ABSTRACT Kaposi sarcoma (KS), an HIV/AIDS-associated malignancy, is one of the most prevalent cancers in people living with HIV-1 (PLWH) in sub-Saharan Africa (SSA). AIDS-associated KS is often aggressive with a high rate of recurrence despite suppressive antiretroviral therapy and chemo/radiotherapy. Kaposi sarcoma- associated herpesvirus (KSHV) is the etiologic agent associated with KS. The high prevalence of both KSHV and HIV-1 put millions of people in SSA at an increased risk of developing KS in their lifetime. Similar to other herpesviruses, KSHV can remain latent with undetected viral load, but infected individuals can be viremic periodically, suggesting the presence of an unknown reservoir or reservoirs that are harboring the KSHV infected or transformed cells and virus emerged after suppressive treatment to lead to KS. Our team has previously shown that KSHV can be found in brain tissues. The lack of a suitable animal model and the inability to systematically sample various tissue compartments from KSHV infected individuals have hindered the quest to locate these KSHV reservoirs in humans. However, with our recently established capability of full-body autopsies on postmortem donors in SSA, we can now assess the presence or absence of KSHV reservoirs throughout the entire human body in KSHV infected individuals. Our overall objective is to identify the KSHV tissue and cellular reservoirs in KSHV seropositive individuals, and to determine the effects of HIV-1 infection and KS on the size and distribution of these reservoirs. We hypothesize that KSHV reservoirs can be found in multiple tissue sites, and the size and distribution of the reservoirs will increase in HIV-1 infected individuals and KS patients. We will accomplish our main objective through the following specific aims: 1) Identify the KSHV tissue reservoirs and determine the magnitude and breadth of the tissue reservoirs in both asymptomatic and symptomatic KS with or without HIV co-infection. 2) Identify the KSHV infected cell types and determine whether HIV-1 infection and symptomatic KS affect the size and distribution of KSHV infected cell types and latency/lytic expression of the KSHV cellular reservoirs. This proposed study is significant as we have the unique opportunity to utilize our full-body autopsy capability in Zambia to address the yet-to-be answered questions of whether there are KSHV tissue reservoirs, the cell types involved, and how HIV-1 infection and development of KS will impact these reservoirs, and simultaneously expand this capability to our other SSA partner in Tanzania. Findings from this study may contribute to our understanding of KS recurrence after treatment and identify the potential target locations for any future novel treatment/therapy that can specifically eliminate KSHV infection and KS development.