title: Hypoxia induces the gene expression and extracellular transmission of persistent lymphocytic choriomeningitis virus.
abstract: The physiological context of virus-infected cells can markedly affect multiplication and spread of the virus progeny. During persistent infection, the virus exploits the host cell without disturbing its vital functions. However, microenvironmental hypoxia can uncouple this intimate relationship and escalate virus pathogenesis. Accumulating evidence suggests that hypoxia-inducible factor (HIF) modulates gene expression of the viruses that pass through a DNA stage, contain hypoxia-responsive promoter elements, and replicate in the nucleus. Here we show that hypoxia can influence the gene expression and transmission of the cytoplasmic RNA virus lymphocytic choriomeningitis virus (LCMV), which is a neglected human pathogen and teratogen. The MX strain of LCMV, which we used as a model, replicates in a persistent mode in human HeLa cells, fails to produce mature envelope glycoproteins, and spreads through cell-cell contacts in the absence of extracellular infectious virions. Both exposure of MX-infected HeLa cells to chronic hypoxia and gene transfer approaches led to increased virus RNA transcription and higher levels of the viral proteins via a HIF-dependent mechanism. Moreover, hypoxia enhanced the formation of infectious virions capable of transmitting LCMV by cell-free medium. This LCMV "reactivation" might have health-compromising consequences in hypoxia-associated situations, such as fetal development and ischemia-related pathologies.
authors.affiliation: Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Tomaskova
authors.forename: Ingrid
authors.initials: I
authors.lastname: Oveckova
authors.forename: Martina
authors.initials: M
authors.lastname: Labudova
authors.forename: Lubomira
authors.initials: L
authors.lastname: Lukacikova
authors.forename: Katarina
authors.initials: K
authors.lastname: Laposova
authors.forename: Juraj
authors.initials: J
authors.lastname: Kopacek
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.forename: Jaromir
authors.initials: J
authors.lastname: Pastorek
mesh_terms: D015687:Cell Hypoxia; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects* / Q000254:growth & development*