Publication Date

2019-12-13

Availability

Open access

Embargo Period

2019-12-16

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2019-10-24

First Committee Member

Samita Andreansky

Second Committee Member

Enrique Mesri

Third Committee Member

Wasif Khan

Fourth Committee Member

Ralf Landgraf

Fifth Committee Member

Scott Tibbetts

Abstract

The hypoxia inducible factor 1 alpha (HIF1α) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV) such as Kaposi' Sarcoma-associated 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 pathogenesis has been challenging due to the lack of animal models for human γ HV. To study the role of HIF1α we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIF1α protein and HIF1α-responsive gene expression in permissive cells. Deletion of HIF1α reduces virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia regulatory element (HRE) such as viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1α transcriptional activity during KSHV infection. Intranasal infection of HIF1αLoxP/LoxP mice with MHV68 expressing Cre-recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Moreover, low oxygen conditions accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIF1α plays a critical role to promote virus replication. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.

Keywords

Gammaherpesvirus, KSHV, MHV68, hypoxia, HIF1alpha, viral pathogenesis, virus-host interactions, cancer

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