The mechanism of pathogenesis leading to immunosuppression and death in AIDS is unclear. At any given time only a small fraction of T cells appear to be productively infected with HIV, yet ultimately the CD4+ T cell population is essentially eliminated. While most attention has focused on the role of virus induced cytopathic effects, some in vitro data have suggested possible autoimmune mechanisms leading to T cell destruction. Whether these play a role in vivo is, however, unclear. In this proposal a murine model to test the hypothesis that HIV induced immunosuppression results from gp120 mediated autoimmunity will be tested. Direct effects of gp120 on T cell function will be measured. Transgenic mice have been generated expressing the human CD4 gene. These mice will also be immunized with gp120, and it will be determined whether class II specific cytotoxic T cell responses or ADCC responses that are gp120 specific can be demonstrated in vitro using cells and antibodies from these immunized mice. If these mechanisms can be demonstrated in vitro, transgenic mice will be chronically immunized with gp120 to determine whether immunosuppression caused by destruction of lymphocytes occurs. Since these mice express human CD4 on both B and T cells, ADCC mechanisms will lead to destruction of both cell populations, whereas class II specific cytotoxic T cells (CTL) responses will cause destruction of B cells only. If the CTL mechanism can be demonstrated to occur, we will generate a second series of transgenic mice which express class II MHC on T cells using constructions that we have previously validated. These mice will be crossed with CD4 transgenic mice and again immunized with gp120. Under these conditions it is to be predicted that class II CTL responses should destroy both T cells and B cells. If the results obtained lead to immunosuppression and loss of lymphocytes in these mice,, then they suggest that a similar mechanism may well occur in vivo in man and suggests further that intervention and treatment of the disease may well be effected by inhibition of these processes. These transgenic mice should then provide a system which can be bred and analyzed in large numbers unlike the SCID-human T cell model.
