ANALYSIS OF HIV-INDUCED AUTO-ANTIBODIES TO CRYPTIC EPITOPES OF HUMAN CD4

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We have continued to define the mechanism of induction and to characterize human anti-CD4 auto-antibodies. This study describes a model for virus induced autoimmunity which supports the hypothesis that, as a consequence of HIV infection, abnormal processing of the CD4 receptor occurs. This process uncovers cryptic epitopes near the membrane anchoring region on CD4, which are then recognized as foreign antigen leading to autoimmune antibody production. Using the CD4 antigen as a model, we are studying how and where in the cell or on the cell surface, HIV and presumably the envelope protein complex interacts with CD4 to induce cleavage of the CD4 molecule at the membrane-external protein junction. These studies are per-formed using live HIV interacting with CD4 positive cells and, in addition, using protein expression systems with vaccinia vectors expressing high levels of mCD4 together with vectors expressing the envelope proteins. Degradation of CD4 has been followed kinetically using radioisotope labelling and immunoprecipitation and western blotting. To determine whether cleavage of CD4 occurs on the membrane surface as a consequence of virus binding, cells expressing high levels of CD4 have been incubated with free virus or purified envelope and then degradation of CD4 monitored. We are also planning to determine whether this autoimmune process extends into the cellular immune compartment by testing patients for cellular response to sCD4. If these are positive we will then attempt to map these reactivities using peptide reagents generated to analyze autoantibodies. This project has led to the hypothesis that abnormal antigen processing can generate autoimmune reactivities and presents a theoretical paradigm which may provide insight into molecular mechanisms involved in other autoimmune disorders.