MOLECULAR CHARACTERIZATION OF 5 HUMAN ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ANTIBODY HEAVY-CHAINS REVEALS EXTENSIVE SOMATIC MUTATION TYPICAL OF AN ANTIGEN-DRIVEN IMMUNE-RESPONSE

We report the heavy chain variable region sequences from the cDNAs of five previously described monoclonal cell lines producing human antibodies specific for the human immunodeficiency virus type 1 and detail the molecular characteristics, germ-line origins, and extent of somatic mutation among these antibodies. Three of the five heavy chain variable regions derive from the V(H)IV gene family, but each has arisen from a different heavy chain variable region (V(H)) gene segment within the V(H)IV family. In addition, one is derived from a V(H)I gene segment, and one is derived from a V(H)V gene segment. Since four of the five antibodies arise from known germ-line V(H) elements, a precise determination of the extent of somatic variation is possible. The amount of variation from the closest germ-line sequence ranges from 4.5% to 14.8% among these antibodies, most of which is concentrated in the complementarity-determining regions. In general, the diversity (D) segments are long, characteristic of D-D fusions and/or extensive terminal deoxynucleotidyltransferase activity; however, definitive homologies cannot be found with the known germ-line D segments. Joining (J(H)) gene segment utilization appears random. The use of five different germ-line V(H) gene segments and extensive somatic mutation provides evidence that a polyclonal, antigen-driven immune response occurs during the natural infection with human immunodeficiency virus.