Indirect detection of an epitope-specific response to HIV-1 gp120 immunization in human subjects

Abstract

A specific response of human serum neutralizing antibodies (nAb) to a conformational epitope as a result of vaccination of human subjects with the surface envelope glycoprotein (gp120) of HIV-1 has not previously been documented. Here, we used computational analysis to assess the epitope-specific responses of human subjects, which were immunized with recombinant gp120 immunogens in the VAX003 and VAX004 clinical trials. Our computational methodology--a variation of sieve analysis--compares the occurrence of specific nAb targeted conformational 3D epitopes on viruses from infected individuals who received vaccination to the occurrence of matched epitopes in the viruses infecting placebo subjects. We specifically studied seven crystallographically defined nAb targeted conformational epitopes in the V3 loop, an immunogenic region of gp120. Of the six epitopes present in the immunogens and targeted by known monoclonal neutralizing antibodies, only the one targeted by the anti-V3 nAb 2219 exhibited a significant reduction in occurrence in vaccinated subjects compared to the placebo group. This difference occurred only in the VAX003 Thailand cohort. No difference was seen between vaccinated and placebo groups for the occurrence of an epitope that was not present in the immunogen. Thus, it can be theorized that a specific 2219-like human neutralizing antibody immune response to AIDSVAX immunization occurred in the VAX003 cohort, and that this response protected subjects from a narrow subset of HIV-1 viruses circulating in Thailand in the 1990s and bearing the conformational epitope targeted by the neutralizing antibody 2219.

Figure 1. Library of signature motifs mapped to the V3 regions of AIDSVAX immunogens.

Signature motifs recognized by each monoclonal antibody are shown in the second column: the numbers indicate the recognized positions in the V3 loop and the letters indicate the amino acid residues at each position required for recognition by that monoclonal antibody. Positions numbering is in the correspondence with the standard V3 loop numbering described elsewhere , . Colored rectangles in the sequence column indicate the amino acid residues composing the signature motif in each of the gp120s. Sequences without colored rectangles do not contain a given motif.