THE V3-DIRECTED IMMUNE-RESPONSE IN NATURAL HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION IS PREDOMINANTLY DIRECTED AGAINST A VARIABLE, DISCONTINUOUS EPITOPE PRESENTED BY THE GP120 V3 DOMAIN

The specific binding of antibodies to the V3 loop in sera from human i mmunodeficiency type 1 (HIV-1)infected individuals was investigated. D ifferent V3 structures were analyzed as full-length loops or by pepsca n, Our data show that on full-length V3 loops, both variable regions o n either side of the tip of the loop (GPGRAF) contribute to a common e pitope for type-specific antibodies, Type-specific antibodies bound st rongly and at high titers to native V3 loops but negligibly once the l oop was denatured, In contrast to the type specific, discontinuous epi tope, the linear, conserved epitopes presented by the full-length V3 l oop, the tip, the amino-terminal base, and the carboxy-terminal base w ere not accessible to serum antibody, When the V3 sequences were analy zed with linear peptides, antibodies bound preferentially to peptides containing the conserved GPGRAF sequence. Thus, two different specific ities of V3-directed antibodies were detected in patient sera. Unlike group-specific antibodies directed against GPGRAF peptides, lack of ty pe-specific antibodies directed against the discontinuous epitope was correlated with viral escape from autologous neutralization. Our data suggest that the full-length conformation of the V3 loop is accessible predominantly to highly type specific antibodies present in sera from HIV-1-infected individuals. These antibodies are directed against dis continuous V3 epitopes, not against conserved linear V3 targets, The i mplications of these findings for viral escape and blockade of infecti on with V3-based vaccines are discussed.