Ectopic expression of murine CD163 enables cell-culture isolation of lactate dehydrogenase-elevating virus 63 years after its discovery

Arteriviruses are RNA viruses related to coronaviruses but have not yet been associated with human infection. A murine arterivirus, lactate dehydrogenase-elevating virus (LDV), was first described in 1960 and quickly became a promising model for understanding immune failure due to its unique ability to persist in immunocompetent adult mice. However, the inability to culture LDV in vitro ultimately limited this system. Here, we demonstrate that the macrophage marker CD163 is essential for LDV infection. Expression of the murine homolog (mCD163) in otherwise mCD163-negative cell lines from mice and nonhuman primates enables productive LDV infection, creating the first immortalized cell-culture system. We also show that mCD163-knockout mice are completely resistant to LDV infection. These findings advance LDV as a model of arterivirus infection and viral persistence while adding to a growing body of literature suggesting that CD163 utilization is a broad feature of arteriviruses.IMPORTANCEMouse models of viral infection play an especially large role in virology. In 1960, a mouse virus, lactate dehydrogenase-elevating virus (LDV), was discovered and found to have the peculiar ability to evade clearance by the immune system, enabling it to persistently infect an individual mouse for its entire lifespan without causing overt disease. However, researchers were unable to grow LDV in culture, ultimately resulting in the demise of this system as a model of failed immunity. We solve this problem by identifying the cell-surface molecule CD163 as the critical missing component in cell-culture systems, enabling the growth of LDV in immortalized cell lines for the first time. This advance creates abundant opportunities for further characterizing LDV in order to study both failed immunity and the family of viruses to which LDV belongs, Arteriviridae (aka, arteriviruses).