TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine

Jemielity, Stephanie; Wang, Jinyize J.; Chan, Ying Kai; Ahmed, Asim A.; Li, Wenhui; Monahan, Sheena; Bu, Xia; Farzan, Michael; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.; Choe, Hyeryun

Because hTIM1 binds PS with high affinity [21] and various viruses contain PS on their virion surfaces [32, 33] , we explored the possibility that the reported hTIM1-mediated EBOV entry [5] is PS dependent. Furthermore, using pseudoviruses, VLPs, and infectious viruses bearing the entry proteins of 19 viruses from 7 different families, we investigated the generality of PS-receptor usage and its underlying mechanisms. We observed that hTIM1 promoted infection by a range of viruses, including members of the filovirus, flavivirus, alphavirus and New World arenavirus families, and that this enhancement required the PS-binding activity of hTIM1. We further demonstrated that additional PS receptors, such as hTIM4 and hAxl enhanced the entry of most hTIM1using pseudoviruses, and that the efficiency of this enhancement largely correlated with that observed with hTIM1. Finally, we explore and discuss the molecular mechanisms that contribute to the differential efficiency of viral PS receptor usage. Collectively our data suggest that hTIM1 and related proteins function as attachment factors for a full range of enveloped viruses.