Project 2

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HIV-associated Kaposi sarcoma (KS), also known as epidemic Kaposi sarcoma (EpKS), is a leading malignancy in sub-Saharan Africa (SSA). It is among the top 10 malignancies by incidence and mortality in most SSA countries. The AIDS Clinical and Trials Group (ACTG) at the National Institutes of Health in the US has developed a criteria for staging EpKS. This criteria has 3 categories including tumor (T; T0 vs. T1) which considers the extent of the tumor, immune status (I; I0 vs. I1) which is based on CD4 counts, and systemic illness (S; S0 vs. S1) which is based on presence of opportunistic infections and other systemic illnesses. Treatment of EpKS involves antiretroviral therapy (ART) alone for early-stage disease (especially T0 stage), and ART plus chemotherapy for more advanced disease. Treatment outcomes for both treatment approaches are variable, with some individuals responding favourably while others have no response or even experience disease progression while on treatment. The T cell immune response is thought to play an important role in the control of both KS and Kaposi sarcoma-associated herpes virus (KSHV), the etiologic agent for KS. This is because a decline in T cell immunity is associated with a dramatic increase (~20,000-fold) in risk of KS development, while restoration of T cell immunity by ART administration for EpKS and by withdrawal of the causative immunosuppressive agent for iatrogenic KS is associated with regression of KS lesions in many instances. Also, metabolic dysregulation has been observed in both KS tumors and KSHV-infected cells. Our group has previously reported that lipid and glucose metabolism pathways are dysregulated in KS tumors, and more recent unpublished data on plasma metabolomes suggests a clustering of metabolites by KS status. Whether KSHV-specific T cell immunity and/or plasma metabolomes correlate with the different ACTG stages at presentation, and with KS treatment outcomes longitudinally during treatment has not been extensively explored previously. We hypothesize that lower ACTG EpKS stages have a higher underlying anti-KSHV T cell response than higher EpKS stages. Also, we hypothesize that a good response to treatment is associated with a better T cell response at baseline, and this response improves over time in good responders, with improved recognition of KSHV proteins after immune reconstitution with ART and/or lysis of KS tumors by chemotherapy resulting in more exposure to KSHV antigens. We also hypothesize that the plasma metabolomic profiles are differential at baseline and by response to treatment, and reflect the extent of metabolic dysregulation associated with stage and response to treatment. We will test these hypotheses through the following specific aims: 1) Determine differences in KSHV-specific T cell responses between KS stages at presentation and by response to treatment during follow-up; and 2) Compare plasma metabolomic profiles by KS stage at presentation and between treatment responders and poor responders.