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A role of hypoxia-inducible factor 1 alpha in Murine Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency.

ABSTRACT: The hypoxia-inducible factor 1 alpha (HIF1?) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (?HV), Kaposi sarcoma herpes virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIF1? during the virus life cycle and its biological relevance in the context of host has been challenging due to the lack of animal models for human ?HV. To study the role of HIF1?, we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIF1? protein and HIF1?-responsive gene expression in permissive cells. siRNA silencing or drug-inhibition of HIF1? reduce virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia-responsive elements (HREs) such as the viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1? transcriptional activity during KSHV infection. We found that the promoter of MHV68 ORF74 is responsive to HIF1? and MHV-68 RTA. Moreover, Intranasal infection of HIF1?LoxP/LoxP mice with MHV68 expressing Cre- recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Low oxygen concentrations accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIF1? plays a critical role in promoting virus replication and reactivation from latency by impacting viral gene expression. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.

SUBMITTER: Lopez-Rodriguez DM

PROVIDER: S-EPMC6975554 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A role of hypoxia-inducible factor 1 alpha in Murine Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency.

López-Rodríguez Darlah M DM Kirillov Varvara V Krug Laurie T LT Mesri Enrique A EA Andreansky Samita S

PLoS pathogens 20191206 12

The hypoxia-inducible factor 1 alpha (HIF1α) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV), Kaposi sarcoma herpes virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIF1α during the virus life cycle and its biological relevance in the context of host has been challenging due to the lack of animal models for human γHV. To study the role of HIF1α, we employed the murine gammaherpesvirus 68 ( ...[more]

PMID: 31809522

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Dataset Information

A role of hypoxia-inducible factor 1 alpha in Murine Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency.

Publications

A role of hypoxia-inducible factor 1 alpha in Murine Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency.

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