Comprehensive Characterization of the T-cell Response to KSHV to Enable Specific Immune Therapy

About This Grant

PROJECT SUMMARY Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease. KS causes significant morbidity and mortality worldwide, particularly in people living with HIV (PLWH) and in sub-Saharan Africa (SSA) where KSHV seroprevalence is high. It is estimated that 80% of the KS burden in SSA, where the impact of KS is heaviest, is attributable to HIV infection. KS most often develops in the setting of T-cell deficiency or dysfunction, such as in KSHV-seropositive individuals with HIV infection or KSHV-seropositive recipients of solid organ or allogeneic hematopoietic cell transplants. In these settings KS can remit following initiation of antiretroviral therapy (ART) or withdrawal of immune suppression. In SSA, primary infection with KSHV is thought to occur in childhood, but most cases of KS and other KSHV-associated disease in both PLWH and people without HIV infection develop many years, often several decades, later. These observations suggest that loss or impairment of a T-cell component of pre- existing KSHV-specific immunity underlie the development of these diseases. Strategies that preserve or restore the T-cell component of KSHV-specific immunity in PLWH and others at risk should, therefore, have potential for the prevention or treatment of KSHV-associated disease. Our studies of tumor biopsies and blood samples from people in Uganda living with HIV and KS (epidemic KS) as well as adults with KS but no concurrent HIV infection (endemic KS) have identified a large repertoire of T- cells that are likely to be specific for KSHV. We have begun to identify the antigenic targets of these putative KSHV-specific T-cells and find that they demonstrate high avidity for KSHV-encoded peptides, recognize KSHV- infected cells, are detectable in KS tumors, circulate in blood, and persist across time. Additional preliminary data from whole exome sequencing and transcriptional profiling of KS tumors reveal a sparse mutational landscape but consistent expression of latent and lytic cycle KSHV genes, supporting the concept that immune interventions that preserve, enhance, or restore the T-cell response to KSHV could prove effective for the prevention or treatment of KS, particularly in PLWH who are at greatest risk. Comprehensive definition of the targets of the KSHV-specific T-cell response in KSHV-seropositive individuals and of how that T-cell response is impaired or disabled in individuals who develop KS will provide the blueprint for such immune interventions. The studies in this application will lay the foundation for specific immune therapy for KS by identifying the major targets of the T-cell response to KSHV, identifying those that are naturally presented by KSHV-infected cells, and defining mechanisms by which KSHV attempts to evade that response.