Mechanisms of Viral Oncogenesis

Cancer is a genetic disease of the cell: it arises when changes activate growth-promoting oncogenes and inactivate growth-restraining tumour-suppressor genes, freeing a cell from the normal limits on its proliferation and survival. Viruses cause a substantial minority of human cancers by tampering with exactly these controls. Some drive transformation directly; others create the conditions in which a cancer eventually emerges. The study of these mechanisms built much of modern cancer biology: the first oncogene, the proto-oncogene concept, and the roles of the retinoblastoma protein (Rb) and p53 were all discovered through tumour viruses.

Direct and indirect oncogenesis

The central distinction is how close the virus sits to the cancer cell’s machinery.

A direct carcinogen expresses viral oncoproteins that act within the tumour cell to drive its transformation. Three features mark this route: the viral genome, or the relevant part of it, is present in essentially every tumour cell; the oncoprotein is continuously expressed; and continued expression is required to maintain the transformed state, a dependence first shown with a temperature-sensitive mutant of Rous sarcoma virus, whose transformed cells reverted to normal when the viral oncoprotein was switched off. High-risk HPV and MCPyV are the most oncogene-dependent of the human tumour viruses, with EBV and KSHV also expressing strong viral oncoproteins.

An indirect carcinogen supplies no such protein. It promotes cancer at one remove, through chronic inflammation and the cycles of cell death and regeneration that accumulate host mutations, or by suppressing the immune system so that cells transformed by other viruses can expand. HIV is the pure case: it encodes no oncogene and contributes solely by causing immunodeficiency. HCV is largely indirect, driving hepatocellular carcinoma through decades of hepatic injury without integrating or carrying a clear oncogene.

Most viruses occupy a spectrum rather than one category. HBV is the clearest mixed case, combining inflammation-driven injury with insertional mutagenesis and the HBx protein. An older and complementary framing describes viruses as both initiators, introducing or activating a cancer-causing genetic change, and promoters, sustaining the proliferation and genetic damage on which a cancer is built.

Subverting the cell cycle: the Rb and p53 pathways

To replicate its genome, a small DNA virus must drive a resting, often differentiated, host cell into S phase, the part of the cell cycle in which DNA is copied. The cell resists this with two master tumour-suppressor pathways, and the oncoproteins of the direct DNA tumour viruses are essentially the means of overcoming them. That three unrelated families, the papillomaviruses, the polyomaviruses and the adenoviruses, independently evolved proteins that bind Rb through the same short sequence motif (LXCXE) is among the strongest evidence of the pathway’s importance.

The Rb–E2F pathway controls entry into the cell cycle. Retinoblastoma protein normally binds and restrains the E2F transcription factors; releasing E2F commits the cell to divide. The p53 pathway is the opposing safeguard: in response to DNA damage or inappropriate proliferation, p53 triggers cell-cycle arrest or apoptosis (programmed cell death), which is why it is called the guardian of the genome. A virus that forced proliferation while leaving p53 intact would trigger the cell’s own apoptotic death, so the successful oncoproteins disable both pathways together.

Virus	Key oncoproteins	Action on the cell
HPV (high-risk)	E6, E7	E7 binds and degrades Rb, releasing E2F and forcing S-phase entry; E6 recruits a cellular ubiquitin ligase (E6AP) to degrade p53
Polyomaviruses (SV40 model; MCPyV)	large T, small t	SV40 large T binds both Rb and p53; MCPyV’s truncated large T inactivates Rb, while small t inhibits protein phosphatase 2A and activates the MYCL oncogene
Adenovirus (laboratory model)	E1A, E1B	E1A binds Rb; E1B inactivates p53. Adenovirus does not cause human cancer but defined the paradigm
KSHV	LANA, viral cyclin	LANA inactivates both Rb and p53; viral cyclin mimics cyclin D to drive the cell past the G1/S checkpoint

The HPV proteins are the model. The E7 protein binds Rb and marks it for destruction, releasing E2F and pushing the cell into S phase; the E6 protein recruits a cellular enzyme to degrade p53, removing the apoptotic safeguard that the forced proliferation would otherwise trigger. Together they immortalise cells, and with a single additional activated oncogene they fully transform them. The polyomaviruses achieve the same end more economically, with one large T antigen that engages both Rb and p53. MCPyV is a special case: the large T antigen is always truncated by the integration that traps the virus in the cell, losing the domain needed for viral replication but keeping the Rb-binding region, so the virus can drive proliferation precisely because it can no longer complete its life cycle. Its small t antigen adds to transformation by inhibiting protein phosphatase 2A and stabilising the MYCL oncogene.

Viral mimicry: hijacking growth and survival signalling

Where the small DNA viruses degrade tumour suppressors, the herpesviral and retroviral oncoproteins take a different route to the same end, mimicking the cell’s own growth and survival signals so that the infected cell receives a constant signal to proliferate and survive.

EBV transforms B cells with a set of latent proteins. LMP1 behaves as a constitutively active version of the CD40 receptor, a B-cell activation receptor, signalling without any ligand to drive the nuclear factor kappa B (NF-κB) and JAK–STAT (Janus kinase and signal transducer and activator of transcription) pathways that promote survival and proliferation. LMP2A supplies a tonic signal mimicking an engaged B-cell receptor, and the EBNA proteins both maintain the viral genome as an episome and drive proliferation. KSHV carries this strategy furthest through viral piracy, having captured and adapted a toolkit of human regulatory genes: beyond LANA and viral cyclin, a viral interleukin-6 promotes survival and angiogenesis, a viral FLIP protein blocks apoptosis and activates NF-κB, and a viral G-protein-coupled receptor drives mitogenic and angiogenic signalling. HTLV-1 acts through its Tax protein, a transcriptional activator that switches on host genes to create an interleukin-2 autocrine loop and constitutive NF-κB signalling, driving the infected T cell to proliferate.

Integration, insertional mutagenesis and the retroviral oncogenes

The retroviruses cause cancer by a separate set of mechanisms rooted in their defining ability to integrate a DNA copy of their genome into the host chromosome. The first oncogene ever identified was src, of Rous sarcoma virus. It was then shown that the viral src (v-src) had a normal cellular counterpart, c-src, present in the vertebrate genome: the virus had captured and corrupted a host gene. This established the proto-oncogene concept, that the genome carries normal genes which, when mutated or misexpressed, become cancer-causing, and it reframed cancer as a disease of host genes. More than sixty such captured oncogenes were subsequently identified, encoding growth factors, growth-factor receptors, intracellular signalling proteins and transcription factors.

Retroviruses cause cancer in three ways, which differ in tempo and mechanism.

Class	Carries an oncogene?	Speed	How it transforms
Transducing	Yes (a captured host oncogene)	Fast (weeks)	The viral oncogene acts directly; the virus is usually replication-defective
Cis-activating	No	Slow (months)	The provirus integrates beside a host proto-oncogene and switches it on (insertional mutagenesis)
Trans-activating	No	Very slow (years)	A viral regulatory protein activates host genes from a distance, as with HTLV-1 Tax

Insertional mutagenesis is the key concept for the slow-acting viruses. Every integration event is in effect a new mutation, so persistent retroviral infection resembles sustained exposure to a mutagen. Occasionally a provirus lands next to a gene controlling growth and drives its inappropriate expression; the affected cell gains an advantage and expands into a tumour in which every cell shares the same integration site. The human tumour retrovirus, HTLV-1, is mainly trans-activating: Tax initiates transformation by switching on host proliferation pathways and also disables DNA-repair pathways, generating the genomic instability on which malignancy is built, while the HBZ protein maintains the malignant clone once Tax expression has fallen silent.

Integration matters for some DNA viruses too, though by different routes. In HPV, progression to cancer is typically accompanied by integration of the viral genome into the host chromosome in a way that disrupts the viral E2 gene; because E2 normally represses E6 and E7, its loss releases these oncogenes to be expressed without restraint, the molecular switch from productive infection to transformation. In HBV, integration of viral DNA contributes both insertional effects and persistent expression of the HBx transactivator. MCPyV is found clonally integrated in its tumours, the hallmark that first revealed the virus.

Indirect oncogenesis: inflammation and immune failure

Viruses that carry no oncogene cause cancer by reshaping the tissue and the host around the cell.

Chronic inflammation and regeneration is the route to hepatocellular carcinoma in chronic hepatitis. Persistent infection with HBV or HCV destroys hepatocytes continuously; the liver responds with continuous regeneration, and each round of cell division carries a risk of error, so chromosomal abnormalities and driver mutations accumulate over decades, often against a background of cirrhosis. Reactive oxygen species from the inflammatory infiltrate add further genetic damage, and external cofactors such as aflatoxin and alcohol compound it. HCV illustrates how powerful this indirect route is on its own: an RNA virus that neither integrates nor encodes an oncogene is nonetheless a leading cause of liver cancer, acting almost entirely through injury and regeneration, although its core and NS5A proteins may also perturb cellular growth signalling. HBV adds direct contributions on top of the same inflammatory base, and can cause cancer even without preceding cirrhosis.

Failure of immune surveillance is the second indirect route, and the one that links oncogenesis to clinical immunosuppression. A healthy immune system recognises and removes many virus-infected and transformed cells, so cancers caused by the latent oncogenic viruses are held in check as long as that surveillance holds. When it fails, in advanced HIV infection, after transplantation, or in primary immunodeficiency, the latently infected cells expand and the associated cancers appear at greatly increased rates: Kaposi sarcoma driven by KSHV, the EBV-driven B-cell lymphomas including post-transplant lymphoproliferative disorder, and HPV-driven cervical and anogenital cancers. This is the whole of HIV’s oncogenic contribution: it encodes no oncogene and transforms no cell itself, but by depleting CD4 T cells it removes the control over the other viruses. The same principle runs in reverse in the clinic, where restoring immune function with antiretroviral therapy reduces, though it does not abolish, the incidence of these cancers.

A multistep process: clonality, latency and causality

No oncogenic virus turns an infected cell into a cancer in a single step. A cell on the way to malignancy must escape its dependence on external growth signals, evade apoptosis, achieve unlimited replicative potential, secure a blood supply, evade immune destruction and, for a malignant tumour, acquire the capacity to invade and metastasise. A virus contributes one or some of these steps; the rest come from host mutations and cofactors accumulated over time. In the laboratory this is explicit, since two cooperating oncogenes, or one viral oncoprotein plus one activated cellular oncogene, are typically needed to transform a normal cell, and a chemical carcinogen can substitute for one of them.

Two consequences follow. First, virus-associated cancers are clonal and late. Because transformation requires the slow accumulation of additional changes, only a small percentage of infected people develop cancer, and they do so years to decades after infection: around two to five per cent of HTLV-1 carriers develop adult T-cell leukaemia after twenty to forty years, and hepatocellular carcinoma follows chronic hepatitis B over a similar span. That every cell of the eventual tumour shares one integration site or one chromosomal translocation shows the virus was present before the clone expanded, which is evidence that it was an early and causal event rather than a passenger.

Second, causality cannot be settled by the old microbiological rules. The classical postulates, which require an agent to be present in every case and to reproduce the disease on transfer, fail for tumour viruses: the cancers are rare outcomes of common infections, take decades to appear, and need cofactors. Causation is instead established by converging lines of evidence: the viral genome and its oncoproteins in the tumour cells, the transforming activity of those proteins in experiment, a distinct mutational pattern, and falling cancer incidence when infection is prevented by vaccination or cleared by treatment. The “hit-and-run” possibility, in which a virus triggers transformation and is then lost from the tumour, leaving no genome to detect, is a recognised caveat to the requirement that the genome be present in every tumour cell, and has been proposed for the role of cutaneous papillomaviruses in ultraviolet-driven skin cancer.

The hallmarks of cancer

The hallmarks of cancer, the capabilities a cell must acquire to become malignant, are engaged between them by almost every tumour virus.

• Evading growth suppressors: HPV E7, polyomavirus large T and adenovirus E1A against Rb; HPV E6, large T and E1B against p53; KSHV LANA against both.
• Sustaining proliferative signalling: HTLV-1 Tax (the interleukin-2 loop), KSHV viral GPCR and viral interleukin-6, EBV LMP1 and LMP2A, and the transduced retroviral oncogenes encoding growth factors and their receptors.
• Resisting cell death: HPV E6 (through p53 degradation), KSHV viral FLIP, and EBV LMP1 survival signalling.
• Inducing angiogenesis: KSHV viral GPCR and viral interleukin-6.
• Genome instability and mutation: HBV integration, retroviral insertional mutagenesis, HTLV-1 Tax suppression of DNA repair, and the oxidative damage of chronic inflammation.
• Avoiding immune destruction: the restricted antigen expression of EBV and KSHV latency, and, at the level of the host, the immunosuppression caused by HIV.
• Tumour-promoting inflammation: chronic hepatitis B and C.

The seven oncoviruses

Seven viruses are recognised as primary human oncoviruses. Six drive transformation directly, through genomic integration or viral oncoproteins that dysregulate the host cell cycle; the seventh, hepatitis C virus, acts strictly indirectly, through chronic inflammation and the cycles of hepatocyte injury and regeneration that lead to cirrhosis. The human immunodeficiency virus (HIV) sits alongside them as a recognised carcinogen of a different kind: it carries no oncogene and contributes only by dismantling the immune surveillance that holds the others in check.

Virus	Family; genome	Principal cancers	Mechanism
Human papillomavirus (HPV), high-risk types	Papillomaviridae; dsDNA	Cervical (near 100 per cent), other anogenital, oropharyngeal	Direct (E6, E7)
Hepatitis B virus (HBV)	Hepadnaviridae; reverse-transcribing DNA	Hepatocellular carcinoma	Mixed (HBx, integration, inflammation)
Hepatitis C virus (HCV)	Flaviviridae; positive-sense RNA	Hepatocellular carcinoma	Indirect (chronic injury, cirrhosis)
Epstein-Barr virus (EBV)	Orthoherpesviridae; dsDNA	Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, B-cell lymphomas, some gastric carcinoma	Direct (LMP1, EBNA)
Kaposi sarcoma-associated herpesvirus (KSHV)	Orthoherpesviridae; dsDNA	Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease	Direct (viral mimics)
Human T-lymphotropic virus type 1 (HTLV-1)	Retroviridae; reverse-transcribing RNA	Adult T-cell leukaemia/lymphoma	Direct (Tax, HBZ)
Merkel cell polyomavirus (MCPyV)	Polyomaviridae; dsDNA	Merkel cell carcinoma	Direct (truncated large T, small t)
Human immunodeficiency virus (HIV)	Retroviridae; reverse-transcribing RNA	Kaposi sarcoma, lymphomas, cervical cancer, via the other viruses	Indirect (immunosuppression; no oncogene)

Each oncovirus combines these mechanisms in a characteristic way, from the molecular lesion to the cancer it produces.

Human papillomavirus

High-risk human papillomavirus, chiefly types 16 and 18, causes squamous cell carcinoma of the cervix and of the rest of the anogenital tract and the oropharynx. Transformation follows integration that disrupts the viral E2 gene and releases the E6 and E7 oncoproteins, E7 degrading the retinoblastoma protein to force the cell into S phase and E6 directing the destruction of p53 to remove the apoptotic brake. Risk rises with persistence of a high-risk infection, immunosuppression (above all HIV co-infection) and smoking. Progression is slow and uncommon, advancing in only a minority over years to decades through graded cervical intraepithelial neoplasia before invasion, the window screening exploits.

The association is the strongest in all of tumour virology: essentially every cervical cancer carries high-risk HPV, and the virus accounts for about 5 per cent of all human cancers and roughly half of those attributable to viruses. The link is graded by genotype. Of some two hundred HPV types only about a dozen mucosal high-risk types are oncogenic; HPV16 and HPV18 alone account for around 72 per cent of HPV-driven cancers, and five further types (31, 33, 45, 52 and 58) for some 17 per cent more. HPV16 is the more replicative and the dominant cause of squamous cancers and of most non-cervical HPV cancers, while HPV18 integrates more readily and is over-represented in cervical adenocarcinoma. The low-risk types 6 and 11 cause genital warts but not cancer, because their E6 and E7 inactivate the tumour-suppressor pathways only weakly and they lack a functional E5. HPV illustrates the productive-versus-transforming distinction plainly: ordinary infection produces virus and may raise a wart, but the cancer cells make no virus, expressing E6 and E7 from integrated DNA alone.

The oncoproteins do more than disable Rb and p53. E6 directs p53 degradation through the cellular ligase E6AP and separately raises telomerase; E7 degrades Rb through a shared LXCXE motif; and in high-risk types E5 hyperactivates the epidermal growth factor receptor (EGFR). E6 and E7 also block the interferon response, E7 binding the innate sensor STING, and it is this immune evasion that permits the persistent infection on which cancer depends, since around 90 per cent of infections clear within two years. That the two oncoproteins must be expressed continuously is shown directly: switching them off in cancer cells restores p53 and Rb and drives the cells into senescence or death. A telling corollary is that HPV-positive head and neck cancers retain wild-type p53, because the virus removes the protein rather than mutating the gene. Cervical cancer incidence tracks inversely with access to screening and is falling in high-income settings even as HPV-positive oropharyngeal and anal cancers rise; high-coverage L1 virus-like-particle vaccination should ultimately prevent 70 to 90 per cent of all HPV cancers, and pre-malignant cervical lesions are excised.

Epstein-Barr virus

Epstein-Barr virus causes Burkitt and other B-cell lymphomas, Hodgkin lymphoma, nasopharyngeal carcinoma and a subset of gastric carcinoma. It transforms cells while remaining episomal, through its latent proteins, chiefly LMP1, a ligand-independent CD40 mimic driving NF-κB and JAK–STAT signalling, with LMP2A and the EBNA proteins; in endemic Burkitt lymphoma it is a cofactor that promotes the t(8;14) translocation placing the c-myc oncogene under immunoglobulin control. The dominant risk is loss of T-cell control, through advanced HIV, transplant immunosuppression or holoendemic malaria. Progression depends on immunity: near-universal infection but cancer in only a small fraction, rising sharply and rapidly when immune control fails.

The defining feature is a paradox: over 95 per cent of adults carry the virus for life, yet its cancers are uncommon, and in every one the malignant cells are latently infected and make no virus. The strength of the association varies widely by tumour, spanning almost the whole attributable-fraction range. Nasopharyngeal carcinoma is over 95 per cent positive, and endemic Burkitt lymphoma about 95 per cent, against only some 30 per cent of sporadic Burkitt lymphoma; the virus accounts for roughly 40 per cent of classic Hodgkin lymphoma and for the 8 to 10 per cent of gastric carcinomas that sit at the low end of the spectrum. Which cancer arises is governed by the latency programme the virus runs, the restricted subset of genes it expresses to stay hidden from the immune system. Burkitt lymphoma uses the most restricted programme, little more than EBNA1, and depends on a cofactor: the c-myc translocation that defines the tumour also primes the cell for apoptosis, and the virus, helped by the immune distraction of holoendemic malaria, lets the translocated clone survive. Nasopharyngeal, gastric and Hodgkin tumours add LMP1, and arise against host genetic and dietary cofactors in the case of nasopharyngeal carcinoma. EBV-associated gastric cancer is a molecularly distinct subtype, marked by amplification of JAK2 and the PD-L1 immune-checkpoint ligand and by largely wild-type p53, which identifies the virus as a driver. No vaccine or anti-EBV drug exists, leaving these among the harder virus-driven cancers to prevent; that targeting viral antigens can work is shown by the use of EBV-specific donor T cells to control the lymphomas of transplant recipients, and after transplantation monitoring the viral load allows immunosuppression to be reduced early.

Hepatitis B virus

Hepatitis B virus causes hepatocellular carcinoma. It acts by both routes at once: integration and the HBx transactivator interfere directly with growth control and p53, while chronic immune-mediated injury and regeneration drive mutation. Risk rises with chronic (especially perinatally acquired) infection, cirrhosis, a high viral load, and cofactors such as aflatoxin and alcohol. Its course is the sequence of chronic hepatitis to cirrhosis to carcinoma over decades, though the integration route allows cancer even without cirrhosis.

Hepatitis B is the leading cause of liver cancer worldwide and, with hepatitis C, underlies about 80 per cent of hepatocellular carcinoma; it is the second commonest cause of virus-related cancer after HPV. Its causal role is settled by the clearest of natural experiments: infant hepatitis B vaccination reduces liver cancer, the first vaccine shown to prevent a human cancer. The three routes act together. Chronic immune-mediated injury drives endless cycles of regeneration in which mutations accumulate; integration of viral DNA, an early initiating event, lands in and activates cell-cycle and immortalisation genes including the telomerase gene TERT and the cyclin genes, and leaves a truncated but still active HBx protein; and HBx itself transactivates growth genes and disables p53 and Rb. The resulting tumours form a distinct molecular class that carries an aflatoxin mutational signature, marking that environmental co-carcinogen as a genuine cofactor, and that characteristically lacks the telomerase-promoter mutation seen in hepatitis C tumours. Because infection acquired in infancy is the most likely to become chronic, it carries the greatest lifetime risk, which is why the infant vaccine, having cut childhood surface-antigen prevalence from over 5 per cent to under 1 per cent where it is used, is so powerful. Nucleos(t)ide analogues that suppress replication further lower the long-term risk.

Hepatitis C virus

Hepatitis C virus causes hepatocellular carcinoma by a strictly indirect route: with no integration and no oncogene, decades of inflammation, oxidative stress and cycles of necrosis and regeneration produce fibrosis and cirrhosis, though the core and NS5A proteins may also perturb growth signalling. Risk concentrates in chronic infection with established cirrhosis, amplified by alcohol and HIV co-infection. Progression is slow and cirrhosis-dependent: chronic in most of those infected, with cancer arising after decades almost always on a cirrhotic background.

Hepatitis C is the most clearly indirect of the tumour viruses: it has no DNA stage, does not integrate, encodes no oncogene, and its proteins are not even found in all the tumour cells, so its contribution is the liver damage itself, sustained over decades into fibrosis and cirrhosis. It also accounts for a minority of non-Hodgkin B-cell lymphomas. Where hepatitis B often produces cancer directly and sometimes without cirrhosis, hepatitis C works almost entirely through chronic injury and, unlike hepatitis B, becomes chronic in most of those it infects. Its tumours carry a molecular signature distinct from hepatitis B, with near-universal telomerase-promoter and beta-catenin mutations, the latter reflecting activation of Wnt signalling by the viral core and non-structural proteins. The clearest demonstration in all of tumour virology that removing a virus prevents cancer comes from here: direct-acting antivirals cure over 98 per cent of infections, and cure measurably lowers the subsequent risk of liver cancer. There is still no vaccine, defeated by the variability of the envelope proteins.

Human T-lymphotropic virus type 1

Human T-lymphotropic virus type 1, the human tumour retrovirus, causes adult T-cell leukaemia/lymphoma. It transforms CD4 T cells through the Tax protein, which switches on proliferation pathways (an interleukin-2 loop and NF-κB) and suppresses DNA repair to create genomic instability, with HBZ sustaining the clone once Tax falls silent. Risk is greatest with infection acquired in infancy, chiefly through breastfeeding, and a high proviral load. Progression is a rare and very late event, in roughly 2 to 5 per cent of carriers after 20 to 40 years, but aggressive once it appears, with hypercalcaemia and characteristic multilobed “flower cells” in the blood.

It was the first human retrovirus discovered, and around twenty million people are infected, in well-defined clusters in southern Japan, the Caribbean, parts of South America and Central Australia, and West and Central Africa. The association is specific in two ways. Only HTLV-1 causes the leukaemia; the closely related HTLV-2 does not. And the virus is the necessary cause but far from sufficient: most carriers remain asymptomatic for life, and the leukaemia emerges only after decades and the accumulation of further host mutations. The same virus also causes a non-malignant inflammatory disease of the spinal cord, HTLV-1-associated myelopathy or tropical spastic paraparesis, and a high proviral load is the principal marker of risk for both outcomes.

The mechanism turns on a division of labour between two proteins encoded on opposite strands at opposite ends of the provirus. Tax, from the 5’ long terminal repeat, is a potent activator that drives proliferation and genomic instability and initiates transformation, but it is highly immunogenic, so cytotoxic T cells select against the cells that display it. Infected cells escape that pressure by silencing the 5’ long terminal repeat, through deletion, methylation or mutation, which shuts Tax off. HBZ, encoded on the antisense 3’ long terminal repeat, is expressed continuously at a low level and is the one viral protein invariably present in leukaemic cells; it maintains the malignant clone. Tax initiates and HBZ maintains. The virus persists and expands not by releasing new virions but by driving the clonal proliferation of infected T cells, and it passes between hosts largely by cell-to-cell contact, which is why breastfeeding is the main route of vertical transmission. There is no vaccine and no licensed antiviral, so prevention rests on screening blood donors and avoiding breastfeeding by infected mothers; established leukaemia is treated with zidovudine and interferon alfa and carries a poor prognosis.

Kaposi sarcoma-associated herpesvirus

Kaposi sarcoma-associated herpesvirus causes Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. It transforms cells by piracy of human regulatory genes: LANA inactivates p53 and Rb, a viral cyclin drives the cell cycle, and a viral interleukin-6, a viral FLIP and a viral G-protein-coupled receptor sustain survival and angiogenesis. The overriding risk is immunosuppression, above all advanced HIV. Progression is immune-dependent: rare and indolent with intact immunity, but frequent, rapid and disseminated in advanced HIV.

The virus is present in every Kaposi sarcoma lesion and is its necessary cause, yet the disease sits awkwardly on the cancer spectrum: the lesions are not monoclonal and the spindle cells often lack the hallmarks of full transformation, so it is better understood as a virus-driven angioproliferative process than as a classical clonal tumour. The association is absolute for primary effusion lymphoma, which is universally positive, and holds for about half of multicentric Castleman disease.

The organising idea is the balance between latency and lytic replication, because both contribute. In latently infected cells a small set of genes maintains the infection and drives proliferation: LANA tethers the viral genome and inhibits p53 and Rb while stabilising beta-catenin to raise Myc, the viral cyclin activates the cell-cycle kinase CDK6 in a form resistant to the cell’s own inhibitors, and the viral FLIP holds NF-κB constitutively on. A minority of cells enter the lytic cycle and become a paracrine engine, secreting the viral interleukin-6 and, through the viral G-protein-coupled receptor, a stream of angiogenic and inflammatory signals that act on neighbouring cells. This paracrine model explains the polyclonal, intensely vascular character of the lesions, in which infected cells drive the proliferation of their neighbours rather than simply expanding as a clone. That the lytic cycle matters is shown clinically, since the herpesvirus DNA-polymerase inhibitor ganciclovir reduces the appearance of new lesions.

Four epidemiological forms are recognised: an indolent classic form in older men of Mediterranean and Eastern European origin, an endemic African form that predated HIV, an iatrogenic form in transplant recipients, and the aggressive epidemic form that rose with the HIV pandemic and fell sharply once antiretroviral therapy became available. HIV worsens the disease beyond immunosuppression alone, its Tat and Nef proteins synergising with KSHV signalling to drive angiogenesis. Antiretroviral therapy is therefore central and is begun immediately in HIV-positive Kaposi sarcoma whatever the CD4 count, with liposomal doxorubicin reserved for advanced disease.

Merkel cell polyomavirus

Merkel cell polyomavirus causes Merkel cell carcinoma, an aggressive neuroendocrine skin cancer. Transformation requires clonal integration with a truncating mutation of the large T antigen that keeps its Rb-binding region but abolishes viral replication, while small t inhibits protein phosphatase 2A and stabilises the MYCL oncogene. Risk rises with older age, immunosuppression and ultraviolet exposure, which acts as a co-mutagen. Progression is rare despite near-ubiquitous infection, but the tumour grows rapidly and metastasises early.

About 80 per cent of Merkel cell carcinomas carry the virus, integrated as a single clone throughout the tumour, and that clonality, present before the cancer expanded, is the main evidence that infection came first and caused it. The remaining fifth are virus-negative and instead carry a heavy ultraviolet mutational signature, and the contrast is instructive: the two routes converge on the same pathways, the virus inactivating Rb and p53 through its T antigens in the one case and ultraviolet mutation achieving the same in the other, so the virus in effect substitutes for the carcinogen. Beyond inactivating Rb, the small t antigen drives a stem-like, undifferentiated state by acting on the chromatin regulator LSD1 to repress the differentiation factor ATOH1. Because the tumour cells express foreign viral antigens they are highly immunogenic, which is why advanced Merkel cell carcinoma, for all its aggressiveness, responds well to PD-1 checkpoint inhibitors.

South African context

Virus-associated cancer is a heavier burden in South Africa than in high-income countries, for two reasons that compound each other. Oncogenic-virus infections are more prevalent, and the large HIV epidemic removes immune control over them in millions of people. Cervical cancer, almost all of it caused by high-risk HPV, is among the leading cancers of South African women and is markedly more common and more aggressive in women living with HIV; the national response combines the schools-based HPV vaccination programme with cervical screening. Kaposi sarcoma, rare in the pre-HIV era, became one of the commonest cancers in parts of the region during the epidemic and has fallen but not disappeared with the rollout of antiretroviral therapy. Chronic hepatitis B, acquired largely in early childhood before the infant vaccine took effect, remains an important cause of hepatocellular carcinoma. The most effective oncology here is therefore preventive: HPV and hepatitis B vaccination, and early, sustained HIV treatment to preserve the immune surveillance that holds the latent tumour viruses in check.

References and recommended reading

• Burrell CJ, Howard CR, Murphy FA. Mechanisms of Viral Oncogenesis. In: Fenner and White’s Medical Virology, 5th edition, Chapter 9. Academic Press / Elsevier; 2017. The principal source for the direct and indirect routes, the viral oncoprotein paradigm, insertional mutagenesis and the retroviral oncogenesis classes.
• DiMaio D, Pipas JM. Tumor Virology. In: Fields Virology, 7th edition, Volume 4, Chapter 11. Wolters Kluwer; 2023. The current reference for the infection-attributable cancer burden, the direct-indirect spectrum, the modern oncoprotein detail (including Merkel cell polyomavirus and the KSHV viral mimics), and the lines-of-evidence approach to causation.
• Xiao Q, Liu Y, Li T, et al. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduction and Targeted Therapy 2025;10:151. DOI 10.1038/s41392-025-02197-9. The current per-virus source for the attributable fractions, the HPV genotype hierarchy and immune evasion, the KSHV latent and lytic gene programmes, and the HTLV-1 Tax and HBZ division of labour.