Journal of Vaccines & Vaccination

Antigenicity, structure and immunogenicity of the HIV-1 trimeric envelope glycoprotein spike

4^th International Conference on Vaccines & Vaccination

September 24-26, 2014 Valencia Convention Centre, Spain

Richard T Wyatt

Scientific Tracks Abstracts: J Vaccines Vaccin

Abstract:

The development of broadly neutralizing antibodies (bNAbs) to HIV-1 is often thought to be a key component of a successful vaccine. A common target of bNAbs is the conserved primary receptor CD4 binding site (CD4bs) on the HIV envelope glycoprotein (Env) trimeric spike. Although CD4bs-directed bNAbs have been isolated from infected individuals, elicitation of such bNAbs by Env vaccination has proven difficult. To help understand the limitations of current immunogens, we structurally characterized vaccine Env trimer-elicited CD4bs-directed non-bNAbs isolated from primates. We demonstrate that these vaccine-elicited antibodies, which cannot neutralize most circulating HIV isolates, attempt a vertical approach to the CD4bs, thereby clashing with the variable region of the trimeric spike cap. In contrast, CD4bs-directed bNAbs adopt angles of approach lateral to the viral membrane that avoid such clashes and achieve potent and broad neutralization of most HIV primary isolates. This analysis has informed our vaccine design efforts to generate more well-ordered trimers to limit routes of access to the CD4bs. We have developed new designs and methods to generate soluble, properly folded trimers that both present the conserved CD4bs and other trimer-specific, conserved quaternary epitopes on the HIV-1 spike revealed by newly discovered bNAbs. Antigenic, biophysical, structural electron microscopic and immunogenicity analysis of selected trimers will be presented, focusing on the capacity of these trimers to to elicit HIV-1 neutralizing antibodies