Cross-reactivity between autoimmune anti-U1 snRNP antibodies and neutralizing epitopes of HIV-1 gp120/41

Abstract

We report extensive amino acid sequence homology between HIV-1 gp120/41, and > 33% of a U1 RNA-associated splicing protein, 70K. The latter is a target of autoimmune anti-RNP antibodies in mixed connective tissue disease (MCTD). The homologies, involving dominant epitopes of 70K and neutralizing epitopes of gp120/41, are the basis for mutual antibody cross-reactivity. A key finding is that the epitope GRAFVTIG in the V3 loop of gp120 (strain IIIB) is homologous to the functionally essential U1 RNA-binding site of 70K. ELISA data reveal a mean reactivity of anti-RNP antibodies to V3 IIIB that is as high as that of HIV sera. V3 MN, containing the framework sequence G-AF-T, also cross-reacts with anti-RNP antibodies, as do hydrophilic epitopes in gp41 homologous to the COOH end of 70K. Further, there is strong cross-reactivity between HIV sera and 70K in Western blots. In contrast, antibodies from a related autoimmune disorder, Sjögren's syndrome (SS), are neither V3 nor gp41 selective. We conclude that the substantial cross-reactivities reported here are due to conserved, antigenically dominant B cell epitopes having homologous counterparts in 70K and gp120/41. Because antibody production in both MCTD and HIV-1 infection is T cell dependent, the results imply that common T cell clones are also activated in these two disease paradigms. Further exploration of the mechanisms that activate these clones, and that control their divergent fates in MCTD and AIDS, may provide new insights into immune dysregulation in HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)