Whatever the form of Kaposi's sarcoma in a patient, a KSHV infection is likely to be present. Before the AIDS epidemic and KSHV infection of gay men, the virus was probably transmitted primarily by non-sexual (though unknown) routes, as it still is in developing countries. It is likely that KSHV became endemic in the North American gay population prior to the AIDS epidemic in the early 1980's but why this occurred is not known. It appears that gay men are at higher risk for infection than heterosexuals and men may be more susceptible to KSHV infection and thus more likely to transmit it to male sex partners. The outbreak of Kaposi's sarcoma in the early stages of the AIDS epidemic probably occurred because HIV caused immune suppression in men who already were KSHV-infected.

There is no evidence that supports a direct role for HIV in the pathogenesis of Kaposi's sarcoma, other than the immunosuppression that is caused by HIV - but  this immunosuppression is important in KSHV replication since it allows the virus to grow unchecked and cause disease. As might be expected, the incidence of the sarcoma is higher in areas where KSHV infections are more common. For example, in sub-Saharan Africa, more than 50% of the population is KSHV-infected. The rate in the Mediterranean region is 5 to 20%, while in northern parts of Europe and North America, it is under 5% of the general population (though it is over 25% in the San Francisco gay population). Thus, it is not surprising that in sub-Saharan Africa, Kaposi's sarcoma is now the most common neoplastic disease.

There may be common risk factors for acquiring HIV and KSHV (homosexual sexual transmission) and this together with the immunosuppression accounts for the high incidence of Kaposi's sarcoma in gay men (but not other HIV-infected populations). But why is KSHV so associated with gay HIV-infected patients? The answer to this is also unknown but KSHV is probably not transmitted through anal intercourse; however, it may be transmitted via oral sex because it is found at high concentrations in saliva.

So KSHV was probably established earlier than HIV in the gay population but was usually controlled until HIV-immunosuppression in the same population allowed it to proliferate and form tumors at greatly elevated rates. Thus, HIV is a cofactor for KSHV-induced neoplasia.