Kaposi sarcoma (KS) is a prototypic virally-driven malignancy that is one of the leading causes of global cancer-associated morbidity and mortality in people living with HIV (PLWH). Mild forms of HIV-associated KS may respond to ART alone (1-3), but patients with advanced or rapidly progressive KS are generally treated with ART and systemic chemotherapy. While treatment is associated with clinical improvement rates of 50-80% in patients with KS in the US and Europe, more than half of patients fail to achieve complete resolution of disease and up to 20% experience disease relapse within 1 year. The 5-year survival rate of HIV-associated KS is only 54% in the US and less than 9% in many countries in subSaharan Africa (SSA) which have the highest global burden of KS.(4, 5) To address these poor outcomes, more effective therapy for KS is urgently needed. The etiologic agent of KS is human herpesvirus-8 (HHV-8), a gamma herpesvirus that is closely related to Epstein-Barr virus, and immunotherapy targeting HHV-8 has great promise utility for the treatment of KS. The development of immunotherapy for KS, however, has to date been stymied by limited understanding of the B- and T-lymphocyte response to HHV-8; indeed, few, if any, antigens encoded by HHV-8 and recognized by CD8+ or CD4+ T-cells have been described. Preliminary data presented in this application provide compelling evidence for the existence of a “public” MHC-restricted CD8+ and CD4+ T-cell response to antigens expressed in KS tumors. We hypothesize that the antigenic targets of this public T-cell response are peptides encoded by translation products of the HHV-8 genome, that these HHV-8-encoded peptides are expressed in KS tumor cells, and that T-cells expressing HHV-8 peptide-specific T-cell receptors (TCRs) will specifically target KS tumor cells. The specific aims of this application are: (1) To express candidate public class I MHC-restricted HHV-8-specific T-cell receptors (TCRs) with therapeutic potential in healthy CD8+ T-cells via transduction with recombinant lentiviruses encoding HHV8-specific TCR transgenes. (2) To test CD8+ T-cells expressing candidate public HHV-8-specific TCRs for recognition of HHV-8, using COS-7 cells co-transfected with expression plasmids encoding HHV-8-encoded open reading frames and predicted MHC presenting molecules.