Restricted Specificity of Anti-V3 Antibodies Induced in Humans by HIV Candidate Vaccines

Abstract

We analyzed the fine specificity of anti-V3 antibodies elicited in three different species (human, guinea pig, and macaque) by various HIV candidate vaccines. Following immunization with recombinant canarypox virus expressing gp160MN or with recombinant gp160MN/LAI, this antibody response was shown to be directed against the NH2-terminal region of the V3 loop. Although this response was increased by a prime-boost regimen using immunization with canarypox expressing gp160 followed by an rgp160 boost, its specificity remained restricted mainly to the recognition of this region of the V3 loop. Pepscan analysis of sera confirmed the results obtained by ELISA and allowed the definition of an immunodominant common binding site for these sera located within the sequence NKRKRIHIGPGR. In contrast to these results, a boost with the V3 peptide was shown to broaden the antibody response and pepscan analysis showed that sera from individuals boosted with the V3 synthetic peptide recognize determinants all along the V3 loop. Similar fine specificity of anti-V3 antibodies was obtained in human, guinea pig, and macaque following immunization by a prime-boost regimen using canarypox recombinants expressing gp160 or gp120 and purified rgp160. In contrast, a V3 synthetic peptide boost stimulated the production of antibodies that recognize multiple epitopes within the V3 loop. Because the induction of antibodies that recognize multiple sites in the V3 loop could be of major importance to neutralize different HIV isolates, these results may have implications for the design and selection of HIV candidate vaccines.

Neutralizing activity of antibodies to the V3 loop region of HIV-1 gp120 relative to their epitope fine specificity

“…For example, it has been shown that isolate-specific V3 responses in subtype B- and D-infected individuals are directed to residues located in the stem segments of the V3 loop (Lawoko et al, 2000; Schreiber et al, 1997) and weakly neutralizing serum antibody responses to V3 in individuals immunized with recombinant gp160 are preferentially directed to the N-terminal stem of V3 (Coeffier et al, 1997). Furthermore, in a recent study seeking to elicit 447-52D-like NAbs by utilizing fusion proteins containing the 447-52D contact epitope 305 KSIHIGPGRAFYTT 320 (Chakraborty et al, 2006), immune sera seemed to require for binding the N-terminal segment of the engrafted motif and neutralized the generally-sensitive virus MN but not the more resistant viruses BaL or JR-FL.…”

Structural Prerequisites for Intersubtype B and D Antigenicity of the Third Variable Envelope Region (V3) of Human Immunodeficiency Virus Type 1

“…In chimpanzees, candidate gp160 vaccines induce anti-V3 antibody responses that are largely restricted to the aminoterminal half of the immunizing loop [12]. When such animals are boosted with synthetic V3 peptides, however, the anti-V3 antibody repertoire broadens.…”

Comparative studies on neutralisation of primary HIV-1 isolates by human sera and rabbit anti-V3 peptide sera

“…Yet one study demonstrated that a near total depletion of IgG antibody to the V3 region (measured in peptide EIA) from HIV-1 positive sera affected only minimally the capacities of the sera to neutralise primary isolates, thereby questioning the whole concept of V3 as an important epitope for neutralisation of HIV-1 in vivo [Vancott et al, 1995]. Nevertheless, there is a vast literature on V3 epitopes, which can either be broadly reactive [Javaherian et al, 1990;Blomberg et al, 1993;Cheingsong-Popov et al, 1994], or isolate specific [Boudet et al, 1996;Coeffier et al, 1997]. Isolate specific V3 epitopes are located mainly in the N-terminal half of the loop.…”