In sub-Saharan Africa, the intersection between the HIV epidemic and the endemic nature of Kaposi's sarcoma-associated herpesvirus (KSHV) infection has resulted in Kaposi's sarcoma (KS) becoming the most common malignancy in many parts of the region. Now that highly active antiretroviral therapy (HAART) is becoming available in Africa, many patients with AIDS-related KS are receiving HAART alone as first-line therapy. We have identified, however, in our ongoing NCI-funded randomized trial of HAART for AIDS-KS in Uganda, that HAART is often complicated by what is termed immune reconstitution inflammatory syndrome (IRIS). In this proposal, our overall objective is to systematically understand the pathology of KS-IRIS by studying IRIS-affected KS lesions. To address this, our multidisciplinary team representing clinical epidemiology, dermatology, molecular virology, pathology and biostatistics will conduct a nested case-control study within our ongoing trial of HAART for AIDS-KS in Uganda. Cases (n=30) will be patients who develop manifestations of cutaneous KS-IRIS within the first 12 weeks of HAART. Biopsies from IRIS-affected KS lesions among the cases will be compared to KS biopsy specimens from 30 controls without KS-IRIS. Biopsy specimens will be evaluated for latent and lytic KSHV antigens (Aim 1) and cellular elements of the adaptive and innate immune response (Aim 2) by immunohistochemistry and for a variety of mediators (Aim 3) via RNA expression microarrays. Novel use of within-subject differences will decrease variability and enhance power. We hypothesize that HAART-mediated immune reconstitution recapitulates an inflammatory milieu where KSHV and KS may flourish. Accordingly, we hypothesize that this results in transient KSHV reactivation and that KSHV lytic antigens are the main antigenic stimuli for KS-IRIS. Findings from this one-year pilot project will systematically and directly address KS-IRIS pathogenesis and will inform the rational construction of an intervention, to be evaluated with subsequent funding, to prevent or treat KS-IRIS.