THE ROLE OF SOMATIC MUTATION IN THE GENERATION OF THE PROTECTIVE HUMORAL IMMUNE-RESPONSE AGAINST VESICULAR STOMATITIS-VIRUS

During most clinically relevant infections with cytopathic viruses, ne utralizing antibodies are generated early, i.e., within the first week of infection, As early as 4 days after immunization of mice with vesi cular stomatitis virus (VSV), a cytopathic virus closely related to ra bies virus, hybridomas could be isolated that secreted virus-neutraliz ing IgGs. Such antibodies were devoid of somatic mutations, showed hig h binding avidities (similar to 10(9) M(-1)), and used V gene fragment s predominantly belonging to the V(H)Q52 and V(K)19-28 families. In co ntrast, most secondary and hyperimmune response IgGs isolated 12 and 1 50 days after infection used several additional V gene combinations. T hese, which used the V(H)Q52/V(K)19-28 combination of early IgGs, were point mutated but showed only marginally enhanced binding avidities. Since all V(H)Q52/V(K)19-28-positive IgGs bound to one subsite within the major antigenic site of VSV-G irrespective of the presence or abse nce of somatic point mutations, fine specificity diversification of se condary and hyperimmune responses was achieved by newly appearing V ge ne combinations.