Lack of induction of antibodies specific for conserved, discontinuous epitopes of HIV-1 envelope glycoprotein by candidate AIDS vaccines

We examined the humoral immune response in both HIV-1 infected and uninfected volunteers immunized with candidate HIV-1 recombinant envelope subunit vaccines (Genentech gp120(IIIB), MicroGeneSys gp160(IIIB), or ImmunoAG gp160(IIIB)). Immunization of both HIV-1 infected and uninfected volunteers with these immunogens resulted in the induction of Abs preferentially reactive with epitopes accessible on a denatured form of gp120. While sera from HIV-1 uninfected gp120/gp160(IIIB) vaccinees bound gp120/gp41, which was expressed on the surface of H9 cells infected with HIV- 1(IIIB), minimal binding to HIV-1(MN) or HIV-1(RF) infected cells was obtained. Induction of qualitatively similar immune responses by these immunogens would not have been predicted based on their different tertiary structures. These data indicate a restriction of the immune response to linear, conserved epitopes poorly accessible on both monomeric gp120 and cell-surface expressed oligomeric gp120/gp41 and a lack of Abs specific for conformational epitopes conserved across divergent HIV-1 strains. Poor recognition of HIV-1 envelope tertiary and quaternary structure may explain the restricted neutralization profiles of vaccinee sera against laboratory- adapted strains of HIV-1 and their inability to neutralize primary HIV-1 isolates. Alternate immunogens or reformulations with the capacity to elicit Abs that preferentially bind to natively folded gp120 should be investigated and correlated with their ability to neutralize more diverse laboratory- adapted and primary HIV-1 isolates.