICN in turn functions as a proto-oncogene and
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stimulates the proliferation of KSHV-infected tumour cells, thus promoting virus-mediated

transformation53 (FIG. 1c). The observation that positive and negative regulation of Notch
signalling can both contribute to viral oncogenesis indicates that transformation depends on
the context of the cellular environment and the infected cell type.

WNT/β-catenin signalling.
The WNT/β-catenin signalling pathway regulates diverse physiological processes, such as
growth control, stem cell renewal, embryonic development and tissue differentiation54 (box
2). Hyperactivation of the downstream transcription targets of WNT/β-catenin signalling can
contribute to many growth-related pathologies, including cancer54. Viral oncoproteins
modulate the WNT/β-catenin pathway and contribute to carcinogenesis (FIG. 1d). For
example, both KSHV LANA and EBV LMP2A proteins can stabilize β-catenin55–57 (FIG.
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1d), which then upregulates downstream genes, such as CCND1 and MYC, to increase cell
proliferation and promote tumorigenesis58. HBV encodes multiple proteins, including HBx
and hepatitis B surface antigen (HBsAg), that aberrantly activate WNT/β-catenin
signalling59 (FIG. 1d). HBx and HBsAg silence antagonists of the pathway or upregulate
and stabilize its key components such as β-catenin. Together, these activities stimulate
abnormal transcription of target genes that drive cell proliferation, which ultimately
contributes to HCC development59. Similarly, continual expression of HTLV-1 HBZ in

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HTLV-1-induced adult T cell leukaemia cells dysregulates the WNT signalling pathway to
promote migration and proliferation60.
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The role of WNT/β-catenin in other viral cancers is less clear, though its function in
oncogenic virus infection may provide important clues. For example, activation of the
pathway stimulates MCPyV infection6. Induction of downstream matrix metalloproteinase
(MMP) genes contributes to MCPyV infection by disrupting the extracellular matrix of the
host cells6. Skin damage induced by ultraviolet light and ionizing radiation, wounding or
ageing processes can lead to the activation of WNT/β-catenin signalling and the expression
of MMPs. This suggests that these major risk factors for MCPyV-associated MCC stimulate
viral infection and thus promote tumour development through MMP induction6.

NF-κB signalling.
Activation of the nuclear factor-κB (NF-κB) pathway by pathogens and inflammatory
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cytokines leads to the induction of genes involved in diverse cellular processes, particularly
the innate immune and inflammatory responses61 (box 2). Activation of NF-κB and
downstream target genes in chronic infection and inflammation also promotes cancer
progression by stimulating cell proliferation, inhibiting apoptosis and enhancing
invasiveness62. NF-κB activation is part of an appropriate response to acute viral infection,
but viruses that establish infections in adaptive immune cells can utilize constitutive NF-κB
activation to expand their host environment (FIG. 1e). For instance, the EBV oncoprotein
LMP1 drives the development of lymphomas by activating NF-κB downstream target
genes63. It does so by mimicking constitutively activated host tumour necrosis factor
receptor (TNFR) and engaging interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF
receptor-associated factor 6 (TRAF6), the upstream signal transducers of the NF-κB
pathway64 (FIG. 1e). This LMP1-induced NF-κB activation promotes the proliferation and
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survival of infected B cells64,65.

NF-κB is also constitutively activated in the majority of KSHV-induced primary effusion

lymphoma (PEL) cells66. In these cells, the KSHV vFLIP protein activates the NF-κB
pathway by associating directly with an inhibitor of NF-κB (IκB) kinase (IKK) complex
component, inducing a conformational change that renders it constitutively active66,67 (FIG.
1e). In transgenic mice that express KSHV vFLIP, vFLIP-activated NF-κB contributes to
enhanced proliferation of lymphocytes and an increased incidence of lymphoma68.
Likewise, the HTLV-1 Tax protein is considered the primary factor by which this virus
transforms T cells, and part of its function involves activating NF-κB69 (FIG. 1e).

The activation of NF-κB highlights the apparently conflicting roles of inflammation in

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infection and cancer. NF-κB-mediated inflammation is crucial for proper innate immune
responses to acute infection or damaged cells, but also mediates pathology (for example,
pain, tissue damage or swelling, and immunosuppression) and cancer progression. The
specific situations in which oncogenic viruses evade or induce inflammation can inform our
understanding of immunity and disease.

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Exploiting the host DNA damage response

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The host DNA damage response (DDR) system is a complex network of signalling pathways
that collectively monitor and repair DNA damage that results from DNA replication, cellular
metabolism and exogenous insults, such as radiation and viral infection70 (box 2).
Stimulation of the major components of the DDR signalling network, such as ataxia
telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR)
kinases, can induce a cascade of phosphorylation events that activates downstream effectors
(for example, p53) to stall cell cycle progression at checkpoints. Cell cycle check-points
allow time to repair damaged DNA or induce senescence or apoptosis70. Cells with
disrupted DNA damage recognition and repair systems can accumulate genetic mutations
that enhance cell survival and proliferation. Failure to control these populations of cells can
ultimately lead to cancer.
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Viruses often elicit host DDRs; however, they have evolved mechanisms to undermine these
responses and manipulate them to their advantage71,72 (FIG. 2). In the process of engaging
the DDR machinery, some viruses optimize the cellular environment for their replication by
promoting progression to the S phase and inhibiting apoptosis73–77. In addition, DNA
viruses such as HPV and MCPyV activate ATM-related and ATR-related DDR factors and
recruit them to viral DNA replication foci, promoting viral DNA replication74–76,78.

The persistent engagement of DDR factors and enforcement of a replicative state by

oncogenic viruses results in genomic instability79 (FIG. 2). Generally, oncogenic virus
infection increases the rate of DNA breaks while depleting host factors that maintain
genome integrity79. Compromised sensing, signalling or repair of damaged DNA may allow
cells to acquire mutations that overcome tumour suppressor barriers during oncogenic
progression71.
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Genomic instability is frequently observed in high-risk HPV-associated cervical neoplasias

and is caused by HPV oncoproteins E6 and E7, which induce DNA damage, mitotic defects
and centrosome-related mitotic defects80 (FIG. 2). High-risk HPV oncoproteins also hinder
DNA repair and destabilize the cellular genome81. By reducing genomic fidelity as cells
divide, these viral oncoproteins increase the chances of acquiring additional genetic changes
that may contribute to HPV-associated carcinogenesis80,81.

Replication stress, nucleotide deficiency and the production of reactive oxygen species
(ROS) during viral infection can also contribute to genomic instability and oncogenesis. For
instance, EBNA1 can increase the transcription of NADPH oxidase to induce ROS
production, leading to host DNA damage and chromosomal aberrations that contribute to
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EBV-associated malignancy82 (FIG. 2). During persistent HCV infection, chronically

activated inflammatory cells release ROS, which can cause oxidative DNA damage and
promote a pro-carcinogenic microenvironment that drives HCC development83.

Although manipulation of the cell cycle and DDR factors can promote a fragile genomic
state, appropriate activation of DDRs to viral stressors remains a major barrier for
progression to cancer. For example, the metabolic and genotoxic stress that is induced by
EBV can trigger cellular senescence84. EBV infection of primary human B cells induces

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transient hyper-proliferation that activates the ATM–checkpoint kinase 2 (CHK2; also

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known as CHEK2) DDR pathway, which subsequently suppresses the growth of infected
cells. Abrogation of ATM and CHK2 kinase activity, however, results in B cell
transformation85.

MCPyV expresses large T antigen carrying carboxy-terminal origin-binding and helicase

domains that cause damage to DNA, stimulate host DDRs and activate the p53 pathway to
inhibit cellular proliferation86. Unlike MCPyV large T antigen expressed in persistent
infection, MCPyV proviruses integrated in malignant MCC cells encode large T antigen
truncation mutants that almost invariably delete this DDR-activating domain but retain the
aminoterminal pRB-inhibiting motif87. This observation supports the notion that DDRs are
an effective barrier to malignant progression, but oncogenic viruses make these defences
vulnerable.
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As a retrovirus, HTLV-1 undermines genomic integrity as part of its life cycle. HTLV-1
DNA integration into T cell genomes induces a lengthy latency period, in which a polyclonal
expansion of the infected cells progresses to an aggressive monoclonal leukaemia in ~5% of
infected individuals88. HTLV-1 proviruses preferentially integrate in the vicinity of tumour
suppressor genes, which are consequently disrupted by provirus-dependent transcription
termination or viral antisense RNA-dependent cis-perturbation88. The same integration
pattern was observed in cells at asymptomatic stages as in leukaemia or lymphoma cells,
suggesting that provirus-dependent gene perturbations trigger initial polyclonal expansion of
the infected clones at non-malignant stages88. Expression of HTLV-1 Tax protein induces
further DNA damage and genomic instability by inhibiting DNA repair pathways and
causing DNA repair infidelity, allowing the accumulation of somatic mutations in clones that
ultimately progress to malignancy89 (FIG. 2).
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Whereas the aforementioned viruses promote the accumulation of mutations indirectly,

HCV, an oncogenic RNA virus with no apparent oncogenes, directly induces a mutator
phenotype90. In B cells, HCV infection induces somatic hypermutations in tumour
suppressors and proto-oncogenes, such as p53 and β-catenin. RNAi and antisense targeting
experiments revealed that the high mutation frequency in HCV infection is caused by the
increased expression of error-prone DNA polymerases and activation-induced cytidine
deaminase (AID), which cause the hypermutation of cellular genes90 (FIG. 2). Mutations in
the tumour suppressors and proto-oncogenes were amplified and selected for in HCV-
associated lymphomas and HCCs but not in similar neoplasias originating from other
causes90. Although HCV-related mutations contribute to the development of HCC, HCV
RNA is not found in most of the virus-induced HCC cells, suggesting a ‘hit and run’
oncogenic mechanism90 (FIG. 2).
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In contrast to the mutator phenotype that is induced by HCV90, HBV engages host DDR
pathways in a different manner91,92. The viral protein HBx induces the degradation of the
structural maintenance of chromosomes complex 5/6 (SMC5/6), which is a host DNA
damage repair regulator that normally binds extrachromosomal HBV genomes to repress
viral transcription91,92 (FIG. 2). In doing so, HBx derepresses transcriptional inhibition,
allowing productive viral gene expression and replication91,92.

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RNA and DNA oncogenic viruses elicit widespread changes to the cellular environment that
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support the viral infection cycle. This induces both direct and indirect stresses on the
integrity of the host genome and the pathways governing cell fate. By repurposing and
undermining the mechanisms that protect the host cell from cellular transformation,
oncogenic viruses establish a precarious balance between the ideal environment for viral
proliferation and termination through cell death or transformation.

Manipulation of host immune responses

Oncogenic viruses interface with host immune systems throughout persistent infections.
Epidemiological evidence suggests that their mechanisms to evade detection and elimination
are adapted to deal with the constant pressure from the host. Oncogenic viruses maintain
persistent infections in immune-competent hosts with few symptoms and are more likely to
induce malignancies in immunocompromised individuals18,19,93. Generally, viruses evolve
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to evade intrinsic restriction, avoid inflammatory responses and prevent targeted killing of
their host cells94. Unique immune evasion strategies are used for distinct phases, such as the
latent and lytic stages of the viral life cycle. Emerging evidence suggests that viral
subversion of immunity potentiates cancer because the same immunomodulatory tactics
directed at evading detection or expanding virus number can also prevent adequate
surveillance of transformed cells or increase cellular proliferation (FIG. 3).

To initiate a response to infection or to aberrant cells, the host must first sense something
atypical to healthy cellular function. Cytosolic DNA represents a danger signal for the cell,
whether it originates endogenously or from an invading DNA virus. As DNA is normally
compartmentalized within the nucleus and mitochondria, loss of organelle or genomic
integrity or the presence of foreign DNA is an ideal signal to trigger an immune response.
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Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that synthesizes a soluble
cyclic dinucleotide (cyclic GMP–AMP (cGAMP)) when bound to duplex DNA. cGAMP, in
addition to second messengers released by intracellular bacteria, activates endoplasmic
reticulum-resident stimulator of interferon genes protein (STING). STING and downstream
Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling
activate interferon-dependent antiviral programmes95 (FIG. 3). Oncogenic DNA viruses
antagonize the cGAS–STING pathway to avoid interferon-mediated restriction (FIG. 3).
KSHV evolved multiple effectors that inhibit this pathway, including ORF52, LANA and
viral interferon regulatory factor 1 (vIRF1)96–98. ORF52 directly binds cGAS and inhibits its
enzymatic activity97. LANA, especially its cytoplasmic isoform, also directly associates with
cGAS to antagonize the activation of its downstream components98. vIRF1 blocks the
interaction between STING and its upstream serine/threonine-protein kinase TBK1, thus
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preventing STING phosphorylation and activation of downstream signalling96. Inhibition of

cGAS–STING by these KSHV oncoproteins contributes not only to the establishment of a
latent infection but also to reactivation from latency96–98, which is crucial for both
disseminating infectious virus and potentiating tumour growth99.

Blockade of the cGAS–STING axis could be a general feature used by oncogenic viruses to
overcome antiviral immune defences (FIG. 3). For instance, HPV E7 binds STING to inhibit
downstream signalling and interferon-β (IFNβ) production in tumour cells100. In addition,

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HTLV-1 oncoprotein Tax suppresses the cGAS–STING pathway to inhibit IRF3

phosphorylation and type I interferon production101. Likewise, HBV polymerase interacts
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directly with STING to abrogate downstream IRF3 activation102. HCV non-structural

protein 4B (NS4B) inhibits this virus-induced interferon signalling pathway by directly
interacting with STING to block its interaction with mitochondrial antiviral-signalling
protein (MAVS), a member of the retinoic acid-inducible gene-I (RIG-I) viral RNA sensing
pathway103. Growing evidence in cancer research suggests that the cGAS–STING pathway
is a crucial early detection system for cells that have sustained substantial DNA damage.
Cells with unresolved DNA breaks may leak chromosomal DNA into the cytoplasm or
exhibit ruptured micronuclei that recruit and activate cGAS104,105. Given the importance of
this pathway in defence against cancer, it is possible that inhibition of cGAS–STING
compromises an early barrier to viral oncogenesis.

Viral immune evasion extends to other sensory pathways (FIG. 3). HBV polymerase and
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HBx proteins can abolish interferon production through RIG-I and Toll-like receptor 3
(TLR3), thus blocking IRF3 activation106,107. KSHV also blocks inflammasome activation,
which normally facilitates inflammatory cell death programmes and the transition from
innate to adaptive response to intracellular pathogens or cell damage. KSHV ORF63 is a
viral homologue of human NOD-, LRR- and pyrin domain-containing 1 (NLRP1), a
cytosolic sensor that activates the inflammasome in response to infections108. ORF63 binds
NLRP1 and inhibits downstream inflammasome-dependent inflammatory cytokine
production, contributing to chronic infection108.

Downstream of intracellular threat detection, a compromised cell may activate

transcriptional programmes to suppress its growth and survival. Oncogenic viruses express
effectors that counteract the anti-proliferative immune response and serve as key drivers of
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their oncogenic potential. This host–pathogen relationship is typified in KSHV-infected

cells. KSHV encodes four homologues of cellular IRFs that mediate broad protection against
viral infection and aberrant cellular proliferation109 (FIG. 3). By dimerizing with cellular
IRFs and other transcription factors, KSHV vIRFs repress the immune response to infection
(by down-regulating interferon signalling) and dysregulate cell growth control (by targeting
the NF-κB, MYC and p53 pathways)109. KSHV infection may still induce interferon despite
vIRF competitive binding, resulting in p21-mediated cell cycle arrest110. To overcome the
growth-limiting effect of interferon, the virus activates an alternative transcriptional
programme that allows only vIL-6 expression in response to interferon stimulation110 (FIG.
3). Human IL-6 (hIL-6) normally binds to its receptor membrane glycoprotein 80 (gp80;
also known as IL-6R), which forms a functional complex with the transmembrane
transducer membrane glycoprotein 130 (gp130; also known as IL6RB) to activate
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transcription of genes that control cell proliferation111. IFNα was found to specifically
downregulate gp80, but this has no effect on gp130 expression110. Unlike hIL-6, vIL-6 can
bypass the interferon–gp80 autoregulatory checkpoint by directly binding to and activating
gp130, establishing an autocrine feedback circuit to overcome interferon-induced growth
inhibition110. KSHV thus provides an example of how oncogenic viruses may subvert innate
immunity at the level of transcription for optimal viral propagation.

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In addition to cell intrinsic changes, oncogenic viruses also modulate interactions between
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infected cells and immune cells. Evasion of extrinsic cellular responses can contribute to the
pathological expansion of host cells by limiting normal immune clearance (FIG. 3). For
instance, many oncogenic viruses have evolved strategies to downregulate major
histocompatibility complex class I (MHC-I), which presents peptides derived from
intracellular proteins to CD8+ T cells for targeted cell killing112. Viral proteins inhibit MHC-
I function by interfering with the synthesis, translocation or assembly of MHC I
molecules113. In addition, KSHV K3 and K5 proteins downregulate cell surface MHC-I
display by promoting endocytosis and endolysosomal degradation of class I chains.114–116

HTLV-1 manipulates immune cell interactions through a unique set of strategies that have
been explored in greater detail (FIG. 3). HTLV-1 p12 down-regulates immune modulator
intercellular adhesion molecule 1 (ICAM1), ICAM2 and MHC-I on the cell surface,
allowing infected cells to escape killing by natural killer cells and cytotoxic T cells117.
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HTLV-1 p8 downregulates T cell signalling to induce T cell anergy. At the same time, p8
induces the formation of plasma membrane conduits between infected and uninfected T
cells, enabling spread without the virion entering the extracellular space118. HTLV-1 HBZ
enhances the immunosuppressive state by upregulating the expression of a T cell co-
inhibitory molecule, T cell immunoreceptor with Ig and ITIM domains (TIGIT), in infected
CD4+ T cells119. TIGIT activity attenuates T cell responses to another HTLV-1 virus
antigen, Tax119. Together, HTLV-1 accessory proteins shape the microenvironment of
adaptive and innate immune cell interactions, allowing the virus to escape host immune
recognition and achieve efficient propagation.

Similar to HTLV-1 modulation of T cells, EBV exploits the ability of B cells to expand and
disseminate continuously in order to propagate and avoid detection120,121 (FIG. 3). LMP1, a
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key viral protein for EBV-driven human B cell transformation, shares functions with the
constitutively active B cell co-stimulatory receptor CD40, and signals through common
down-stream pathways, such as JUN N-terminal kinase (JNK), ERK, p38 and NF-κB, to
promote B cell survival and proliferation93. EBV LMP2A mimics constitutively activated B
cell receptors to stimulate B cell proliferation and associated pathogenesis122,123. By
augmenting the natural propensity of B cells to be long-lived, invasive and self-renewing,
EBV drives infected populations to a state conducive to malignant
lymphoproliferation120,121. The fact that EBV causes solid tumours in addition to
lymphomas highlights its capacity to evade detection and promote cellular expansion in
different cellular environments.

Cellular immune responses to intracellular pathogens are often similar to responses to

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nascent transformation, including detection of abnormal molecular signals, cell cycle arrest,
cytokine release, inflammation and directed killing of affected cells. Oncogenic viruses
employ related strategies to undermine these processes. By enhancing cell survival and
proliferation while blocking extrinsic immune destruction, they establish and maintain an
optimal environment for viral persistence. In this way, virus immune evasion can contribute
to tumorigenesis and associated pathologies. These observations provide support for the
anti-antivirus hypothesis, which suggests that, when disabling host antiviral defences,
oncogenic viruses incidentally drive infected cells towards cancer2.

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Conclusions and outlook

Author Manuscript

Viruses have evolved an array of tactics to exploit and subvert the host cellular machinery
for propagation. In parallel, their hosts evolved mechanisms to maintain the integrity of the
cellular environment and perform life-sustaining functions for the organism. As discussed in
this Review, the fate of both host and pathogen is decided by the extent to which either one
controls growth signalling pathways, genome maintenance machinery and immune
surveillance. During persistent and asymptomatic infections of many oncogenic viruses, an
equilibrium between these conflicting interests can be achieved. However, cumulative or
chance events during infection and outside forces causing immune suppression or DNA
damage can disrupt the fragile balance. In these instances, viral strategies that normally
support infection instead drive uncontrolled cellular proliferation, accumulation of mutations
and evasion of antitumour immunity. Understanding these mechanisms and the contexts in
which they promote tumorigenesis is essential to preventing and treating viral cancers.
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Oncogenic viruses have been instrumental in divulging key features of normal cellular
function and pathology. Recent advances suggest that they remain an effective tool for
conducting and guiding basic research. For instance, oncogenic viruses have made it
apparent that cellular processes, once thought discrete, are intertwined. It has been proposed
that there is overlap between the tumour suppressor and innate immune signalling pathways
because both of these pathways can initiate cell cycle arrest and induce host cell death
during infection2. It was further suggested that, by targeting key cellular components that are
at the interface of these signalling pathways, oncogenic viruses disable both the host
antiviral and anticancer mechanisms, priming the infected cells for cancerous
transformation. Innate immune responses to intracellular pathogens double as early tumour
suppressor measures, supporting the notion that viral oncogenesis is a product of immune
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evasion mechanisms2. Given that inflammation drives later stages of malignant disease,
understanding how and when viral factors engage innate responses may clarify this
complicated aspect of cancer. Recent oncogenic virus research has also revealed that double-
stranded DNA introduced by viral infection and DNA damage generated during viral
proliferation can stimulate innate immune DNA sensing pathways, leading to the production
of cytokines that have both antiviral and antitumour function124. It will be particularly
exciting to understand how DDRs coordinate with antiviral and antitumour immune
signalling pathways throughout oncogenic progression and in the context of viral
manipulation.

The seven viruses known to cause cancer in humans employ divergent replication and
transmission strategies. Despite their differences, they are all highly adapted to maintain
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chronic infections in humans. Adaptation to coexist with a single host for prolonged periods
requires continuous manipulation of immunity and cell fate decisions. Viruses that cause
acute pathology or self-limiting infections, however, do not persist long enough to inflict the
changes necessary for metastatic disease.

Although oncogenic viruses have evolved to persist in their host foryears, they are still under
selective pressure to propagate to new hosts. The success of this propagation depends on
avoiding a terminal fate such as cancer. This helps explain why oncogenic viruses do not

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 Krump and You Page 14

cause cancer during most infections and only do so after many years. During years of limited
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pathology, when the host factors enabling coexistence shift drastically, viral strategies
influencing cellular growth and survival can lead to neoplasms. Central to future discussions
will be how immune suppression disrupts the interplay between host and pathogen to result
in cancer. It may be that inadequate immune surveillance allows unchecked viral replication
and expression of viral effectors that dysregulate host cell proliferation. Because immunity
to tumours overlaps that of viruses, it may also be that healthy immune systems typically
eliminate nascent transformed cells but may fail to do so once compromised.

Each cancer is multifactorial in terms of initiation and progression, making them challenging
to treat. Thus, a logical approach to prevent or treat cancers of a viral aetiology is to target
the virus. This principle has been given credence by successes in the clinic that have
drastically reduced the burden of viral cancers. Innovations in antiviral therapy against the
HCV RNA-dependent RNA polymerase have greatly reduced drug toxicity and continue to
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be effective at clearing HCV infections and preventing HCC125. Vaccinations against HPV
and HBV have effectively reduced the incidence of their associated cancers in populations
for whom the vaccines are accessible. Beyond preventive measures, reinstating immune
activity in ‘cold’ viral tumours (that is, tumours that elicit little to no immune response) has
proved to be an effective strategy. A general activator of T cell killing, anti-PD1–PDL1
immune checkpoint blockade in individuals with MCPyV+ MCC improves their
survival126,127. Application of this exciting new therapy in MCC and other viral tumours
supports the idea that viral factors may dampen immune responses in the tumour
microenvironment. If targeted chemotherapies or immunotherapies were developed with
specificity to the oncogenic or immune repressive mechanisms induced by viruses, even
better clinical outcomes could be expected.
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Pursuing novel therapeutics for viral cancers and basic research on virus–host interactions
has recently become more practical owing to advances in omics technologies43. For
example, deep sequencing and gene expression profiling led to the discovery of MCPyV7
and a better understanding of how the microRNA milieu is affected by oncogenic viruses
during oncogenesis (box 3). The combination of high-throughput technologies and big data
platforms allows investigators to decipher viral oncogenic mechanisms with the speed and
efficiency of omics-level computational biology. These systems-level studies will reveal
novel drug targets to advance the development of innovative intervention strategies for viral
malignancy and will help resolve the dynamics between host and pathogen during infection
and oncogenesis.

Acknowledgements
Author Manuscript

The authors thank E. A. White, C. B. Buck and the members of the You laboratory for valuable comments and
suggestions on the manuscript. The authors apologize to all colleagues whose primary research papers could not be
cited owing to space constraints. Research on human papilloma virus (HPV) and Merkel cell polyomavirus
(MCPyV) in the You laboratory has been supported by National Institutes of Health (NIH) grants (R01CA187718,
R01CA148768 and R01CA142723) and the National Cancer Institute (NCI) Cancer Center Support grant (NCI P30
CA016520).

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 Krump and You Page 15

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Box 1 |
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Merkel cell polyomavirus

Merkel cell polyomavirus (MCPyv) is the most recently discovered human oncogenic
virus and is associated with Merkel cell carcinoma (MCC), an aggressive malignancy of
the dermis7. MCPyv belongs to the Polyomaviridae family. it is a small, non-enveloped,
double-stranded DNa virus with a genome of ~5,400 base pairs. More than a decade after
identifying Kaposi sarcoma-associated herpesvirus (KsHv) as the causative agent of
Kaposi sarcoma, Chang and Moore led the next effort to identify an oncogenic virus in
humans7. in keeping with the guiding principle of that prior discovery, it was reasoned
that because MCC skin cancer disproportionately affects immunosuppressed and elderly
individuals, an infectious agent may contribute to its pathogenesis7. in their search, they
performed transcriptomic sequencing of human MCC tumours and then compared these
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sequences with the human genome to subtract background and non-viral sequence reads
from the total sequence data. using this approach, they identified an integrated
polyomavirus large t antigen transcript with homology to known animal polyomaviruses.
they then used 3′ rapid amplification of cDNa ends (raCe) and viral genome walking to
retrieve the sequence of this virus — MCPyv. By comparing integrated MCPyv sequence
in metastatic tumours between patients, the group also established that MCPyv integrates
monoclonally in the host genome before metastasis. this early observation supported the
notion that, like other oncogenic viruses, viral integration is a major event in MCC
tumorigenesis. since its discovery, MCPyv has been recognized as a ubiquitous virus that
asymptomatically infects most individuals during childhood, yet it can be linked to ~80%
of MCC cases. MCPyv can productively infect fibroblasts within the dermal layer of
human skin6. However, the details of the MCPyv life cycle and the events driving MCC
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oncogenesis remain unknown.

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Box 2 |
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Signalling pathways manipulated by oncogenic viruses

Pi3K–AKT–mTor signalling pathway
In the phosphatidylinositol 3-kinase–aKt–mechanistic target of rapamycin (Pi3K–aKt–
mtOr) pathway, stimulation of a diverse group of growth factor receptors by various
stimuli leads to the activation of Pi3K128. activated Pi3K phosphorylates
phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate, which
further activates aKt. aKt subsequently triggers the phosphorylation and activation of
diverse downstream effectors, including mTOR128. activated mtOr can stimulate the
translation of proteins needed for cell cycle progression by inducing the phosphorylation
of eukaryotic translation initiation factor 4e-binding protein 1 (4e-BP1)129. By
integrating various growth stimuli and acting through multiple cellular effectors, this
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pathway has an important role in the regulation of cellular growth, proliferation and
survival.

MAPK signalling pathway

Upon stimulation by either extracellular signals (for example, growth factors) or stress
stimuli (for example, osmotic stress, heat shock, ultraviolet irradiation and oxidative
stress), cell surface receptor kinases activate a mitogen-activated protein kinase (MAPK)
cascade, ultimately regulating the transcription of diverse genes involved in cell cycle
progression, growth, differentiation, programmed cell death and the antiviral immune
response34. the three best-characterized subfamilies of MAPKs are the extracellular-
signal-regulated kinases (erKs), JUN N-terminal kinases (JNKs) and p38 enzymes34.
each of these MAPKs is activated by their cognate kinases, which respond to distinct
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stimuli34.

Notch signalling pathway

The Notch signalling pathway is present in a variety of cell types. in this pathway, Notch
ligand binding promotes proteolysis of the Notch receptor and translocation of the
intracellular domain of the receptor to the nucleus, where it activates transcription of
downstream genes, including HES1, CCND1, MYC and BCL2 (REF.41). these genes
work together to regulate many fundamental cellular processes, including cell fate
determination, differentiation, development, cell proliferation, survival, apoptosis,
invasion and metastasis41.

WNT/β-catenin signalling pathway

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In this pathway, activation of the frizzled family cell surface receptors by WNT ligands
prevents the degradation of β-catenin, allowing stabilized β-catenin to engage DNA-
bound transcription factors and stimulate the transcription of downstream target genes
that control many important biological processes, including cellular proliferation, stem
cell renewal, embryonic development and tissue regeneration54. For example, in human
skin, WNT ligands released from basal epidermal keratinocytes promote the proliferation
of the dermal fibroblasts underneath130. in addition, wNt signalling from epidermal

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keratinocytes localized in the outer root sheath of hair follicles is essential for stimulating
the growth of surrounding dermal fibroblasts to support hair follicle regeneration130.
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NF-κB signalling pathway

Nuclear factor-κB (NF-κB), a key family of transcription factors, is normally sequestered
in the cytoplasm in an inactive form in complex with members of the inhibitors of NF-κB
(iκB) family of proteins61. stimulation of the NF-κB signalling pathway by extracellular
signals, including infectious agents, inflammatory cytokines and other pathogenic insults,
leads to a cascade of orderly responses that culminate in the activation of the iκB kinase
(iKK) complex. activated iKK in turn induces phosphorylation and degradation of iκB.
the released NF-κB can translocate into the nucleus and coordinate the expression of a
large number of genes involved in inflammation, immunity, cell death and proliferation61.

DNA damage response

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The major components in this signalling network are ataxia telangiectasia mutated
(ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases. theATM kinase
pathway is primarily activated by double-stranded DNa breaks, whereas the ATR kinase
pathway responds mostly to single-stranded breaks70. activated ATM and ATR
phosphorylate the downstream kinases checkpoint kinase 2 (CHK2) and CHK1,
respectively70. CHK2 and CHK1 phosphorylate downstream effectors, including cellular
tumour antigen p53, to activate the checkpoints that stall cell cycle progression while
recruiting the necessary proteins to repair DNA damage70. Depending on the severity of
the damage, these pathways can also induce senescence or apoptosis70.
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Box 3 |
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The role of mirNA targeting in viral oncogenesis

MicrorNas (mirNas) are naturally occurring 20–22 nucleotide single-stranded rNas that
can pair to mrNas in higher eukaryotes and repress their translation131. the processing
and function of these genetically encoded regulatory molecules are tightly regulated to
support timely modulation of gene expression that controls cellular growth, proliferation,
development, apoptosis and the stress response132. Dysregulation of miRNA synthesis or
processing machinery or the expression of certain individual miRNAs could compromise
cellular function and lead to pathological processes, including cancer133. Deep
sequencing and gene expression profiling studies have led to the increasing appreciation
that interactions between viruses and the miRNA milieu contribute to both viral infection
and oncogenesis. the strategies used by oncogenic viruses to contribute to oncogenesis
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include encoding viral mirNas that target cellular mRNAs and promote a
hyperproliferative state; upregulating host miRNAs to stimulate the growth of virus-
infected cells; and sequestering host miRNAs with tumour suppressor function.

Herpesviruses, including Kaposi sarcoma-associated herpesvirus (KsHv) and epstein–

Barr virus (eBv), establish stable latency programmes in which only a small percentage
of their protein-coding OrFs are expressed. the reliance on viral miRNAs rather than viral
proteins enables these viruses to escape immune surveillance. viral miRNAs modulate
numerous pathways without generating foreign protein antigens that could elicit an
immune response. During KsHv and eBv infection, viral miRNAs contribute to the
mechanisms by which these viruses affect cell survival or proliferation and ultimately
oncogenesis. For example, the seed sequence of KsHv mir-K12–11 miRNA is identical to
that of cellular miRNA mir-155, which targets mRNAs involved in the regulation of cell
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proliferation134. expression of mir-K12–11 leads to downregulation of mir-155 cellular

targets and may participate in the induction of B cell transformation134.

A transcriptome-wide analysis of KSHV-induced primary effusion lymphoma (PEL) cells

identified hundreds of cellular target mRNAs involved in transcription and cell survival
or proliferation as direct targets of KsHv miRNAs135. remarkably, more than half of the
host mRNAs identified are also targeted by miRNAs encoded by eBv, which frequently
co-infects KSHV-associated PEL cells135. additionally, expression of an extensive array
of viral miRNAs in eBv-infected gastric epithelial cells coincides with downregulation of
their cellular target genes involved in cellular transformation, suggesting that the eBv-
encoded miRNAs function as major contributors to the virus-induced transformation136.

Viruses also dysregulate host miRNAs. For example, human papillomavirus (HPv) e6 or
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e7 oncogene expression upregulates a cluster of host miRNAs that contribute to the

growth of HPv-positive cancer cells through the regulation of cell proliferation,
senescence and apoptosis137. The human T-lymphotropic virus 1 (HTLV-1) basic zipper
factor (HBZ) protein activates the oncogenic miRNAs mir17 and mir21 to promote host
genetic instability and abnormal cell proliferation138. alternatively, hepatitis C virus
(HCv) genomic RNA sequesters the liver-specific mirNa mir-122 for viral RNA
stabilization and replication, impeding its binding to cellular mRNAs139. as a tumour

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suppressor function has been observed for mir-122, sequestration of mir-122 by HCv
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genomic RNA and the resulting derepression of the normal host oncogenic targets of
mir-122 may contribute to oncogenesis during chronic HCv infection139.
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Oncogenic viruses
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Viruses that cause cancer. Sometimes also called tumour viruses. However, some tumour
viruses, such as adenovirus and polyomavirus SV40 promote tumorigenesis in other
organisms and infect humans but do not cause human cancers.
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Solid tumours
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Masses of transformed and supporting cells that arise in stationary tissues (sarcomas and
carcinomas) and not from cells of haematopoietic origin.
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Lymphoma
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Tumour arising from a lymphoid cell type that occurs predominantly in the lymphatics,
as opposed to leukaemias, in which the cancer cells are found in the blood.
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Cellular transformation
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Selective acquisition of cellular traits, such as replicative immortality, increased

stemness, growth factor independence, resistance to growth suppressors and alterations to
metabolic flux.
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Metastasis
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Tumour migration, invasion and colonization of body sites other than the primary site.
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p53
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A transcription factor and key tumour suppressor downstream of exogenous signals and
DNa damage-sensing pathways that maintains genome integrity and governs cell fate by
promoting expression of effectors of DNa repair, cell cycle arrest, senescence and
apoptosis.
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pRB
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(Retinoblastoma protein). A tumour suppressor that is responsible for a major g1

checkpoint that blocks S-phase entry and cellular growth.
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Oncoproteins
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Translated gene products that have the capacity to drive cellular transformation.
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Kaposi sarcoma
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A family of endothelial malignancies that are associated with Kaposi sarcoma-associated

virus (KSHV) and whose members are classified by the type of immunosuppression that
enabled KSHV-mediated oncogenesis.
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Carcinomas
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Tumours arising from cells of an epithelial origin, as opposed to sarcomas, which arise
from mesenchymal cells.
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Rapamycin
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An inhibitor of mechanistic target of rapamycin (mTor)-mediated proliferative function

that acts through direct binding of the peptidyl-prolyl cis-trans isomerase fKbP1a–
mechanistic target of rapamycin complex and has shown promise as an
immunosuppressant and antitumour drug.
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Sarcomagenesis
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The seminal event or events leading to cancer progression from mesenchymal-derived

cell types.
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Cap-dependent translation
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Translation in which initiation is mediated by recognition of the 5′ cap that is specific to

eukaryotic mRNAs.
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MEK1
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(MAPK/ERK kinase 1 (also known as MaP2K1)). a crucial protein kinase that mediates
an intermediate step of the raf–MeK–erK phosphorylation cascade responsible for
activating expression of pro-proliferative, survival and differentiation genes in response
to external stimuli.
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Invasive cells
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Tumour cells with characteristics that enable them to metastasize and invade other
tissues.
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CHK1
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(Checkpoint kinase 1). A protein kinase essential to normal cell division and
development that is activated by ataxia telangiectasia and Rad3-related protein (ATR) in
response to single-stranded DNa to facilitate proper DNA replication, cell cycle
progression and response to DNA insults.
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Endothelial-to-mesenchymal transition
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A process essential to cardiac development and normal angiogenesis by which

endothelial cells acquire stem-like, mesenchymal traits including enhanced migration
that, in certain cancers, contribute to metastatic ability.
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Proto-oncogene
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A type of endogenous gene that, when overexpressed or abnormally activated as a result

of mutation, can promote cancer development, at which point it is referred to as an
oncogene.
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CHK2
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(Checkpoint kinase 2). A tumour suppressor kinase activated by ataxia telangiectasia

mutated (ATM) in response to double-stranded breaks in DNA that maintains genomic
integrity by mediating cell cycle arrest and DNA repair.
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Second messengers
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Soluble small molecules that transduce intracellular signals, which can be secreted by
intracellular bacteria to coordinate responses to their environment.
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Inflammasome
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A cytoplasmic complex of NoD-, LRR- and pyrin domain-containing proteins (NLRPs),

adaptor proteins and caspases that forms in response to cellular damage or bacterial
effectors that cause rapid caspase-mediated inflammatory cytokine release and/or a type
of lytic cell death called pyroptosis.
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T cell anergy
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A process by which CD4+ or CD8+ T cells become tolerant to antigens and functionally
inactivated owing to stimulation in the absence of a necessary signal.
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Seed sequence
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An eight-nucleotide sequence near the 5′-end of a micro RNA that undergoes Watson–
Crick base pairing with a target RNA with high specificity and that is required for
efficient targeting.
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Fig. 1 |. Signalling pathways targeted by oncogenic viruses.

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Human oncogenic viruses modulate signal transduction pathways that control cell growth,
proliferation and survival to optimize cellular conditions for viral replication, virion
assembly and autophagic evasion in the absence of growth or survival signals. Dysregulation
of these pathways through mutation or viral factors has been implicated in many cancers.
Targeting of critical axes in these pathways by human oncogenic viral factors is indicated by
yellow boxes. Arrows represent activation, whereas blocking arrows represent inhibition.
Dashed arrows indicate activation or promotion with multiple steps not shown. a |

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Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator that

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coordinates biomolecule availability and stress stimuli to yield tuned responses that promote
cell growth and inhibit autophagy. Growth factor binding to receptor tyrosine kinases
(RTKs) regulates mTORC1 activity through phosphatidylinositol 3-kinase (PI3K) and the
serine/threonine kinase AKT. Ligand-bound RTKs autophosphorylate and recruit PI3K to
the plasma membrane, where it converts phosphatidylinositol 4,5-bisphosphate (PIP2) to
phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 recruits 3-phosphoinositide-dependent
protein kinase 1 (PDK1) and AKT. Multiple viruses modulate the activity of the AKT
pathway and downstream components, such as eukaryotic translation initiation factor 4E
binding protein 1 (4E-BP1) and ribosomal protein S6 kinase β1 (S6K1). b | The mitogen-
activated-protein kinase (MAPK) pathway is also activated by ligand-bound RTKs.
Autophosphorylated tyrosine residues bind SH2 domains of growth factor receptor-bound
protein 2 (GRB2), which localizes the guanine-exchange factor son-of-sevenless (SOS) to
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the inner membrane. SOS allows for the exchange of GDP for GTP on RAS. Activated
GTP-bound RAS initiates a MAPK cascade, which activates transcription factors such as
forkhead box protein M1 (FOXM1) and additional effectors such as MK2 kinase (MK2K).
Together, they enhance the expression of pro-survival and pro-inflammatory genes through
increased transcription and stabilization of mRNAs, respectively. c | A conformational
change in Notch when bound to ligands on neighbouring cells enables sequential cleavages
by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and γ-
secretase. Cleavage releases intracellular domain of Notch (ICN) into the cytoplasm, where
it can translocate to the nucleus and coordinate the transcription of proliferation and
differentiation-related genes with DNA-bound CSL protein and the co-activator mastermind-
like 1 (MAML1). ICN is downregulated by SEL10 polyubiquitylation-mediated proteasomal
degradation. d | β-Catenin (βcat) is inactivated in a complex with adenomatous polyposis
coli gene product (APC) and axin, which phosphorylates βcat and targets it for proteasomal
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degradation. Upon WNT glycolipoprotein binding to extracellular domains of prolow-

density lipoprotein receptor related protein 1 (LRP1) and frizzled (Frzl), dishevelled (Dsvl)
is recruited to the cytoplasmic domain of Frzl. Subsequent phosphorylation of LRP
sequesters axin and prevents degradation of βcat. Accumulating βcat translocates to the
nucleus, where it co-activates Drosophila T cell factor (dTCF)-mediated transcription of cell
growth genes. e | Several immunity-related cell surface receptors, including Toll-like
receptor 4 (TLR4) and tumour necrosis factor receptor (TNFR), activate the canonical
nuclear factor-κB (NF-κB) pathway when bound to their respective ligands. TLR4 activation
leads to phosphorylation and recruitment of interleukin-1 receptor-associated kinase 1
(IRAK1) to the adaptor protein myeloid differentiation primary response protein MYD88. A
complex containing the E3-ubiquitin kinase TNF receptor-associated factor 6 (TRAF6)
forms, which generates a scaffold for the polyubiquitin-binding NF-κB essential modulator
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(NEMO) of inhibitors of NF-κB (IκB) kinase (IKK). Orphan nuclear receptor TAK1 (also
known as NR2C2) activates IKK, which then phosphorylates the inhibitory subunit (IκB)
and targets it for polyubiquitylation and proteasomal degradation. A conformational change
between the NF-κB subunits p50 and p65 allows activating phosphorylation and
translocation to the nucleus, where it induces expression of inflammatory and pro-survival
genes. BCR, B cell receptor; E5, E6, E7, early proteins 5, 6 and 7; EBV, Epstein–Barr virus;
ERK1, extracellular-signal-regulated kinase 1; HBsAg, hepatitis B surface antigen; HBV,

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hepatitis B virus; HBx, HBVX protein; HPV, human papilloma virus; HTLV-1, human T-
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lymphotropic virus 1; JNK, JUN N-terminal kinase; KSHV, Kaposi sarcoma-associated

virus; LANA, latency-associated nuclear antigen; LMP, latent membrane protein; MCPyV,
Merkel cell polyomavirus; MEK, MAPK/ERK kinase; MKK, mitogen-activated protein
kinase kinase; RAF, RAF proto-oncogene serine/threonine-protein kinase; RANK, receptor
activator of NF-κB (also known as TNFRSF11A); RTA, replication and transcription
activator; sT, small tumour antigen; Tax, transactivator from X-gene region; TCR, T cell
receptor; vFLIP, viral FLICE inhibitory protein; vGPCR, viral G protein-coupled receptor.
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Fig. 2 |. Viral oncoproteins and DNA damage responses influence the fate of the host cell.
The schematic depicts changes to the cellular environment as a result of oncogenic virus
infection. Red ellipses represent stages of the life cycle that are shared by oncogenic viruses;
red boxes represent effects caused by the indicated viral effector. Blue ellipses represent the
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immediate changes to the cellular environment resulting from virus infection; blue boxes
represent subsequent effects on the cell; blue boxes with white text are the possible fates of
the infected cell. Arrows signify that the factor or status promotes the effect it points to,
whereas blocking arrows signify inhibition. For example, genomic instability and viral
genome replication can both induce DNA damage responses, which in turn support or hinder
viral replication, depending on the viral infection context. Successful viruses avoid abortive
fates (virion with a line through it), such as programmed cell death or cancer, to persist and
infect new hosts. AID, activation-induced cytidine deaminase; ATM, ataxia telangiectasia

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mutated; CHK2, checkpoint kinase 2; E6, E7, early proteins 6 and 7; EBNA1, Epstein–Barr
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virus nuclear antigen 1; EBV, Epstein–Barr virus; HBV, hepatitis B virus; HCV, hepatitis
Cvirus; HPV, human papilloma virus; HTLV-1, human T-lymphotropic virus 1; MCPyV,
Merkel cell polyomavirus; p53, cellular tumour antigen p53; pol, polymerase; pRB,
retinoblastoma protein; SMC5/6, structural maintenance of chromosomes complex 5/6.
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Fig. 3 |. Modulation of host immune responses by oncogenic viruses.

Proteins encoded by oncogenic viruses can target the host immune response (blue boxes
with white text), including sensing of pathogen-associated molecular patterns, immune gene
expression profiles and intercellular signalling. Arrows indicate activation, whereas blocking
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arrows indicate inhibition. Viral DNA and RNA structures are detected by pattern
recognition receptors (blue ellipses), including cyclic GMP–AMP synthase (cGAS), retinoic
acid-inducible gene I (RIG-I) and endosomal Toll-like receptors (TLRs). Activation is
transduced through intermediates or adaptors (purple ellipses), such as stimulator of
interferon genes protein (STING), mitochondrial antiviral-signalling protein (MAVS), TIR
domain-containing adaptor molecule 1 (TRIF; also known as TICAM1) and myeloid
differentiation primary response 88 (MYD88). Activated transcription factors, such as

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interferon regulatory factors (IRFs) and nuclear factor-κB (NF-κB), upregulate expression
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of immune genes (yellow box). Alternatively, inflammasome activation by NOD-, LRR- and
pyrin domains-containing 3 (NLRP3) can mediate proteolytic activation of inflammatory
cytokines and inflammatory cell death in response to bacterial effectors or cell damage
signals. Oncogenic viruses undermine inflammatory responses at the level of pathogen
sensing and signal transduction (red boxes). They also limit recruitment of leukocytes to
infected cells by reducing immune modulator intercellular adhesion molecule (ICAM)
expression and downregulating the display of viral peptides on major histocompatibility
complex I (MHC-I). Oncogenic viruses that infect adaptive immune cells can induce or
simulate pro-expansion signals and promote a state that is unresponsive to antigen and
endogenous cytokines (green boxes). BCR, B cell receptor; E7, early protein 7; gp80,
glycoprotein 80; HBV, hepatitis B virus; HBx, HBV-X protein; HBZ, HTLV-1 basic zipper
factor; HCV, hepatitis C virus; HPV, human papilloma virus; HTLV-1, human T-
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lymphotropic virus 1; KSHV, Kaposi sarcoma-associated virus; LANA, latency-associated

nuclear antigen; LMP, latent membrane protein; NS4B, non-structural protein 4B; pol,
polymerase; TIGIT, T cell immunoglobulin and ITIM domain; vIL-6, viral interleukin-6;
vIRF1–4, viral interferon regulatory factors 1–4.
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Table 1 |

The global burden of viral cancers at a glance

Virus Cancer Major regions affected Refs

Epstein–Barr virus • 40% of Hodgkin lymphoma • East Asia 140,141
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• >95% of endemic Burkitt lymphoma • East Africa

• 10% gastric carcinoma • Regions of the Americas
• Most (type II and III) nasopharyngeal carcinoma
• Kaposi sarcoma
• Other lymphomas

Hepatitis B virus • 53% of hepatocellular carcinoma • Asia 142

• Sub-Saharan Africa
• Regions of South America

Human T-lymphotropic virus 1 • >99% of adult T cell leukaemia • Japan 143,144

• Australia
• Regions of Africa, South America and the Middle East

Human papillomavirus • >95% of cervical carcinoma • Central America 145,146

• 70% of oropharyngeal carcinoma • South America
• Other anogenital carcinomas • Sub-Saharan Africa
• Regions of Asia

Hepatitis C virus • 25% of hepatocellular carcinoma • Regions of Asia, the Americas, North Africa and the Mediterranean 147,148
• Non-Hodgkin B cell lymphomas

Kaposi sarcoma-associated herpesvirus • >99% of Kaposi sarcoma • Regions of Europe and sub-Saharan Africa 149
• >99% of primary effusion lymphoma

Merkel cell polyomavirus • 80% of Merkel cell carcinoma • North America 19,150
• Australia
• Europe

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