HIV-1 Env gp140 trimers elicit neutralizing antibodies without efficient induction of conformational antibodies

Abstract

Currently, no vaccine for human immunodeficiency virus (HIV-1) provides protection from virus infection. One reason for these disappointing results has been the difficulty of current vaccine candidates to elicit high-titer, broadly reactive immunity to a large number of viral proteins. Recently, our laboratory demonstrated that the coupling of C3d to a soluble trimerized HIV-1 envelope (Env gp140(FT)) elicited higher titers of neutralizing antibodies than monomers of Env gp120 coupled to C3d [Bower JF, Yang X, Sodroski J, Ross TM. Elicitation of neutralizing antibodies with DNA vaccines expressing soluble stabilized human immunodeficiency virus type 1 envelope glycoprotein trimers conjugated to C3d. J Virol 2004;78(9):4710–9]. To determine if the induction of conformational antibodies correlated with neutralization, mice (BALB/c) were primed (2×) with DNA plasmids expressing monomeric Env gp120 or trimeric Env gp140 alone or fused to mC3d 3 at one of two doses (2.0 μg or 0.2 μg), followed by a boost of recombinant uncleaved, trimeric Env gp140. Regardless of the priming dose of DNA, all mice had high-titer anti-Env IgG antibodies. Interestingly, Env gp140 trimers did not elicit higher titers of antibodies that recognized conformational Env epitopes compared to monomers of Env gp120. Therefore, additional parameters were examined for correlation with neutralization. For neutralization-resistant HIV-1 isolates, ADA and YU-2, neutralization correlated with high-titer, high avidity antibodies, with Env gp140 eliciting slightly higher neutralization titers than Env gp120. In contrast, none of the measured parameters correlated with neutralization for the more neutralization-sensitive isolates, MN or 89.6. Therefore, even though soluble, uncleaved Env gp140 trimers may be marginally more effective at eliciting neutralizing antibodies than Env gp120, neutralization does not appear to correlate with the elicitation of conformationally dependent antibodies.