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Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi's sarcoma-associated Herpesvirus (KSHV), a defined human oncogenic virus, leads to profound alterations of host metabolic landscape to favor development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection through modulation of key enzymes (ODC1 and DHPS) of these pathways. During KSHV latency, ODC1 and DHPS are upregulated along with increase of hypusinated eIF5A (hyp-eIF5A), while hyp-eIF5A is further induced along with reduction of ODC1 and intracellular polyamines during KSHV lytic reactivation. In return these metabolic pathways are required for both KSHV lytic reactivation and de novo infection. Further analysis unraveled that synthesis of critical KSHV latent and lytic proteins (LANA, RTA) depends on hypusinated-eIF5A. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by inhibitors targeting these pathways. Collectively, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination pathways promote viral propagation, thus defining new therapeutic targets to treat KSHV-associated malignancies. Author summary: Understanding virus-host interactions is crucial to develop and improve therapies. Kaposi's sarcoma associated Herpesvirus (KSHV) is a human gamma-herpesvirus which deeply modulates the host metabolism and is associated with various cancers of endothelial and lymphoid origin. Polyamines are critical metabolites often dysregulated in cancers. In this study we demonstrated KSHV dynamically modulates polyamine metabolism to favor eIF5A hypusination and translation of critical KSHV latent and lytic proteins (LANA, RTA). Consequently, we found KSHV lytic switch from latency and de novo infection were dependent on polyamines and hypusination and pharmacological inhibition efficiently and specifically restricted KSHV infection. Our study provides new insights into KSHV alteration of the host metabolism and describe new therapeutic targets to treat KSHV-associated malignancies. [ABSTRACT FROM AUTHOR]