Simian hemorrhagic fever virus: Recent advances

Brinton, Margo A.; Di, Han; Vatter, Heather A.

Simian hemorrhagic fever virus (SHFV) is an understudied arterivirus that typically causes asymptomatic, persistent infections in multiple species of African nonhuman primates (NHPs) which are natural hosts but fatal hemorrhagic fever disease in macaques. SHFV genomes found in different species of African primates have recently been sequenced but no biological data for these viruses has yet been reported. The sequence of one SHFV isolate from a long term persistently infected baboon showed a high degree of identity to the genome of SHFV-LVR, the prototype strain isolated in the 1960s. Similar to what was observed in early studies with the prototype SHFV isolate LVR, infection of Japanese macaques with 100 PFU of the baboon isolate efficiently induced fatal hemorrhagic fever disease in macaques. Consistent with the differential infection outcomes observed in macaques and baboons, SHFV infection of macaque macrophages and dendritic cells is more efficiently than that of baboons and infection induces pro39 inflammatory cytokine production in macaque but not baboon cells. A stable full-length SHFV LVR infectious clone was constructed and basic knowledge about the unique functions of SHFV has been expanded by several recent studies. The SHFV genome encodes extra genes compared to those of other arteriviruses; three instead of two papain-like protease one (PLP1) domains are encoded at the 5’ end and two adjacent sets of four minor structural proteins at the 3’ end. SHFV PLP1α, PLP1β and PLP1γ were each shown to be active proteases in vitro and the three expected nsp1proteins were detected in infected cells. The catalytic Cys of PLP1α is adjacent to an Ala instead of canonical Typ and PLP1γ is unique among arterivirus PLPs in being able to cleave at both downstream and upstream sites. Although the duplicated sets of SHFV minor structural proteins were predicted to be functionally redundant, data obtained with a set of mutant infectious clones, each with the start codon of one of the minor structural proteins mutated, showed that all eight of the minor structural proteins are required for production of infectious extracellular virus.