We determined that the highly pathogenic avian reovirus strain 176 (ARV-176) possesses an enhanced ability to establish productive infections in HD-11 avian macrophages compared to avian fibroblasts. Conversely, the weakly pathogenic strain ARV-138 shows no such macrophagotropic tendency. The macrophage infection capability of the two viruses did not reflect differences in the ability to either induce or inhibit nitric oxide production. Moderate increases in the ARV-138 multiplicity of infection resulted in a concomitant increase in macrophage infection, and under such conditions the kinetics and extent of the ARV-138 replication cycle were equivalent to those of the highly infectious ARV-176 strain. These results indicated that both viruses are apparently equally capable of replicating in an infected macrophage, but they differ in the ability to establish productive infections in these cells. Using a genetic reassortant approach, we determined that the macrophagotropic property of ARV-176 reflects a post-receptor-binding step in the virus replication cycle and that the ARV-176 M2 genome segment is required for efficient infection of HD-11 cells. The M2 genome segment encodes the major -class outer capsid protein (B) of the virus, which is involved in virus entry and transcriptase activation, suggesting that a host-specific influence on ARV entry and/or uncoating may affect the likelihood of the virus establishing a productive infection in a macrophage cell.The avian reoviruses (ARV) differ from the prototypical mammalian reoviruses (MRV) based on several biological properties other than just their distinct host ranges. Unlike MRV, ARV is naturally pathogenic in its avian host, lacks hemagglutinating ability, and is one of the few nonenveloped viruses capable of inducing syncytium formation in infected cell cultures and in vivo (14,18,24,28). Although ARV pathogenesis has been extensively described (5,6,15,34), the viral factors that influence ARV-host cell interactions and pathogenesis remain poorly understood.We have been investigating two ARV strains that possess distinct pathogenic and syncytium-inducing potentials. Previous results demonstrated that ARV-176 is highly pathogenic relative to ARV-138 in an embryonated egg model of virus pathogenesis, an attribute that correlates with the relative fusogenic capability of the virus (8). Both viruses infect and replicate with equal efficiency in cultured fibroblast cells, they display 94 to 98% amino acid sequence identity in the three sequenced S-class genome segment-encoded proteins (7a), and all 10 of their individual genome segments can be resolved by electrophoretic analysis (8); these properties make these two ARV strains ideal parental virus candidates for genetic and molecular approaches to identify viral determinants of host interaction and pathogenicity. We previously used a genetic reassortant approach to reveal that the S1 genome segment of ARV-176 is solely responsible for the syncytium-inducing property of the virus (8). Subsequent molecular and bio...