Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS) - one of the most common pediatric cancers in sub-Saharan Africa - however, the factors that lead to disease progression are not fully understood. HIV infection is known to significantly increase the risk of developing KS, which is likely imparted by the immune dysregulation from HIV infection. Moreover, high KSHV viral load is strongly predictive of KS development, suggesting the loss of an effective anti-KSHV immune response. However, very little is known about the KSHV-specific immune response prior to KS. Still less is known about the immune response during the very early stages of KSHV infection or whether an effective immune response during early infection can limit KSHV replication and subsequently the development of KS. Furthermore, the impact of antiretroviral treatment (ART) in HIV infected individuals on eliciting an effective immune response against KSHV during primary infection is unknown. Our data from a Zambian mother-child cohort demonstrated that primary KSHV acquisition is common during early childhood and HIV infection is a major risk factor. Recently, there has been a scale up in the use of antiretroviral therapy (ART) programs in Africa, and HIV infected children are being treated early. Collectively, this presents a unique opportunity to investigate the role of ART on KSHV during primary infection and whether this reduces KS progression. The overall goal of this project is to reduce the risk of KS development in children in endemic regions. The current objective is to delineate the role of ART on the KSHV-specific humoral immune response and the effect this has on KSHV reactivation and replication during the early stages of infection in HIV+ children. The central hypothesis is that the risk of disease progression to KS will be lower in HIV uninfected children and HIV+ children who undergo effective ART compared to HIV+ children who were not treated or failed ART, due to a more robust anti-KSHV humoral immune response reducing KSHV reactivation. We are ideally positioned to test our hypothesis because we have previously obtained samples from a large mother-infant cohort in Zambia that was established to investigate the role of ART on KSHV incidence in HIV+ children. Our preliminary data suggest that KSHV incidence is similar between HIV+ children on ART and HIV uninfected children, whereas KSHV incidence is significantly higher in HIV+ children not on ART. To test our hypothesis, we are proposing two aims: 1) Quantify humoral immune responses and viral replication at primary KSHV seroconversion in ART treated or untreated HIV infected children, and HIV uninfected controls, and 2) determine the impact of ART on acute KSHV humoral response and virus replication in KSHV/HIV co-infected children. The present study is of significance because the data generated will be useful for developing intervention strategies to reduce KSHV spread and the potential for KS progression in HIV+ children.