STRUCTURE OF THE V(H) AND V(L) SEGMENTS OF POLYREACTIVE AND MONOREACTIVE HUMAN NATURAL ANTIBODIES TO HIV-1 AND ESCHERICHIA-COLI BETA-GALACTOSIDASE

B lymphocytes committed to the production of antibodies binding to ant igens on pathogenic bacteria and viruses (natural antibodies) are comm on components of the normal human B cell repertoire. A major proportio n of natural antibodies is capable of binding multiple antigens (polyr eactive antibodies). Using B cells from three HIV-1 seronegative healt hy subjects, and purified HIV-1 and beta-galactosidase from Escherichi a coli as selecting antigen, we generated three natural IgM mAb to HIV -1 and a natural IgM mAb to beta-galactosidase. The three HIV-1-select ed antibodies (mAb102, mAb103, and mAb104) were polyreactive. They bou nd with different affinities (K(d) = 10(-6) to 10(-8) M) to the HIV-1 envelope gp160, the p24 core protein, and the p66 reverse transcriptas e, but not to the 120 glycosilated env protein. They also bound to bet a-galactosidase (K(d) approximately 10(-7) M), tetanus toxoid, and var ious self antigens. In contrast, the natural mAb selected for binding to beta-galactosidase (mAb207.F1) was monoreactive, in that it bound w ith a high affinity (K(d) < 10(-8) M) to this antigen, but to none of the other antigens tested, including HIV-1. Structural analysis of the V(H) and V(L) segments revealed that the natural mAb utilized three s egments of the V(H)IV gene family and one of the V(H)III family, in co njunction with V(L) segments of the V(lambda)I, V(lambda)II, V(lambda) III, or V(chi)IV subgroups. In addition, the natural mAb V(H) and V(L) segments were in unmutated or virtually unmutated (germline) configur ation, including those of the monoreactive mAb207.F1 to beta-galactosi dase, and were identical or closely related to those utilized by speci fic autoantibodies or specific antibodies to viral and/or bacterial pa thogens. Thus, the present data show that both polyreactive and monore active natural antibodies to foreign antigen can be isolated from the normal human B cell repertoire. They also suggest that the V(H) and V( L) segments of not only polyreactive but also monoreactive natural ant ibodies can be encoded in unmutated or minimally mutated genes, and po ssibly provide the templates for the specific high affinity antibodies elicited by self or foreign antigens.