Alloimmunity, autoimmunity, and AIDS

The sensitivity of the human immune system to the retrovirus HIV is difficult to explain on the basis of viral cytopathicity. AIDS develops often long after initial HIV infection in spite of a vigorous and sustained immune response against the virus which effectively contains viral replication. Although more virulent strains of HIV can be isolated from immunodeficient persons, there is no evidence that these strains predominate in vivo or that a large increase in production of infectious virus accompanies progression to disease. There is as yet no satisfactory mechanism to explain the immunosuppression, T4 cell depletion, autoimmunity, and immunodeficiency associated with HIV infection. An hypothesis that AIDS results from immune responses to HIV gp120 and to allogeneic cells stems from recent developments in the symmetrical network theory. It is proposed that T-cell selection processes produce a T-cell idiotypic network "centrepole," which bears an internal image of self MHC class II within T-cell receptors. This network centrepole interacts with the anti-class II helper cell repertoire to stabilize both its own expression and expression of the helper T-cell repertoire. The idiotypes involved in this mutual stabilization are related to certain idiotypes present on allogeneic lymphocytes and to the envelope glycoprotein of HIV gp120. Through its relationship to CD4 protein, and hence class II MHC, HTV gp120 is thought to mimic the T-cell network centrepole. Anti-host class II receptors on allogeneic lymphocytes induce antibodies which also mimic the proposed centrepole. The immune response to gp120 is directed against the centrepole and against the antibodies (anti-anti-class II) induced by the receptors of allogeneic lymphocytes. The hypothesis evaluated in this thesis project is that the immune responses described above synergize in an attack on both the centrepole and the helper cell repertoire, resulting in aberrant immune regulation, autoimmunity, and eventually, AIDS. Sera from persons with AIDS or at risk of AIDS were examined for antibodies implicated in the above scheme. Anti-anti-CD4/anti-gp120 antibodies (putative anti-centrepole) were found in only a small minority of subjects and did not correlate with disease, while anti-anti-class II antibodies were almost never detected. Anti-MHC class I antibodies, reflecting alloimmunity, were associated with HIV infection and to some extent with disease progression. Autoantibodies against denatured collagen, reflecting autoimmunity, were found in almost all AIDS patients. The prevalence of these autoantibodies increases in HIV infection and with disease expression. Antibodies against denatured collagen show an interesting distribution which suggests they are related to the idiotypic determinants involved in the pathogenesis of AIDS and other similar immune disorders. The specificity of these antibodies suggests they arise through immunoregulatory defects induced through idiotypic network interactions.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat