The role of hypoxia and cellular metabolism in the persistence and dissemination of human cytomegalovirus

Human cytomegalovirus (HCMV) is a persistent, ubiquitous pathogen that causes morbidity and mortality for immunosuppressed and immunonaïve people, particularly in transplant settings. Persistence is underpinned by latency: maintenance of viral genomes without virus production in CD34+ haematopoietic progenitor cells and CD14+ monocytes. HCMV can reactivate as these undifferentiated cells migrate and differentiate in peripheral tissue. This differentiation occurs in transit from bone marrow through the bloodstream to deep tissue which involves changing oxygen tensions, causing hypoxic and mitochondrial stresses on the infected cell, producing reactive oxygen species (ROS). Despite transplanted tissues experiencing similar hypoxia, hypoxia's role in latency and reactivation has not been studied. My preliminary data show that hypoxic, mitochondrial and ROS stresses induce HCMV reactivation in vitro, more so than the paradigmatic mechanisms: cellular differentiation and inflammation. I aim to understand how these stresses cause reactivation at the molecular level, focusing on hypoxia-inducible factor (HIF)1?-mediated epigenetic changes in the HCMV genome and changes in infected cell metabolism. I will identify how HCMV modulates cellular responses to hypoxia-induced stresses to support persistence. This work will build a foundation for understanding reactivation under physiological conditions, opening new avenues to suppress HCMV disease in vulnerable patients.