Zika Virus (ZIKV) caused global concern when outbreaks in South America were linked to dramatic increases in microcephaly and other neurological complications in babies born to infected mothers. This was due to infection of the foetus via the placenta, particularly following maternal infection in the first trimester, while in contrast term placenta appears refractory to infection.
Virus replication is highly dependent on the host cellular environment with virus-host factor interactions significantly impacting outcomes of virus infection. It is thus unsurprising that oxygen tension, and subsequent changes to the cellular environment, can also impact replication of many viruses in cell culture models. Different tissue microenvironments within the body have varying oxygen tensions and current evidence suggests most viruses replicate most efficiently at an oxygen tension reflecting that in the tissue they most readily infect. Low oxygen tension is a hallmark of the early placenta and subsequent stabilisation of hypoxia inducible factors (HIFs) are key to normal placental development. The early placenta is a target of ZIKV infection, however this virus has a broad tissue tropism leading us to investigate the effect of oxygen tension on ZIKV replication.
Experiments in HTR8 cells, a human first trimester placental trophoblast cell line, suggest that hypoxia may restrict ZIKV infection, while in Huh7 cells, a human hepatocyte cell line, hypoxia appeared to enhance ZIKV replication. Although contradictory to the HTR8 results, these Huh7 results concur with previous studies using Huh7 cells to investigate hypoxia and Dengue Virus infection, a related flavivirus. Ongoing experiments are investigating the role HIF plays in ZIKV infection, and the potential impact hypoxia has on other flaviviruses in a cell type dependent manner. Investigating the diverse effects hypoxia has on viral replication will increase understanding of cell specific pathways important in regulating both hypoxic responses and virus replication.