Determinants of Kaposi's sarcoma-associated herpesvirus seropositivity, viral DNA detection and cellular immune responses in Uganda

Abstract

Kaposi's Sarcoma-associated Herpesvirus (KSHV), is a necessary cause of Kaposi's sarcoma (KS), the risk of which increases among people with immune suppression, such as that caused by infection with HIV. KS incidence varies, being highest in places with a high prevalence of KSHV. Controlling KSHV transmission is key in reducing KS incidence. Documented KSHV prevalence is reported to be higher in rural Uganda than has been found elsewhere. This PhD research focused on investigating environmental and immunological factors associated with KSHV antibody responses and viral detection/shedding in blood and in saliva as well as KSHV specific cell-mediated immune responses in Uganda. ELISA and Luminex were used for antibody measurements, real-time PCR for viral detection and quantification and an ELISPOT assay for cell-mediated IFN-γ response measurement. Infections such as malaria and helminths were the main environmental risk factors analysed. The factors associated with higher KSHV antibody responses included early age of infection, malaria parasitaemia, low haemoglobin levels and Schistosoma mansoni infection. Malaria infection was also associated with higher levels of KSHV DNA in blood while male sex was associated with increased viral shedding in saliva. Children had the highest proportion of individuals with detectable KSHV DNA in blood and in saliva. In relation to IFN- production, individuals responded to a wide variety of KSHV peptides without any immune dominance. In conclusion, KSHV transmission in endemic areas occurs mainly in childhood; this may play a role in the failure to control the virus, leading to increased viral shedding and increased viral transmission. Parasite infections such as malaria and worms may play a significant role in rendering children susceptible to KSHV infection as well as in enhancing reactivation of the virus, increasing lytic replication and, thereby increasing transmission and 3 pathogenesis.The cell-mediated immune response to KSHV is complex due to the lack of immunodominance.