Reoviruses and the host cell.

Reovirus infection of target cells can perturb cell cycle regulation and induce apoptosis. Differences in the capacity of reovirus strains to induce cell cycle arrest at G1 and G2/M have been mapped to the viral S1 genome segment, which also determines differences in the ability of reovirus strains to induce apoptosis and to activate specific mitogen-activated protein kinase (MAPK) cascades selectively. Reovirus-induced apoptosis involves members of the tumor necrosis factor (TNF) superfamily of death receptors and is associated with activation of both death receptor- and mitochondrial-associated caspases. Reovirus infection is also associated with the activation of a variety of transcription factors, including nuclear factor (NF)-kappaB. Junctional adhesion molecule (JAM) has recently been identified as a novel reovirus receptor. Reovirus binding to JAM appears to be required for induction of apoptosis and activation of NF-kappaB, although the precise cellular pathways involved have not yet been identified.

Reovirus-induced sigma1s-dependent G(2)/M phase cell cycle arrest is associated with inhibition of p34(cdc2).

Serotype 3 reoviruses inhibit cellular proliferation by inducing a G(2)/M phase cell cycle arrest. Reovirus-induced G(2)/M phase arrest requires the viral S1 gene-encoded sigma1s nonstructural protein. The G(2)-to-M transition represents a cell cycle checkpoint that is regulated by the kinase p34(cdc2). We now report that infection with serotype 3 reovirus strain Abney, but not serotype 1 reovirus strain Lang, is associated with inhibition and hyperphosphorylation of p34(cdc2). The sigma1s protein is necessary and sufficient for inhibitory phosphorylation of p34(cdc2), since a viral mutant lacking sigma1s fails to hyperphosphorylate p34(cdc2) and inducible expression of sigma1s is sufficient for p34(cdc2) hyperphosphorylation. These studies establish a mechanism by which reovirus can perturb cell cycle regulation.

Reovirus-induced G(2)/M cell cycle arrest requires sigma1s and occurs in the absence of apoptosis.

Serotype-specific differences in the capacity of reovirus strains to inhibit proliferation of murine L929 cells correlate with the capacity to induce apoptosis. The prototype serotype 3 reovirus strains Abney (T3A) and Dearing (T3D) inhibit cellular proliferation and induce apoptosis to a greater extent than the prototype serotype 1 reovirus strain Lang (T1L). We now show that reovirus-induced inhibition of cellular proliferation results from a G(2)/M cell cycle arrest. Using T1L x T3D reassortant viruses, we found that strain-specific differences in the capacity to induce G(2)/M arrest, like the differences in the capacity to induce apoptosis, are determined by the viral S1 gene. The S1 gene is bicistronic, encoding the viral attachment protein sigma1 and the nonstructural protein sigma1s. A sigma1s-deficient reovirus strain, T3C84-MA, fails to induce G(2)/M arrest, yet retains the capacity to induce apoptosis, indicating that sigma1s is required for reovirus-induced G(2)/M arrest. Expression of sigma1s in C127 cells increases the percentage of cells in the G(2)/M phase of the cell cycle, supporting a role for this protein in reovirus-induced G(2)/M arrest. Inhibition of reovirus-induced apoptosis failed to prevent virus-induced G(2)/M arrest, indicating that G(2)/M arrest is not the result of apoptosis related DNA damage and suggests that these two processes occur through distinct pathways.