LINEAR DIMERIC INTERLEUKIN-2 OBTAINED BY THE USE OF A DEFECTIVE HERPES-SIMPLEX VIRAL VECTOR - CONFORMATION-ACTIVITY RELATIONSHIP

An interleukin-2 dimer, produced enzymatically by a nerve-derived tran sglutaminase in vitro, is cytotoxic to oligodendrocytes, unlike the im mune-derived monomeric interleukin-2. The abject of this study was to establish a way to produce a dimer of interleukin-2 in quantities, by means of genetic engineering, and to confirm that the structure of the resulting molecule is critical for its function. A defective herpes s implex virus vector was utilized for overproduction of a dimeric inter leukin-2. The resulting linear dimer, which is a translational product , differs from the enzymatically produced dimer, which is a posttransl ational modification of interleukin-2. The linear dimer, while retaini ng the known interleukin-2 activity of monomeric interleukin-2 with re spect to mitogenicity on T cells, was not cytotoxic to oligodendrocyte s. This finding suggests that the lack of cytotoxicity of the linear d imeric interleukin-2 is not caused by a loss of activity during its pr eparation but is related to its conformational structure, which eviden tly does not meet the requirements for cytotoxicity. This study opens the way to the design at the transcriptional level of modified protein s and their efficient production, provided that the new transcript enc odes for the desired modification in the protein at the appropriate si tes.