Receptor use by the Whitewater Arroyo virus glycoprotein

Whitewater Arroyo virus (WWAV) is a North American New World arenavirus, first isolated from rats in New Mexico in 1993, and tentatively associated with three human fatalities in California in 1999-2000. However, it remains unclear whether WWAV was the cause of these, or any other, human infections. One important characteristic of viruses that influences pathogenic potential is the choice of cellular receptor and the corresponding tropism of the virus. In the arenaviruses, these properties are determined largely by the viral glycoprotein (GP). We have previously noted for the New World clade B arenaviruses, which include four severe human pathogens, that the ability to cause human disease correlates with the ability of the GP to use the human transferrin receptor 1 (hTfR1) to enter cells. In addition, pseudotyped retroviral vectors displaying the GPs from pathogenic clade B viruses transduced a range of cell lines in vitro that were distinct from those that could be transduced by non-pathogenic clade B viruses. WWAV was initially classified as a New World clade A virus, based on sequence analysis of its nucleoprotein gene. However, more extensive analyses have revealed that WWAV and the other North American arenaviruses are probably recombinant clade A/B viruses, and that the WWAV GP is more closely related to the clade B GPs. Based on this finding, we sought to understand more about the possible pathogenic potential of WWAV by determining whether its clade B-like GP exhibited the characteristics of a pathogenic or non-pathogenic clade B virus. Our studies found that WWAV GP did not use hTfR1 for entry, and that its overall in vitro tropism was most similar to the GPs from the non-pathogenic clade B viruses. Although many viral factors in addition to GP receptor use and tropism determine whether a virus is able to cause disease in humans, our analysis of the WWAV GP does not support the idea that WWAV is a human pathogen.