Individual viral proteins are expressed in transgenic mice in order to answer two fundamental questions in viral pathogenesis: what are the mechanisms of induction of an immune response against a virus and what effect does a particular viral protein have on the metabolism of a cell in vivo? To address an example of the first question, induction of an immune response, the envelope glycoprotein G of vesicular stomatitis virus, serotype Indiana, was expressed in transgenics. When these mice are immunized with purified G protein, or when challenged with a recombinant vaccinia virus expressing this protein, only IgM and not IgG antibodies able to neutralize wildtype Indiana VSV are formed. However,the response with neutralizing antibodies is normal when the corresponding wildtype Indiana VSV is used. Thus, tolerance breaks down, and autoimmunity is established, when wildtype virus is used for immunization, and not when G protein is presented in other ways. These mice may become a model for those autoimmune phenomena of humans for which viral infections may be the triggering event. To address an example of the second question, we have expressed the regulatory protein Tax of the human retrovirus HTLV-L known to be associated with certain forms of T-cell leukemias, and tropical spastic paraparesis. To date we have found that low level Tax expression in transgenic mice may cause a thymic hypoplasia but no gross pathology. Since in these mice the Tax protein is under the control of an inducible promoter, we will be able in the future to study the effect of higher levels of expression. However, in one transgenic line the Tax transgene is apparently inserted into a host gene whose product is neccessary for normal embryonic development of the vertebra: mice of this line, when homozygous for the transgene, show a severe malformation of the vertebra characterized by hemivertebrae, spina bifida occulta, fusions of vertebral bodies, and short kinky tails. The molecular characterization of the corresponding gene that we have mapped to mouse chromosome 11 is under way.
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