Abstract
Kaposi’s sarcoma herpesvirus (KSHV) is a γ herpesvirus associated with the human cancer Kaposi’s Sarcoma (KS) that can successfully establish a life-long infection in the mammalian host. To establish virus persistence in the host, KSHV has evolved molecular strategies to usurp cellular components contributing to its oncogenicity. For instance, KSHV by upregulating the hypoxia-inducible factors (HIFs) reprograms infected cells to a hypoxia-like state. In this study, we investigated if KSHV targeting of the hypoxia response is also part of a replication strategy to enhance viral protein synthesis. Here, we show a link between KSHV replicative biology and oncogenicity by uncovering that KSHV ability to regulate HIF2α levels and localization in normoxia enables translation of viral mRNAs through the HIF2α-regulated eIF4FH translation-initiation complex. This mechanism of translation in infected cells enhances lytic protein synthesis favoring viral replication and contributes to KSHV-induced oncogenic mechanisms. More importantly, we found HIF2α to be strongly expressed in both the nucleus and the cytoplasm of spindle cells in AIDS-KS tumors, suggesting that it may promote eIF4FH translation initiation in tumors.
In summary, this study revealed that KSHV by exploiting the hypoxia response has access to “TRanslation Initiation Plasticity” (TRIP), defined as the ability of this virus to alternatively initiate viral proteins synthesis using both the mTOR-regulated eIF4F complex and the mTOR-independent/HIF2α-activated eIF4FH translation complex. TRIP is an oncoviral strategy used to optimize viral protein expression that links molecular strategies of viral replication to angiogenicity and oncogenesis. This remarkable finding could improve KS therapies that mainly target the mTOR/eIF4F pathway and points to a novel oncoviral mechanism of host control leading to the discovery of new anti-viral therapeutic targets, such as HIF2α. Moreover, it uncovers a totally new role for the transcription factor HIF2α in virology, as regulator of translation initiation of viral genes.