CROSS-REACTIVITY BETWEEN AUTOIMMUNE ANTI-U1 SNRNP ANTIBODIES AND NEUTRALIZING EPITOPES OF HIV-1 GP120 41/

We report extensive amino acid sequence homology between HIV-1 gp120/4 1, and >33% of a U1 RNA-associated splicing protein, 70K. The latter i s a target of autoimmune anti-RNP antibodies in mixed connective tissu e disease (MCTD). The homologies, involving dominant epitopes of 70K a nd neutralizing epitopes of gp120/41, are the basis for mutual antibod y cross-reactivity. A key finding is that the epitope GRAFVTIG in the V3 loop of gp120 (strain IIIB) is homologous to the functionally essen tial U1 RNA-binding site of 70K. ELISA data reveal a mean reactivity o f 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 wit h anti-RNP antibodies, as do hydrophilic epitopes in gp41 homologous t o the COOH end of 70K. Further, there is strong cross-reactivity betwe en HIV sera and 70K in Western blots. In contrast, antibodies from a r elated autoimmune disorder, Sjogren's syndrome (SS), are neither V3 no r gp41 selective. We conclude that the substantial cross-reactivities reported here are due to conserved, antigenically dominant B cell epit opes having homologous counterparts in 70K and gp120/41. Because antib ody production in both MCTD and HIV-1 infection is T cell dependent, t he results imply that common T cell clones are also activated in these two disease paradigms. Further exploration of the mechanisms that act ivate these clones, and that control their divergent fates in MCTD and AIDS, may provide new insights into immune dysregulation in HIV infec tion. Another implication of the current findings is that ligands spec ific to the U1 RNA-binding site of 70K may also bind to and abrogate V 3 functions in a broad spectrum of HIV-1 strains.