The environmental factors associated with systemic lupus erythematosus (SLE) include Epstein-Barr virus (EBV). Once infected, EBV is well known to persist in all human hosts for life. We believe that novel approaches to the detection of this pathogen and to the assessment of the host response to this pathogen are warranted. Among the most interesting viral products is Epstein-Barr virus Nuclear Antigen-l (EBNAl), which contains a peptide sequence that inhibits antigen presentation and class I HLA-dependent cytotoxic T cell responses. Preliminary data show that EBNA-l also contains sequences that appear to be differentially bound by SLE as opposed to normal sera. We propose to study SLE from the perspectives of the anti-EBNA-l humoral immune response, of EBNA-l expression in B cells, and of EBNA-l sequence variants. We plan to use the Early-lmmediate antigen-l (El-l) of cytomegalovirus (CMV) as a control antigen. This project is a competitive renewal for AI 31584 for year 09. Work in the current funding period is focused upon serology before diagnosis of SLE, made possible by over 20,000,000 sera in the Army Navy Serum Bank. The results to date from the first 130 SLE patients and 520 controls have established that autoimmune serological changes are present years before clinical manifestations and that autoantibody specificities vary greatly with regard to their temporal relationship to illness. Because of the high EBV infection rate among women and African-American men, the temporal relationship between EBV infection and SLE could not be tested. The final aim of this competitive renewal is to continue accruing the appropriate military cases and controls to provide sufficient power to test the hypotheses that EBV infection precedes clinical onset of SLE and that anti-EBNA-l precedes the onset of lupus autoantibodies. Establishing the role of ubiquitous agents, such as EBV, in chronic disease is especially difficult. In this situation, specific associations of SLE with immune response variations, with viral gene product expression, and with viral variants will be sought in an effort to explore particular mechanisms of pathogenesis as a strategy to more convincingly implicate EBV in the etiology of SLE.