Kaposi Sarcoma: How HHV-8 Drives Tumor Growth

Kaposi sarcoma is a cancer of the cells lining blood and lymph vessels, caused by infection with a virus called human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV). First described in 1872 by the Hungarian dermatologist Moritz Kaposi, the disease remained relatively obscure for over a century until it surged during the AIDS epidemic of the 1980s.¹ Today it exists in four recognized forms, affects populations on every continent unevenly, and has become a window into how viral infections, immune suppression, and cancer intersect.

The Virus That Drives It

HHV-8 is the necessary ingredient. Without it, Kaposi sarcoma does not develop. The virus belongs to the gamma-herpesvirus family and, like other herpesviruses, establishes a lifelong infection once acquired. It spreads mainly through saliva, but transmission can also occur through sexual contact, blood transfusion, and organ transplantation.² Most people who carry HHV-8 never develop Kaposi sarcoma. The virus on its own is not enough; it takes an additional hit to the immune system, whether from HIV, immunosuppressive drugs after an organ transplant, or aging, to tip the balance toward cancer.

Once inside the body, HHV-8 infects endothelial cells, the cells that form the inner lining of blood and lymph vessels. The tumor cells found in Kaposi sarcoma lesions, often called spindle cells because of their elongated shape, are of endothelial origin, most closely resembling lymphatic endothelial cells but in a poorly differentiated state.³ The virus can actually reprogram these cells, pushing endothelial cells toward a more mesenchymal (connective-tissue-like) identity and vice versa, which likely helps the tumor establish itself and persist.⁴

How HHV-8 Hijacks the Cell

HHV-8 has two modes of existence inside a cell. During latency, the virus stays quiet, producing only a handful of proteins. The most important of these is a protein called LANA (latency-associated nuclear antigen), which keeps the viral DNA tethered to the host cell’s chromosomes so it replicates along with the cell. LANA also manipulates host survival pathways, helping infected cells resist the normal signals that would tell a damaged cell to self-destruct.⁵

The second mode, lytic replication, is when the virus becomes active and produces new viral particles. This phase is far from silent bystander behavior. During lytic activation, the virus expresses a protein called vGPCR (a viral version of a human signaling receptor) that drives the growth of new blood vessels by triggering the release of vascular endothelial growth factor (VEGF).⁶ This is why Kaposi sarcoma lesions are so vascular, appearing red, purple, or brown and bleeding easily. The vGPCR protein can actually immortalize human endothelial cells on its own and recreate many features of Kaposi sarcoma in laboratory settings, underscoring its central role in the disease.⁷

Hiding From the Immune System

A healthy immune system keeps HHV-8 in check for most carriers, which is why the majority of infected people never get sick. The virus, however, has evolved sophisticated countermeasures for the times when the immune system weakens. HHV-8 encodes two proteins, known as MIR1 and MIR2 (or K3 and K5), that strip immune-recognition molecules off the surface of infected cells. These molecules, called MHC class I, are the flags cells display so that immune cells can identify and destroy anything foreign.⁸ By forcing these flags to be swallowed back into the cell and broken down, HHV-8 effectively makes infected cells invisible to immune surveillance.⁹

K3 and K5 are similar but not identical. K3 is a broader weapon, targeting all four major types of these surface flags, while K5 is more selective, strongly downregulating two types but leaving others relatively intact.¹⁰ MIR2 also removes other immune-signaling molecules from the cell surface, including B7-2, which is needed to activate T cells.¹¹ This multilayered cloaking strategy explains why even modest immune suppression can allow HHV-8 to gain the upper hand.

The Four Clinical Forms

Kaposi sarcoma is classified into four epidemiological types, all caused by HHV-8 but arising in distinct populations and clinical settings.¹²

Classic Kaposi sarcoma: the form originally described in the 1870s, typically appearing in older men of Mediterranean, Eastern European, or Middle Eastern descent. It usually involves slow-growing skin lesions on the legs and feet, and many patients live for years or decades with relatively indolent disease.
Endemic Kaposi sarcoma: found in sub-Saharan Africa, sometimes in younger adults and even children. This form predates the HIV epidemic and can be more aggressive, affecting lymph nodes and internal organs.
AIDS-associated Kaposi sarcoma: the form that drew worldwide attention in the 1980s, occurring in people with HIV whose immune systems are severely weakened. It tends to be the most aggressive variant, often spreading widely across skin and internal organs. It is particularly common among men who acquired HIV through sexual contact.¹³
Iatrogenic (transplant-related) Kaposi sarcoma: occurs in people taking immunosuppressive drugs, most commonly after an organ transplant. Reducing or switching immunosuppression sometimes causes the disease to regress on its own.

What the Lesions Look Like

Kaposi sarcoma typically starts on the skin. The lesions progress through three histological stages: patch, plaque, and nodular.¹⁴ Early patches are flat, pink or reddish-purple discolorations that can be mistaken for bruises. As they advance, they thicken into raised plaques, and eventually form firm, sometimes painful nodules. The color darkens toward deep purple or brown as the lesion matures, reflecting the dense tangle of new blood vessels inside. Lesions can appear anywhere on the body but favor the legs, face, and trunk. Swelling of the surrounding tissue, especially in the legs and around the eyes, is common when the disease involves the lymphatic system.

Kaposi sarcoma is not always confined to the skin. It can affect the gastrointestinal tract, lungs, and other organs. Gastrointestinal involvement is frequently silent; many patients have no symptoms at all, and lesions are discovered only during endoscopy performed for other reasons. When GI lesions do cause trouble, symptoms range from abdominal pain and nausea to iron-deficiency anemia from slow bleeding. Rarely, lesions can obstruct the bowel or even cause perforation.¹⁵

Why HIV Makes It Worse

HIV and HHV-8 are a dangerous combination, and the interaction goes beyond simple immune suppression. HIV produces a protein called Tat that directly promotes the growth of new blood vessels and increases HHV-8 replication, making the virus more aggressive in co-infected individuals.¹⁶ Laboratory studies have shown that Tat accelerates tumor formation driven by a specific HHV-8 protein called Kaposin A, boosting cell proliferation and activating multiple cancer-promoting signaling pathways. This synergy was confirmed in animal experiments where Tat dramatically sped up the development of tumors in mice.¹⁷ This molecular collaboration means that AIDS-associated Kaposi sarcoma is not just opportunistic cancer thriving in a weakened immune environment; the two viruses actively cooperate to drive the disease.

Diagnosis and Staging

A doctor might suspect Kaposi sarcoma from the appearance of the skin lesions, but a biopsy is needed for a definitive diagnosis. Under the microscope, pathologists look for the characteristic spindle cells and slit-like vascular spaces. A key confirmatory test involves staining for LANA, the latency protein produced by HHV-8. In one study, LANA expression was detected in 92% of Kaposi sarcoma cases and in none of the non-Kaposi sarcoma vascular tumors tested, making it a highly sensitive and specific diagnostic marker.¹⁸

For AIDS-associated Kaposi sarcoma, staging follows a system developed by the AIDS Clinical Trials Group (ACTG) rather than the traditional staging frameworks used for most cancers. It evaluates three factors: the extent of the tumor itself, the degree of immune suppression (measured by CD4 cell count), and the presence of other HIV-related systemic illness. Each factor is scored as either good risk or poor risk.¹⁹ This approach recognizes that in AIDS-associated Kaposi sarcoma, the patient’s overall immune health and HIV status matter at least as much as tumor size for predicting outcomes.²⁰

Treatment Approaches

Treatment depends heavily on which form of Kaposi sarcoma a person has and how advanced it is. The strategies range from simply restoring immune function to aggressive chemotherapy, with newer immunotherapies showing real promise.

Antiretroviral Therapy for HIV-Associated Disease

For people with AIDS-associated Kaposi sarcoma, antiretroviral therapy (ART) is the foundation of treatment. By suppressing HIV and allowing the immune system to recover, ART can shrink or even eliminate Kaposi sarcoma lesions without any cancer-specific treatment. In one early study, patients treated with combination antiretroviral therapy achieved six complete and three partial responses, with the cancer regression closely tracking drops in HIV viral load and rises in CD4 cell counts.²¹ ART alone is not always sufficient, however. In a larger study, half of participants saw their disease regress or stabilize on antiretroviral therapy, but the other half experienced progression, highlighting the need for additional treatment in many cases.²²

Chemotherapy

When Kaposi sarcoma is widespread or progressing despite immune recovery, systemic chemotherapy enters the picture. The two agents with the strongest track record are pegylated liposomal doxorubicin (PLD) and paclitaxel. A randomized trial comparing the two in advanced HIV-associated Kaposi sarcoma found similar response rates (roughly 46% for PLD and 56% for paclitaxel), comparable two-year survival (about 78–79%), and similar progression-free survival. Paclitaxel carried somewhat more severe side effects.²³ In practice, PLD tends to be the first-line choice because of its marginally better tolerability, though paclitaxel serves as a strong alternative.

Radiation for Localized Disease

For classic Kaposi sarcoma with limited skin involvement, localized radiation therapy can be remarkably effective. One analysis of patients with classic Kaposi sarcoma treated with radiation found a 100% overall response rate across all treated lesions, with about 93% achieving a complete response and the remainder achieving a partial response. Typical doses ranged from 20 to 54 Gy, and all symptoms had resolved completely by follow-up.²⁴

Immunotherapy With Checkpoint Inhibitors

The emergence of checkpoint inhibitors has opened a new front. Pembrolizumab, which blocks the PD-1 receptor on immune cells, has shown striking results across multiple forms of Kaposi sarcoma. In a trial of people with HIV-associated Kaposi sarcoma, pembrolizumab produced an overall response rate of about 62%, and among those who had not received prior cancer therapy, the response rate climbed to nearly 88%. Responses were durable: the median duration of response had not been reached at the time of analysis, and over 90% of responders maintained their response for at least 12 months.²⁵ A separate trial in patients with classic and endemic Kaposi sarcoma (without HIV) found an overall response rate of 71%, with two complete and ten partial responses among 17 patients.²⁶ These are still relatively small trials, but the consistency of results across different forms of the disease suggests that immunotherapy may become a standard option.

The Global Burden and Where It Falls Hardest

Kaposi sarcoma is not distributed evenly around the world. Sub-Saharan Africa bears a vastly disproportionate share, accounting for over 70% of new cases globally, driven by high rates of both HHV-8 infection and HIV.²⁷ In parts of East Africa, one-year mortality for HIV-associated Kaposi sarcoma remains above 40%, a figure that reflects late diagnosis, advanced disease at presentation, and limited access to the drugs that have transformed outcomes in wealthier settings.²⁸ Access to PLD, the preferred chemotherapy, is constrained in many low-income countries by cost, unreliable supply chains, and a shortage of infusion infrastructure and trained personnel.

The disease affects both men and women in Africa, sometimes from an early age, a pattern quite different from classic Kaposi sarcoma in the Mediterranean, which predominantly strikes older men.²⁹ The highest age-standardized incidence rates in men have been reported in Mozambique and Zambia, while the lowest are found in South Asia.³⁰ This geography makes clear that Kaposi sarcoma is, at its core, a disease of health-system inequity: the virus is widespread, but the immune compromise and lack of treatment access that allow it to become lethal are concentrated in the poorest regions.

Other Diseases Caused by HHV-8

Kaposi sarcoma is the most well-known consequence of HHV-8 infection, but it is not the only one. The same virus is linked to two other serious conditions: multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). MCD involves overgrowth of lymph node tissue and episodes of systemic inflammation, while PEL is a rare and aggressive lymphoma that typically presents as fluid collections in body cavities rather than a solid tumor mass.³¹ Which disease develops depends partly on which viral genes are expressed and in which cell types; variations in the virus’s gene expression program give rise to these three distinct malignancies from one infection.

More recently, researchers have described a fourth HHV-8-associated condition called KSHV inflammatory cytokine syndrome (KICS). Patients with KICS develop symptoms that look much like MCD, including fevers, elevated inflammatory markers, and high viral loads, but they lack the characteristic lymph-node changes seen in Castleman disease. KICS can occur alongside severe Kaposi sarcoma or primary effusion lymphoma, and it appears to be driven by the same viral inflammatory protein (vIL-6) that plays a role in the other HHV-8 diseases.³² The recognition of KICS is relatively new, and understanding how it relates to the spectrum of HHV-8 disease is still evolving. For clinicians caring for patients with known HHV-8 infection, it means that unexplained inflammatory episodes should raise a flag even when Castleman disease criteria are not met.