THE ANTIPROLIFERATIVE AND ANTIVIRAL ACTIVITIES OF IFN-TAU VARIANTS INHUMAN-CELLS

The IFN-gamma are type I IFN expressed by the early trophoblast of cat tle and sheep but have activity on human cells and have been predicted to have potential therapeutic value, We have compared a series of mut ant bovine and ovine IFN-I with regard to their ability to inhibit the proliferation of Daudi cells and to evoke an antiviral (AV) response in WISH cells, Whereas Daudi cell growth was inhibited by Bo-IFN-tau 1 in the 1 nM range, WISH cells were much less responsive, requiring ex posure to 150 nM for protection against vesicular stomatitis virus, Re placement of lysines at positions 34, 107, 121, and 132 in Bo-IFN-tau, which are in regions predicted to interact with the type I receptor, led to modest but significant alterations in antiproliferative (AP) an d AV activities, Replacement of the lysine residues at 160 and 164 had marked effects on biopotency, with K160 being particularly important, The different IFN-tau were able to activate the transcription factors ISGF3 and AAF (GAF) in Daudi cells at concentrations that correlated reasonably web with their AP potencies, Stat activation occurred in WI SH cells in response to similar to 2 nM Bo-IFN-tau 1, but ISGF3 format ion could not be demonstrated even at the 100-fold higher IFN-tau conc entrations that gave viral protection, Pretreatment of WISH cells with Hu-IFN-gamma allowed ISGF3 formation to be observed in response to su bsequent treatment with Bo-IFN-tau 1 or type I human IFN but did not i ncrease the AV responsiveness of the cells, No evidence was found that IFN-tau elicit uniquely different responses on human cells than type I Hu-IFN, except they are much less potent, The data emphasize the imp ortance of a region near the carboxyl terminus for the functional acti vity of type I IFN, and that although ISFG3 formation may be necessary , its mere presence is not sufficient to provide an antiviral response .