Title : Metabolic reprogramming of KSHV infection and tumorigenesis
Abstract:
Kaposi’s Sarcoma-associated herpes virus (KSHV), one of human gamma-herpesviruses, is a large double-stranded DNA virus that establishes long-term persistent infection. Primary infection of KSHV is usually asymptomatic, but its infection causes cancer under immunocompromised states, such as acquired immunodeficiency syndrome (AIDS) and organ transplantation. KSHV highly associates with certain AIDS-defined tumors. KSHV causes Kaposi’s sarcoma (KS), the most common AIDS-defined soft tissue tumor. KSHV is also the etiologic agent of primary effusion lymphoma (PEL), a rare but aggressive B-cell Non-Hodgkin lymphoma (NHL) that primarily affects HIV-infected individuals as well. Additionally, KSHV associates with the multicentric Castleman's disease (MCD), a distinct lymphoproliferative disorder that most often presents in HIV-infected individuals, which can further lead to the rise of large B-cell lymphoma. There are currently no effective therapies to treat KSHV-associated, AIDS-defined tumors, nor eliminate persistent KSHV infection. Our recent results showed that polyamine biosynthesis and its downstream eIF5A hypusination are required for KSHV viral infection and tumorigenesis, and that in return KSHV regulates the dynamics of these metabolic processes. Furthermore, hyp-eIF5A is required for translation of key KSHV viral proteins, including LANA that is required for KSHV viral episome tethering and its persistent infection. In addition, we demonstrated that certain FDA-approved drugs targeting these metabolic processes are effective to block KSHV persistent infection and growth of KSHV-infected tumor cells. These findings are novel, as it has never been examined that the polyamine-hypusine-eIF5A (hyp-eIF5A) pathway plays a role in regulating KSHV viral infection and tumorigenesis previously.
