Objective. To evaluate the correlation between the presence of antibodies to an endogenous retroviral element-encoded nuclear protein autoantigen, HRES-1, and the presence of other antinuclear antibodies and HLA class I1 alleles in patients with systemic lupus erythematosus (SLE) and overlap syndromes.Methods. Antibody reactivities to native and recombinant proteins and synthetic peptides were assessed by counterimmunoelectrophoresis, enzyme-linked immunosorbent assay, and Western blotting. HLA class I1 alleles were determined by oligonucleotide typing.Results. significant association between anti-HRES-1 and anti-RNP and an inverse correlation between HRES-1 and RolLa autoantibodies in patients with SLE or overlap syndromes. Antigenic epitopes of HRES-1 and the retroviral gag-related region of the 70-kd protein component of U1 small nuclear RNP, which share 3 consecutive highly charged amino acids (Arg-Arg-Glu), an additional Arg, and functionally similar ArgILys residues, represent cross-reactive epitopes between the two proteins. Selective removal of HRES-1 antibodies from sera of HRES-l-seropositive/RNP-seropositive patients by absorption on recombinant HRES-l/glutathione-Stransferase-conjugated agarose beads had no effect on anti-RNP reactivities. A comparative multivariate analysis of HLA class I1 genes revealed a differential segregation of DQBl alleles in HRES-l-seropositive versus HRES-1-seronegative patients (P = 0.04). While a relative increase of DQB1*0402 among HRES-1-seropositive patients was noted across ethnic groups (P = 0.02), a decrease of DQB1*0201 and DQB1*0301 was found in white HRES-l-seropositive patients (P = 0.04).Conclusion. Autoantibodies to HRES-1 are detectable in a distinct subset of patients with autoimmune disease, primarily in those who do not have antibodies to Ro and La. Anti-HRES-1 and anti-RNP reactivities are mediated by cross-reactive but separate antibody molecules. HLA-DQB genes, rather than HLA-DRB or DQA genes, may have a more significant influence on generation of these antinuclear autoantibodies.A hallmark of the destructive autoimmune process in patients with systemic lupus erythematosus