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Functional Imaging of Viral Transcription Factories Using 3D Fluorescence Microscopy
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Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral

Guillaume N Fiches1, Zhenyu Wu1, Dawei Zhou1

  • 1Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America.

Plos Pathogens
|April 29, 2022
PubMed

Insights

Kaposi's sarcoma-associated Herpesvirus (KSHV) manipulates host polyamine metabolism and eIF5A hypusination. Targeting these pathways inhibits KSHV replication and offers new therapeutic strategies for KSHV-associated cancers.

Area of Science:

  • Virology
  • Molecular Biology
  • Cancer Research

Background:

  • Polyamines are vital cellular metabolites frequently altered in cancer.
  • Kaposi's sarcoma-associated Herpesvirus (KSHV) is a human oncogenic virus that alters host metabolism.
  • KSHV infection promotes oncogenesis through metabolic reprogramming.

Purpose of the Study:

  • To investigate the dynamic regulation of polyamine biosynthesis and eIF5A hypusination by KSHV.
  • To determine the role of these pathways in KSHV lytic reactivation and infection.
  • To explore therapeutic strategies targeting these metabolic pathways for KSHV-associated malignancies.

Main Methods:

  • Analysis of key enzymes (ODC1, DHPS) in polyamine biosynthesis and eIF5A hypusination during KSHV infection.
  • Quantification of hypusinated eIF5A (hyp-eIF5A) levels.
  • Assessment of viral protein synthesis (LANA, RTA) dependence on hyp-eIF5A.
  • Evaluation of KSHV suppression using pathway-specific inhibitors.

Main Results:

  • KSHV infection dynamically modulates ODC1 and DHPS, affecting polyamine levels and hyp-eIF5A.
  • ODC1 and DHPS are upregulated during latency, while hyp-eIF5A increases with reduced ODC1 during lytic reactivation.
  • Hypusinated-eIF5A is essential for the synthesis of key KSHV latent and lytic proteins.
  • Inhibitors targeting these pathways effectively suppress KSHV infection.

Conclusions:

  • KSHV extensively interacts with host polyamine biosynthesis and eIF5A hypusination pathways.
  • These interactions are crucial for viral propagation, including reactivation and de novo infection.
  • Targeting these metabolic pathways represents a promising therapeutic approach for KSHV-associated cancers.

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