Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection

Ross River virus (RRV) is an indigenous Australian arthropod-borne alphavir us responsible for epidemic polyarthritis (EPA), myalgia, and lethargy in h umans. rc Macrophages and monocytes have been associated with human RRV dis ease, and previous studies have shown that RRV is capable of infecting macr ophages,ia both a natural virus receptor and by Fc receptor-mediated antibo dy-dependent enhancement (ADE). Similar to other viruses, such as human imm unodeficiency virus and dengue virus, ADE infection results in dramatic RRV growth increases for in vitro macrophage cultures. This study demonstrates that RRV could resist lipopolysaccharide (LPS)-induced antiviral activity in macrophage cultures when infection was via the ADE pathway, Investigatio n of this infection pathway found that RRV was able to suppress the transcr iption and translation of key antiviral genes (tumor necrosis factor and in ducible nitric oxide synthase) in LPS-stimulated macrophages by disrupting the transcription into mRNA of the genes coding for the associated transcri ption factors IRF-1 and NF-kappa B. The transcription of non-antiviral cont rol genes was not perturbed by RRV-ADE infection, and de novo protein synth esis also was not significantly affected in RR-ADE infected cells. The ADE pathway of infection allowed RRV to specifically target antiviral genes In macrophages, resulting in unrestricted virus replication. As ADE has been o bserved for several virus families and associated with disease and adverse vaccination outcomes, these findings mag have broad relevance to viral dise ase formation and antiviral vaccination strategies.