P0157 Role of HERV-K NP9 protein transactivation in AIDS-related Kaposi’s sarcoma

Abstract

Background Kaposi’s sarcoma-associated herpesvirus (KSHV) is the aetiological agent of Kaposi’s sarcoma, which preferentially arise in patients with AIDS. Although the introduction of combined antiretroviral therapy (cART) has dramatically reduced the incidence of Kaposi’s sarcoma, it remains a significant burden of morbidity and mortality in patients with AIDS. KSHV infection is necessary, but not sufficient to cause Kaposi’s sarcoma, indicating that microenvironmental factors are also required. Human endogenous retrovirus sequences (HERVs) constitute up to 8% of human genome and have resided in human genome for several million years. Interestingly, not all HERVs remain silent passengers; some, especially the HERV type K (HERV-K), have been found to be transactivated frequently in a variety of inflammatory diseases and human cancers. The HERV-K NP9 protein has been shown to be exclusively present in some tumours and has the oncogenic functions via regulating multiple signalling pathways. However, the role of HERV-K NP9 transactivation in viral oncogenesis, in particular in Kaposi’s sarcoma, and the potential value as a therapeutic target remain unknown. Methods We investigated the interaction between KSHV and HERV-K NP9. Findings We found that KSHV de novo infection or ectopic expression of KSHV-encoded Latency-associated Nuclear Antigen (LANA) protein transactivate HERV-K NP9 from human primary endothelial cells (the major cellular components within Kaposi’s sarcoma). We noted a higher level of HERV-K transactivation in peripheral blood mononuclear cells (PBMCs) from our cohort of HIV-positive/KSHV-positive patients than those from HIV-positive/KSHV-negative patients. Abundant NP9 expression was noted in Kaposi’s sarcoma tissue collected from HIV-positive patients. Further data indicate that the transactivation of NP9 is responsible for cell invasiveness and anchorage-independent growth of KSHV-infected endothelial cells. Interpretation Our data provide insights into the contribution of HERV-K NP9 transactivation to KSHV pathogenesis and tumorigenesis, and provide the framework for developing novel strategies targeting NP9 transactivation for improved treatment and/or prevention of Kaposi’s sarcoma in high-risk HIV-positive patients.