PROJECT SUMMARY / ABSTRACT Kaposi sarcoma-associated herpesvirus (KSHV) remains an important cause of human disease worldwide. While KSHV was first discovered nearly 25 years ago, many basic questions remain unanswered regarding the timing of acquisition, route of transmission, risk factors for infection, as well as the virologic and immunologic drivers of transmission. Addressing these questions is essential to the rational design of strategies to prevent and treat KSHV-related disease. Our group at the Fred Hutchinson Cancer Research Center (FHCRC) and the Uganda Cancer Institute (UCI) has conducted comprehensive studies of primary human herpesvirus infections among children in Uganda as part of our “PHICS” cohort study. By intensively following households of mothers and young children in Uganda for one year, we were able to identify incident infections for multiple herpesviruses and to characterize kinetics of oral shedding during primary and chronic infection for each virus. Importantly, we did not observe any incident KSHV infection among infants, suggesting that the dynamics of KSHV transmission are unique, may be less efficient than other human herpesviruses, and are likely to occur at an older age. We now propose to extend the PHICS study approaches to comprehensively study KSHV. By precisely defining the timing of primary infection, we aim to address several hypotheses related to the biology of the initial steps of KSHV infection. To complete these studies, we will enroll a cohort of 80 KSHV-infected mothers and their children in Kampala, Uganda. We will perform weekly home visits to document risk behaviors and to obtain weekly oral swabs and monthly blood samples over a period of 18 months. Samples will be tested for KSHV DNA by polymerase chain reaction (PCR) to identify incident KSHV infection in susceptible children and adolescents as well as to characterize KSHV shedding in potential household exposures. Our specific aims are: 1) To determine the incidence and to define the viral, immunologic, and clinical features of primary KSHV infection. 2) To identify the biologic and behavioral risk factors associated with primary KSHV infection. 3) To develop mathematical models that characterize KSHV shedding dynamics and virologic drivers required for transmission.