Role of Kaposi’s sarcoma-associated herpesvirus complement control protein in cell migration and angiogenesis

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According to the WHO, there are currently seven human oncogenic viruses that are responsible for more than 20% of all tumours worldwide. One of these viruses, Kaposi’s sarcoma-associated herpesvirus (KSHV) causes three malignancies: Kaposi’s sarcoma (KS), primary effusion lymphoma and multicentric Castleman’s disease. KS is the most common tumour in sub-Saharan Africa, in patients with acquired immunodeficiency syndrome and a risk for transplant recipients. KSHV-associated malignancies, KS in particular, are characterized by the presence of a pro-inflammatory infiltrate and angiogenesis. Despite the relevance of this virus in oncogenesis, there are no specific treatments for KSHV. Moreover, the molecular mechanisms that lead to disease and the role of specific viral proteins in disease progression are not well characterized. KSHV complement control protein (KCP) is a homolog of human regulators of complement activation that inhibits predominantly the classical complement pathway. We have discovered, through different approaches, that KCP binds to fibronectin leucine-rich repeat transmembrane proteins (FLRT) and chemokines, suggesting that KCP is involved in functions other than complement inhibition during KHSV infection. FLRT1-3 are type I transmembrane proteins involved in cell adhesion, cell migration, and angiogenesis. Chemokines are chemoattractant cytokines that play fundamental roles in leukocyte migration, angiogenesis, tumour development and metastasis. Despite the differences between chemokines and FLRTs, one commonality is that they influence cell migration and angiogenesis. Interestingly, KCP binding to chemokines enhanced chemokine-mediated cell migration, suggesting that KCP could contribute to leukocyte infiltration and potentially modulate the angiogenic properties of chemokines. Our main objective is to address the hypothesis that an interaction between KCP, chemokines and FLRTs influences cell migration and angiogenesis, two hallmarks of KS, playing a role in pathogenesis. To achieve this objective we will combine molecular biology, biochemistry, cell-based functional assays, infection experiments and structural analysis. We will characterize the interactions between KCP, chemokines and FLRTs at the molecular level, using X-ray diffraction analysis of KCP complex crystals. We will also determine the functional relevance of the interactions in the context of KSHV infection. Overall, this project will shed light on the role of KCP in the pathogenesis of KSHV, providing novel potential targets for intervention. Moreover, the obtained knowledge in the fields of cell migration and angiogenesis will contribute to our understanding of virus-mediated oncogenesis.