SINGLE PEPTIDE AND ANTIIDIOTYPE BASED IMMUNIZATIONS CAN BROADEN THE ANTIBODY-RESPONSE AGAINST THE VARIABLE V3 DOMAIN OF HIV-1 IN MICE

The third variable (V3) domain of the human immunodeficiency virus typ e 1 (HIV-1) external envelope glycoprotein gp120 is a major target of neutralizing antibodies in infected persons and in experimental immuni zed animals. Given the high degree of sequence variability of V3, the humoral response toward this region is very type-specific. In the pres ent study, we evaluated the potential of a single peptide and an anti- idiotypic antibody to broaden the anti-V3 antibody specificity in BALB /c mice. We show that a synthetic peptide derived from the V3 determin ant of HIV-1 MN isolate (V3MN), when used as an immunogen, was able to induce an antibody response to multiple (up to six) HIV-1 strains. Th e extent of this cross-reactivity, which tended to enlarge as the inje ctions increased, appeared to be inversely correlated with the binding affinity to V3MN peptide. These data thus present evidence that, desp ite its great sequence heterogeneity, the V3 loop encompasses conserve d amino-acid positions and/or stretches which may be less immunogenic than their variable counterparts. We additionally demonstrate that a r abbit anti-idiotype (Ab2), recognizing a binding site related idiotype on a V3-specific mouse monoclonal antibody (Ab1), could mount a broad ened humoral response (Ab3) in mice. Unlike nominal antibody Abl which strictly reacted with the European HIV-1 LAI isolate, elicited Ab3 re cognized the two divergent HIV-1 strains SF2 and 1286, originating res pectively from North America and Central Africa, in addition to LAI. T he rr:asons accounting for this Ab2-induced enlargement of the V3 anti body response are discussed. Our findings suggest that single peptide and anti-idiotype based immunizations may provide viable approaches to overcome, at least in part, HIV epitope variability.