Single peptide and anti-idiotype 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 type 1 (HIV-1) external envelope glycoprotein gp120 is a major target of neutralizing antibodies in infected persons and in experimental immunized animals. Given the high degree of sequence variability of V3, the humoral response toward this region is very type-specific. In the present 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 determinant 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. The extent of this cross-reactivity, which tended to enlarge as the injections increased, appeared to be inversely correlated with the binding affinity to V3MN peptide. These data thus present evidence that, despite its great sequence heterogeneity, the V3 loop encompasses conserved amino-acid positions and/or stretches which may be less immunogenic than their variable counterparts. We additionally demonstrate that a rabbit anti-idiotype (Ab2), recognizing a binding site related idiotype on a V3-specific mouse monoclonal antibody (Ab1), could mount a broadened humoral response (Ab3) in mice. Unlike nominal antibody Ab1 which strictly reacted with the European HIV-1 LAI isolate, elicited Ab3 recognized the two divergent HIV-1 strains SF2 and 1286, originating respectively from North America and Central Africa, in addition to LAI. The reasons accounting for this Ab2-induced enlargement of the V3 antibody 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.