Kaposi's sarcoma-associated herpesvirus

Kaposi sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is the eighth and most recently discovered human herpesvirus and, with Epstein-Barr virus, one of only two human gammaherpesviruses. It is the cause of three malignancies: Kaposi sarcoma, an angioproliferative tumour of endothelial origin, and two B-cell lymphoproliferative disorders, primary effusion lymphoma and most multicentric Castleman disease. Like all herpesviruses it establishes lifelong latency, and it causes disease overwhelmingly when immune control fails, so its clinical importance is bound up with the HIV pandemic, in which Kaposi sarcoma became the defining cancer of advanced disease. Its seroprevalence is strikingly geographic: low across most of the West, intermediate around the Mediterranean, and very high in sub-Saharan Africa, where infection is acquired in childhood through saliva and Kaposi sarcoma is among the commonest cancers. That distribution, set against a large HIV epidemic, makes KSHV disease a particular burden in southern Africa. There is no vaccine and no way to clear the latent virus, so prevention and treatment both turn on preserving or restoring the immune control that normally holds it silent.

Discovery and historical significance

The sarcoma was described in 1872 by the dermatologist Moritz Kaposi as an indolent pigmented tumour of the skin in elderly men, and for a century it remained a medical curiosity, later recognised to be more common around the Mediterranean and in parts of Africa. The HIV pandemic transformed it: a sudden epidemic of aggressive Kaposi sarcoma in young homosexual men became one of the first signals of AIDS. A crucial epidemiological clue was that the cancer was far more common in men who acquired HIV sexually than in those infected through blood products, which argued that a second, separately transmitted agent, rather than HIV itself, was the cause. In 1994 Yuan Chang, Patrick Moore and Ethel Cesarman found fragments of a new herpesvirus genome in Kaposi sarcoma tissue using representational difference analysis, a subtractive technique that isolates DNA present in diseased but not healthy tissue. The virus was soon found in all forms of Kaposi sarcoma and in primary effusion lymphoma and multicentric Castleman disease, and its genome was sequenced in 1996, revealing the remarkable cargo of pirated human genes that underlies its biology.

Classification, structure, and genome

Classification

KSHV is a gammaherpesvirus, in the genus Rhadinovirus, subfamily Gammaherpesvirinae, family Orthoherpesviridae. The gammaherpesviruses are the lymphotropic herpesviruses that establish latency in lymphocytes and carry oncogenic potential; KSHV is the only human member of the rhadinovirus genus, and its sole human relative in the subfamily is Epstein-Barr virus, a lymphocryptovirus, with which it shares both the latency-based lifestyle and the capacity to cause B-cell lymphoma. Its genotypes are defined mainly by the hypervariable ORF K1 gene, which falls into geographically structured clades, and by the K15 locus, which exists as two highly divergent alleles, the predominant (P) and minor (M) forms.

Virion structure

The particle has the standard herpesvirus architecture: a linear genome inside an icosahedral capsid of T=16 symmetry, wrapped in a protein layer called the tegument, and enclosed by a lipid envelope studded with glycoproteins (gB, gH, gL, gM, gN and the KSHV-specific K8.1). The tegument delivers viral proteins and messenger RNAs into the cell at entry, priming the first events of infection before any new viral protein is made.

Genome organisation

The genome is a large linear double-stranded DNA molecule of about 165 to 170 kilobases. A central unique region of roughly 145 kilobases carries the genes, flanked by high-GC direct terminal repeats. Alongside the conserved blocks of herpesvirus replication and structural genes, KSHV carries a distinctive set of genes pirated from the human genome over evolutionary time, homologues of a cyclin, an anti-apoptotic FLIP protein, interleukin-6, chemokines, interferon regulatory factors and a G-protein-coupled receptor, together with twelve viral microRNAs. The KSHV-specific genes, numbered K1 to K15, lie interspersed among the conserved herpesvirus blocks, and it is this captured cargo of human-like genes, rather than any single classical oncogene, that the virus deploys to transform cells and drive angiogenesis. In latently infected cells the genome circularises and persists as a multicopy episome.

Replication cycle

As in Epstein-Barr virus, the organising feature of the KSHV life cycle is the choice between latency and lytic replication, and in the host latency is the default.

The virus attaches to cells by binding heparan sulphate proteoglycans, then engages integrins and the EphA2 receptor to be taken in by endocytosis, the act of entry itself triggering signalling through the ERK and NF-κB pathways that primes early gene expression. The incoming genome is met by the cell’s innate DNA sensors, among them cGAS-STING and IFI16, which the virus in turn moves to counter. Once the genome reaches the nucleus the latency-versus-lytic decision is made. In the great majority of infected cells in the host the genome circularises into an episome and enters latency: it is copied once per cell division by the host’s own machinery and partitioned to daughter cells by the latency-associated nuclear antigen (LANA), which tethers it to the host chromosomes. Only a handful of latent genes are expressed, no virions are made, and the infection is essentially silent, yet the full capacity for lytic replication is retained.

The switch into the lytic cycle is controlled by a single master protein, the replication and transcription activator (RTA, encoded by ORF50), whose expression alone is sufficient to start the lytic programme; in latency LANA holds RTA in check by repressing its promoter. The physiological triggers for reactivation in the host are poorly defined, but inflammation, hypoxia and other cellular stresses can flip the switch. When reactivation occurs, the lytic genes are expressed in the usual herpesvirus order of immediate-early, then early, then late, the genome is replicated and packaged into new capsids, and progeny virions are assembled and released. Lytic replication in the oral epithelium sheds virus into saliva, the main route of transmission. The crucial point for disease is that the tumour cells are latently infected and make no virus, so the cancers are a consequence of latency, not of viral replication.

Pathogenesis

KSHV infects endothelial cells, which become the spindle cells of Kaposi sarcoma, and B lymphocytes, the cells of its lymphomas. Its pathogenesis is unusual in drawing on both its latent and its lytic genes.

The latent proteins are the persistent drivers. LANA, besides tethering the genome, inactivates the two master tumour suppressors, binding p53 to blunt apoptosis and the retinoblastoma protein to release the cell cycle, and stabilises beta-catenin and Myc. The viral cyclin mimics cyclin D and drives the cell-cycle kinase CDK6 in a form resistant to the cell’s own inhibitors; left unchecked this forced division would itself trigger apoptosis, but LANA’s inactivation of p53 removes that safeguard, so the two latent proteins cooperate. The viral FLIP switches on nuclear factor kappa B (NF-κB), the central survival signal of the lymphoma cells. A latent interferon regulatory factor, vIRF3, stabilises the hypoxia factor HIF-1-alpha to drive the angiogenic factor VEGF.

Gene	Phase	Function
LANA	Latent	Tethers the episome; inactivates p53 and Rb; raises beta-catenin and Myc; represses RTA
Viral cyclin	Latent	Cyclin D homologue; activates CDK6 to force the cell cycle
Viral FLIP	Latent	Constitutive NF-κB activation; blocks apoptosis
vIRF3	Latent	Stabilises HIF-1-alpha, driving VEGF and angiogenesis
RTA (ORF50)	Lytic	Master lytic switch
Viral GPCR	Lytic	Constitutively active receptor; secretes VEGF and angiogenic factors
Viral interleukin-6	Lytic	Interleukin-6 homologue; drives B-cell proliferation and inflammation

The lytic and paracrine genes explain why Kaposi sarcoma behaves unlike a classical cancer. Only a minority of cells in a lesion enter the lytic cycle, but their secreted products, the viral G-protein-coupled receptor driving VEGF, the viral interleukin-6, and other angiogenic and inflammatory mediators, act on neighbouring cells. This paracrine model accounts for the lesion being intensely vascular, polyclonal rather than clonal, and reversible when immune control is restored, in contrast to the monoclonal primary effusion lymphoma and the polyclonal, interleukin-6-driven Castleman disease. Its Kaposins and its twelve viral microRNAs further tune the survival, angiogenic and metabolic state of the infected cell.

Throughout, the virus is equipped to evade immunity. Its K3 and K5 proteins drive surface MHC class I from the cell to hide it from cytotoxic T cells; its viral interferon regulatory factors block both the induction and the signalling of interferon; a viral Bcl-2 and the viral FLIP suppress apoptosis; and viral chemokine homologues subvert the recruitment of immune cells. Even with this arsenal an intact immune system contains the infection, and disease emerges only when immunosuppression removes that control, which is why Kaposi sarcoma is so tightly linked to advanced HIV and to transplantation. In HIV co-infection the relationship is more than permissive: the HIV Tat and Nef proteins synergise with KSHV signalling to promote angiogenesis, compounding the effect of the immune failure itself.

Epidemiology

KSHV is far from evenly distributed. Seroprevalence is low across Western Europe and North America (a few per cent), intermediate around the Mediterranean and in parts of Eastern Europe and Asia, and very high in sub-Saharan Africa, where in some regions approaching half of adults are infected and most children are seropositive by adolescence. The route of transmission follows this geography. In endemic areas the virus spreads chiefly through saliva, horizontally and within families from early childhood. In low-prevalence Western settings it spreads mainly sexually, and is efficiently transmitted among men who have sex with men, in whom seroprevalence reaches 25 to 60 per cent. It was among this group that Kaposi sarcoma proved far more common than in people who had acquired HIV through blood products, the very observation that first pointed to a separate, sexually transmitted cause. Transmission by transplanted organs and by transfusion is documented but inefficient, and donor-derived virus can cause Kaposi sarcoma in a transplant recipient. The clinical expression of infection falls into four long-recognised epidemiological forms of Kaposi sarcoma, set out below.

Natural history

Infection is acquired in childhood in endemic regions and in adulthood where spread is sexual, and is followed by lifelong latency that an intact immune system, chiefly through its cytotoxic T cells, holds silent in most people; the virus persists quietly in B lymphocytes and endothelial cells. Disease appears only when that control fails: through HIV-associated immunosuppression, iatrogenic immunosuppression after transplantation, or the waning immunity of old age that underlies classic Kaposi sarcoma. At that point the latent reservoir, sporadic lytic reactivation and paracrine signalling combine to produce Kaposi sarcoma, or the latent infection of B cells expands into lymphoma or Castleman disease. How far disease progresses then depends on the depth and duration of the immunosuppression, so that restoring immunity can reverse it where deepening immunosuppression drives it on.

Clinical presentations and complications

Kaposi sarcoma

Kaposi sarcoma is a tumour of endothelial-derived spindle cells whose lesions evolve through patch, plaque and nodular stages, beginning on the skin, especially of the legs, and extending to mucosa, lymph nodes and viscera. The cutaneous lesions are characteristically violaceous, ranging from flat patches through raised plaques to nodules, and can be accompanied by disfiguring lymphoedema where lymphatic drainage is obstructed. All four epidemiological forms are KSHV-positive and look identical under the microscope, differing only in their clinical setting and behaviour.

Form	Setting	Course
Classic	Elderly men of Mediterranean, Eastern European or Middle Eastern origin	Indolent, mainly cutaneous
Endemic (African)	Adults and children in pre-AIDS Africa	Variable; can be aggressive or lymphadenopathic
Iatrogenic	Solid-organ transplant immunosuppression	Often regresses when immunosuppression is reduced
Epidemic (AIDS-associated)	Advanced HIV, especially men who have sex with men	Aggressive, often visceral; the defining cancer of the epidemic

In AIDS-associated disease, lesions of the oral cavity and gut are common and the gut lesions may bleed, while pulmonary involvement carries a markedly worse prognosis. Advanced disease is staged by the AIDS Clinical Trials Group system, which weighs the extent of the tumour, the degree of immune suppression and the presence of systemic illness to separate good-risk from poor-risk patients. Starting antiretroviral therapy can occasionally provoke a paradoxical worsening, the immune reconstitution inflammatory syndrome, in which the lesions flare as immunity returns; it carries appreciable mortality in sub-Saharan Africa and shapes how treatment is sequenced.

Primary effusion lymphoma

Primary effusion lymphoma is a rare and aggressive B-cell lymphoma that is universally KSHV-positive, the virus being its defining feature, and in most cases is co-infected with Epstein-Barr virus. It arises from postgerminal-centre plasmablastic B cells that characteristically lack the surface markers of mature B cells, it is monoclonal, and it presents typically as malignant effusions in the pleural, peritoneal or pericardial cavities without a solid tumour mass, though a solid extracavitary variant occurs. It is aggressive and its prognosis remains poor.

Multicentric Castleman disease

Multicentric Castleman disease is a polyclonal lymphoproliferative disorder driven by excess interleukin-6 activity, both the host cytokine and the viral homologue. It is KSHV-associated in essentially all cases arising in HIV-positive people and in a substantial minority of HIV-negative cases, the virus residing in plasmablastic B cells of the lymph-node mantle zone. It runs a relapsing and remitting course, with flares of fever, lymphadenopathy, hepatosplenomegaly and cytopenias, and the blood KSHV viral load rises with disease activity. It often coexists with Kaposi sarcoma and carries a risk of progression to overt lymphoma.

KSHV inflammatory cytokine syndrome

A more recently recognised entity, KSHV inflammatory cytokine syndrome, is a severe systemic illness with high circulating interleukin-6 and interleukin-10 and a high KSHV blood viral load, often alongside Kaposi sarcoma, but without the lymph node pathology of Castleman disease. It is increasingly recognised in advanced HIV and is associated with high mortality.

Other KSHV-associated lymphomas

KSHV is found, usually together with Epstein-Barr virus, in two further rare B-cell entities: a KSHV-positive diffuse large B-cell lymphoma and a germinotropic lymphoproliferative disorder. Both are uncommon and arise in the same immunosuppressed populations.

Diagnosis

The confirmatory test across all the KSHV diseases is immunohistochemical staining for LANA on biopsy tissue, which shows a characteristic stippled nuclear pattern in the infected tumour cells. The histology of Kaposi sarcoma itself, proliferating spindle cells forming slit-like vascular channels with extravasated red cells, is distinctive but must be distinguished from mimics such as bacillary angiomatosis. KSHV PCR detects viral DNA in blood, effusion fluid and tissue; the blood viral load is low or undetectable in stable Kaposi sarcoma but rises with the activity of Castleman disease and the cytokine syndrome, so it is most useful for monitoring those B-cell disorders. Serology, using latent (LANA) and lytic antigen assays, is limited by cross-reactivity with other herpesviruses and by imperfect sensitivity, and so is more useful for population seroprevalence studies and for screening organ donors than for diagnosing disease in an individual, where biopsy and immunohistochemistry remain definitive.

Management

For Kaposi sarcoma, the decisive intervention in AIDS-associated disease is antiretroviral therapy, which restores immune control and alone often causes regression, while transplant-associated disease is managed by reducing immunosuppression, where possible switching to an mTOR inhibitor. Advanced, visceral or rapidly progressive disease is treated with systemic chemotherapy, pegylated liposomal doxorubicin first and paclitaxel second, and limited cutaneous lesions with local measures such as radiotherapy or intralesional chemotherapy. The unifying principle is that, because Kaposi sarcoma is driven by the loss of immune control rather than by an autonomous clone, restoring that control achieves more than any cytotoxic drug. Primary effusion lymphoma is treated with systemic chemotherapy alongside antiretroviral therapy, though its prognosis remains poor, and the proteasome inhibitor bortezomib, which targets the NF-κB survival pathway, is under investigation. Multicentric Castleman disease is treated principally with rituximab to deplete the B cells that harbour the virus, with agents directed against the interleukin-6 pathway, such as siltuximab or tocilizumab, where the cytokine-driven inflammation dominates. Antiviral drugs such as ganciclovir act only on the lytic cycle and so do not touch the latency-driven tumours; their role is confined to the cytokine-driven disease and to reducing shedding. No treatment eradicates the latent virus.

Prevention and public health

Vaccination

There is no licensed KSHV vaccine and no candidate in advanced development. As with Epstein-Barr virus, a vaccine is difficult to achieve, and prevention is further complicated in endemic regions because transmission occurs mainly through saliva within families in early childhood.

Treatment as prevention

Drugs that block lytic replication can reduce viral shedding, and historical data from the use of ganciclovir for cytomegalovirus retinitis showed a reduction in Kaposi sarcoma incidence, but their toxicity makes them impractical for routine prophylaxis. The most powerful preventive measure is the preservation of immune function: effective HIV treatment has substantially reduced the incidence of Kaposi sarcoma.

South African context

Kaposi sarcoma is a major HIV-associated cancer in South Africa, set against the very high background KSHV seroprevalence of the sub-Saharan African population, where the virus is acquired in childhood through saliva. The rollout of antiretroviral therapy has reshaped both the incidence and the course of the disease, but a locally important caveat is that the immune reconstitution inflammatory syndrome, in which Kaposi sarcoma flares after antiretroviral therapy is started, carries appreciable mortality in this setting and influences how treatment is sequenced.

References and recommended reading

• Damania B, Cesarman E. Kaposi’s Sarcoma Herpesvirus. In: Fields Virology, 7th edition, Volume 2, Chapter 15. Wolters Kluwer; 2022. The primary reference for the virology, the latency-lytic biology, the pirated-gene repertoire and the KSHV-associated diseases.
• Chang Y, Gao SJ, Moore PS. Kaposi’s Sarcoma-Associated Herpesvirus. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. ASM Press; 2016. The clinical account of the Kaposi sarcoma forms, the lymphomas, diagnosis and management, by the virus’s discoverers.