Kaposi’s Sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma and two B cell malignancies: primary effusion lymphoma and multicentric Castelman’s disease. Kaposi’s Sarcoma is a tumour of endothelial cells which is inactive in subjects with healthy immune system, but disseminates as an aggressive tumour in immunosuppressed e.g. HIV-infected individuals, particularly affecting the lungs and gastrointestinal tract. In fact, Kaposi’s Sarcoma is one of the commonest tumours of AIDS patients, with an often fatal outcome. The number of KSHV-seropositive individuals varies depending on geographical location, with a maximum of more than 50% in sub-Saharan Africa, where Kaposi’s Sarcoma is the second largest contributor to the cancer burden (Plummer, Lancet 2016). Investigation of the molecular mechanisms of KSHV infection will contribute to our knowledge on KSHV pathogenesis and may open new perspectives for therapeutic treatment of KSHV-associated malignancies.
KSHV manipulates its host cell environment to enable replication and evade the host immune response, but these changes have been predominantly analysed at the transcriptional level. Changes in mRNA may not accurately reflect changes in cellular proteins, nor do they reflect the post-translational changes (such as degradation) induced by viral infection. How KSHV infection alters cellular proteins has only been analysed at the individual protein level or through proteomic studies of individual viral genes e.g. K5. During lytic stage infection, KSHV mediates degradation of several host proteins, including adhesion molecules, immune receptors, transcription and restriction factors, but an unbiased systematic analysis of the KSHV-induced changes in the host cell proteome is lacking. Therefore, the goal of this study was to perform a quantitative proteomics analysis of KSHV-infected cells to unravel virus-induced changes in host cells and determine how these changes impact the host immune system.
The objectives of this project were to: (1) establish a KSHV reactivation model in human endothelial cells, a physiologically relevant cell type for KSHV infection; (2) apply systematic and unbiased approaches to resolve changes in both the host and viral proteomes in endothelial cells upon KSHV reactivation; (3) identify host molecules modulated (i.e. degraded) by KSHV and (4) investigate these novel aspects of virus-host interaction.
