Kaposi’s sarcoma herpesvirus activates the hypoxia response to usurp HIF2α-dependent translation initiation for replication and oncogenesis

Abstract

Kaposi's sarcoma herpesvirus (KSHV) is an angiogenesis-inducing oncovirus whose ability to usurp the oxygen-sensing machinery is central to its oncogenicity. By upregulating the hypoxia-inducible factors (HIFs), KSHV reprograms infected cells to a hypoxia-like state, triggering angiogenesis. Here we identify a link between KSHV replicative biology and oncogenicity by showing that KSHV's ability to regulate HIF2a levels and localization to the endoplasmic reticulum (ER) in normoxia enables translation of viral lytic mRNAs through the HIF2a-regulated eIF4E2 translation-initiation complex. This mechanism of translation in infected cells is critical for lytic protein synthesis and contributes to KSHV-induced PDGFRA activation and VEGF secretion. Thus, KSHV regulation of the oxygen-sensing machinery allows virally infected cells to initiate translation via the mTOR-dependent eIF4E1 or the HIF2a-dependent, mTOR-independent, eIF4E2. This ''translation initiation plasticity'' (TRIP) is an oncoviral strategy used to optimize viral protein expression that links molecular strategies of viral replication to angiogenicity and oncogenesis.

Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions

“…Moreover, the putative association of SDH mutations with HIFα protein accumulation has yielded contradictory results in cell lines [ 22 , 23 , 24 ]. Finally, besides the expected HIF2α localization at the cell nuclei, there are reports showing that this protein also accumulates in the cytoplasm [ 41 , 42 ] where it can regulate translation via non-transcriptional activity, as previously suggested [ 43 , 44 , 45 ]. Thus, we decided to perform immunohistochemical analysis of HIF2α in PPGL, analyze its relationship with the genotype of the tumors and pay attention to the subcellular distribution of the protein.…”

Hypoxia and hypoxia‐inducible factors in Kaposi sarcoma‐associated herpesvirus infection and disease pathogenesis

“…18,49,70 A study published by Dr. Mesri's group in 2021 revealed a novel role for HIF-2α in initiation of translation of viral lytic mRNAs. 71 In this study, they found that lytic replication in iSLK cells initially increased HIF-2α levels within 24 h but decreased its expression level in later stages (48-72 h). They also found that suppressing HIF-2α led to a 50% decrease in viral reactivation that did not occur with HIF-1α suppression.…”

“…Indeed, latent KSHV infection of endothelial cells induces both HIF‐1α and HIF‐2α expression, and these factors are increased in KS tissue 18,49,70 . A study published by Dr. Mesri's group in 2021 revealed a novel role for HIF‐2α in initiation of translation of viral lytic mRNAs 71 . In this study, they found that lytic replication in iSLK cells initially increased HIF‐2α levels within 24 h but decreased its expression level in later stages (48–72 h).…”

“…To this end, belzutifan, a specific HIF-2α inhibitor that binds to HIF-2α and prevents its dimerization with HIF-1β, was recently approved by the FDA for the treatment of various tumors in patients with von Hippel-Lindau disease. 90 As HIF-2α is expressed in KS tissues from patients where it likely contributes to KS pathology based on several in vitro and in vivo studies 18,49,65,71 belzutifan provides a potential drug candidate for testing in KS. As for a direct inhibitor of HIF-1α, acriflavine, an FDAapproved compound, was identified as the most potent inhibitor of HIF-1α in a study screening 3120 drugs that are either FDAapproved or in phase II clinical trials.…”