Kaposi sarcoma is caused by infection with human herpesvirus 8 (HHV-8), also called Kaposi sarcoma-associated herpesvirus. But the virus alone rarely triggers the cancer. In nearly every case, something else has to go wrong, usually a weakened immune system, for the infection to progress into tumors. That’s why Kaposi sarcoma overwhelmingly affects people with HIV, organ transplant recipients on immune-suppressing medications, and older adults whose immune function has naturally declined.
The Virus Behind Every Case
HHV-8 is a herpesvirus in the same family as Epstein-Barr virus, which causes mono and is linked to certain lymphomas. Once HHV-8 infects the cells lining blood and lymph vessels (endothelial cells), it can lie dormant for years or decades. The virus produces a protein that interferes with a cell’s built-in braking system for growth. Normally, a protein called pRb keeps cells from dividing too quickly. HHV-8’s protein outcompetes pRb’s partner, freeing the cell to keep cycling and multiplying.
At the same time, infected cells pump out growth factors that stimulate new blood vessel formation, which is why Kaposi sarcoma lesions are so richly vascular and appear red or purple. Inflammatory signals like those produced during chronic HIV infection amplify this process, pushing infected cells to release even more of these growth-promoting compounds. The result is a feedback loop: inflammation drives cell growth, the growing cells attract more blood supply, and the lesions expand.
How HHV-8 Spreads
HHV-8 spreads primarily through saliva. Studies of people carrying the virus show it is shed in saliva far more frequently than in semen, urine, or stool. This makes casual transmission through kissing or shared saliva a likely route, particularly in regions where HHV-8 is common. In sub-Saharan Africa, where infection rates are high, the virus often spreads during childhood through household contact.
Sexual transmission also plays a role. Risk factors for HHV-8 infection include a higher number of sexual partners and a history of sexually transmitted infections. Early in the HIV epidemic, the sharp rise of Kaposi sarcoma among gay men initially pointed researchers toward sexual spread. People with HIV are about twice as likely to shed HHV-8 from oral and genital sites compared to those without HIV, which increases the chance of passing the virus to others.
Organ transplantation is another route. A donated organ from an HHV-8-positive donor can transmit the virus directly to the recipient, who is already on drugs that suppress the immune system.
HIV and AIDS-Related Kaposi Sarcoma
The most common form of Kaposi sarcoma develops in people living with HIV, and it remains one of the cancers that defines an AIDS diagnosis. HIV doesn’t cause Kaposi sarcoma directly, but it dismantles the immune surveillance that normally keeps HHV-8 in check. For every increase of 50 immune cells (CD4 T-cells) per cubic millimeter of blood, the risk of developing Kaposi sarcoma drops by roughly 30%. People with CD4 counts below 350 face about eight times the risk compared to those above that threshold who are on antiretroviral therapy.
Historically, most cases appeared when CD4 counts had fallen below 200, the point at which AIDS is typically diagnosed. That pattern has shifted. In recent years, more than a third of new Kaposi sarcoma cases in people with HIV are now diagnosed at CD4 counts of 350 or higher. This means the cancer can develop even when the immune system appears relatively intact, suggesting HHV-8 itself and chronic inflammation play a larger role than CD4 count alone.
Antiretroviral therapy has dramatically reduced Kaposi sarcoma rates. Once combination therapy became widespread in the mid-1990s, incidence dropped sharply, particularly among white men in the United States. Regimens containing protease inhibitors may be especially effective, not only by restoring immune function but by directly suppressing HHV-8 replication in the mouth and other mucosal sites. Still, rates among Black and Hispanic populations in the U.S. have remained largely unchanged, pointing to gaps in HIV treatment access.
Transplant-Related Kaposi Sarcoma
Organ transplant recipients take medications that deliberately suppress the immune system to prevent rejection of the new organ. This creates an opening for HHV-8. In the Cincinnati Transplant Tumor Registry, about 6% of all graft recipients developed Kaposi sarcoma. The risk roughly tripled, from 3% to 10%, after the introduction of cyclosporine, a more potent immune-suppressing drug than the older alternatives.
The standard treatment approach is to reduce or stop immunosuppressive therapy, which usually causes the skin lesions to shrink. The tradeoff is a higher risk of organ rejection. Some transplant centers now switch patients to alternative medications that suppress the immune system through a different pathway while also having anti-tumor properties.
Classic Kaposi Sarcoma
Before HIV existed as a recognized epidemic, Kaposi sarcoma was known as a slow-growing cancer of elderly men, particularly those of Mediterranean, Middle Eastern, or Eastern European descent. Classic Kaposi sarcoma typically appears as dark patches or nodules on the lower legs and feet. It progresses slowly over years or decades and is rarely life-threatening.
The cause is still HHV-8, but in classic cases there is no obvious immunosuppression. The natural decline of immune function with aging likely plays a role, and genetic factors tied to certain ethnic backgrounds may influence susceptibility. Intriguingly, the geographic distribution of classic Kaposi sarcoma correlates less with geography itself than with ethnicity, suggesting inherited immune traits matter more than where someone lives.
A Possible Environmental Factor
One unexpected finding involves soil. In Sicily, residents of communities with high concentrations of iron-rich clay soils called luvisols were roughly 2.7 times more likely to develop classic Kaposi sarcoma. Those who bathed frequently or drank tap water in these high-luvisol areas had about five times the risk. Laboratory studies offer a possible explanation: iron appears to block the natural cell-death process in Kaposi sarcoma cells while boosting their growth. This hypothesis, first proposed after researchers noticed that endemic Kaposi sarcoma in Africa clustered in volcanic regions, remains under investigation but suggests that prolonged skin exposure to certain mineral-rich soils could act as a co-factor alongside HHV-8 infection.
Endemic (African) Kaposi Sarcoma
In sub-Saharan Africa, Kaposi sarcoma existed long before the HIV epidemic and affects people of all ages, including children. Unlike the classic form, endemic African Kaposi sarcoma often invades the lymphatic system and internal organs, progresses rapidly, and carries a much shorter survival time. The high prevalence of HHV-8 across the region, combined with other immune stressors like malaria and malnutrition, likely explains why the disease is more aggressive and widespread here than anywhere else. Sub-Saharan Africa continues to have the world’s highest Kaposi sarcoma incidence, mirroring HHV-8 infection rates in the population.
Why the Virus Alone Isn’t Enough
Most people infected with HHV-8 never develop Kaposi sarcoma. In the Mediterranean, where up to 20-30% of the population may carry the virus in some communities, classic Kaposi sarcoma remains relatively rare. The virus needs a permissive environment to cause cancer, and that environment is created by immune suppression in one form or another.
Chronic inflammation acts as an accelerant. In people with HIV, the constant immune activation produces inflammatory signals that directly stimulate HHV-8-infected cells to grow and form new blood vessels. This is why Kaposi sarcoma was especially common among people with untreated HIV who had high viral loads and persistent immune activation, even before their CD4 counts dropped to critically low levels. The combination of a weakened immune system, active HHV-8 replication, and an inflammatory environment creates the conditions for tumors to take hold.