Hantaviruses primarily infect human endothelial cells (ECs) and cause two highly lethal human diseases. Early addition of Type I interferon (IFN) to ECs blocks hantavirus replication and thus for hantaviruses to be pathogenic they need to prevent early interferon induction. PHV replication is blocked in human ECs, but not inhibited in IFN deficient VeroE6 cells and consistent with this, infecting ECs with PHV results in the early induction of IFNβ and an array of interferon stimulated genes (ISGs). In contrast, ANDV, HTNV, NY-1V and TULV hantaviruses, inhibit early ISG induction and successfully replicate within human ECs. Hantavirus inhibition of IFN responses has been attributed to several viral proteins including regulation by the Gn proteins cytoplasmic tail (Gn-T). The Gn-T interferes with the formation of STING-TBK1-TRAF3 complexes required for IRF3 activation and IFN induction, while the PHV Gn-T fails to alter this complex or regulate IFN induction. These findings indicate that interfering with early IFN induction is necessary for hantaviruses to replicate in human ECs, and suggest that additional determinants are required for hantaviruses to be pathogenic. The mechanism by which Gn-Ts disrupt IFN signaling is likely to reveal potential therapeutic interventions and suggest protein targets for attenuating hantaviruses. 1. Introduction 1.1. Disease Hantaviruses are present worldwide and responsible for two diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS is primarily present in Eurasia and caused by several hantaviruses including Hantaan virus (HTNV), Seoul virus (SEOV), Puumala virus (PUUV) and Dobrava virus (DOBV) [1–3]. HFRS has a mortality rate ranging from 0.1–5% with causes of death including shock (75%), uremia (50%), pulmonary edema (15%), and central nervous system hemorrhage or encephalopathy (5%) [1–7]. In 1993, a discrete North American hantavirus (Sin Nombre virus, SNV) was found in the southwestern United States as the cause of a new highly lethal respiratory syndrome termed HPS [1, 2, 8–14]. HPS causing hantaviruses have since been found throughout the Americas [15–20]. Andes virus (ANDV) is a prototypic South American HPS causing hantavirus and the only hantavirus that is reportedly spread from person to person [21–24]. Although hantaviruses are predominantly pathogenic, Prospect Hill virus (PHV) and Tula virus (TULV) are hantaviruses which are not associated with human disease, and are referred to here as nonpathogenic, although it is unclear whether these viruses cause
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