title: Identification and characterization of a ross river virus variant that grows persistently in macrophages, shows altered disease kinetics in a mouse model, and exhibits resistance to type I interferon.
abstract: Alphaviruses, such as chikungunya virus, o'nyong-nyong virus, and Ross River virus (RRV), cause outbreaks of human rheumatic disease worldwide. RRV is a positive-sense single-stranded RNA virus endemic to Australia and Papua New Guinea. In this study, we sought to establish an in vitro model of RRV evolution in response to cellular antiviral defense mechanisms. RRV was able to establish persistent infection in activated macrophages, and a small-plaque variant (RRV(PERS)) was isolated after several weeks of culture. Nucleotide sequence analysis of RRV(PERS) found several nucleotide differences in the nonstructural protein (nsP) region of the RRV(PERS) genome. A point mutation was also detected in the E2 gene. Compared to the parent virus (RRV-T48), RRV(PERS) showed significantly enhanced resistance to beta interferon (IFN-β)-stimulated antiviral activity. RRV(PERS) infection of RAW 264.7 macrophages induced lower levels of IFN-β expression and production than infection with RRV-T48. RRV(PERS) was also able to inhibit type I IFN signaling. Mice infected with RRV(PERS) exhibited significantly enhanced disease severity and mortality compared to mice infected with RRV-T48. These results provide strong evidence that the cellular antiviral response can direct selective pressure for viral sequence evolution that impacts on virus fitness and sensitivity to alpha/beta IFN (IFN-α/β).
authors.affiliation: Virus and Inﬂammation Research Group, Faculty of Applied Science, University of Canberra, Canberra, ACT 2601, Australia. s.mahalingam@griffith.edu.au.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Lidbury
authors.forename: Nestor E
authors.initials: NE
authors.lastname: Rulli
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Musso
authors.forename: Susan B
authors.initials: SB
authors.lastname: Cossetto
authors.forename: Ali
authors.initials: A
authors.lastname: Zaid
authors.forename: Andreas
authors.initials: A
authors.lastname: Suhrbier
authors.forename: Harald S
authors.initials: HS
authors.lastname: Rothenfluh
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rolph
authors.forename: Suresh
authors.initials: S
authors.lastname: Mahalingam
mesh_terms: D000220:Adaptation, Biological; D018354:Alphavirus Infections / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000821:virology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D057131:Immune Evasion; D007370:Interferon Type I / Q000276:immunology*; D008264:Macrophages / Q000821:virology*; D051379:Mice; D020125:Mutation, Missense; D012398:Ross River virus / Q000302:isolation & purification* / Q000472:pathogenicity*; D012692:Serial Passage; D016019:Survival Analysis; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000235:genetics
chemical_list: D007370:Interferon Type I; D014764:Viral Proteins