Progress in the rational design of an AIDS vaccine

Abstract

Human immunodeficiency virus-1 (HIV-1) has a high degree of genetic and antigenic diversity that has impeded the development of an effective vaccine using traditional methods. We are attempting to develop an AIDS vaccine by employing strategies that include structural biology and computational modelling, in an effort to develop immunogens capable of eliciting neutralizing antibodies of the requisite breadth and potency against circulating strains of HIV-1.

Figure 1.

Structure of the HIV-1 viral spike. (a) HIV-1 viral spike. Density is shown in light blue for the cryoelectron miscroscopy tomogram of the HIV-1 spike [14]. This has been fitted with the crystal structure of the HIV-1 gp120 envelope glycoprotein [15], with N-linked glycosylation shown in cyan as space-filling spheres and polypeptide backbone displayed in ribbon representation and coloured grey for inner domain, red for outer domain and blue for bridging sheet. Sites of known vulnerability to neutralizing antibodies are labelled and highlighted with arrows. (b) HIV-1 gp120 envelope glycoprotein. A close-up for a single gp120 subunit from the spike is shown with the same colouring and representation as (a). Modelled N-linked glycan is displayed in transparent surface representation, to allow the gp120 to be visualized.

Figure 2.

Resurfaced stabilized core proteins derived from HIV-1 Env can serve as probes to define antibodies to the CD4-binding site and as prototype immunogens. By modifying surface exposed residues of the HIV-1 Env (left) and replacing them with alternative amino acids from SIV Env or other acceptable substitutions (red), it is possible to develop a defined protein (right) that can be used both for analysis of sera and as prototype immunogens.

Figure 3.

Strategy for isolation of new monoclonal antibodies based on HIV. Protein structure: rescue of antigen-specific B-cells. Selective probes (left) are labelled and used to identify B-cells that express broadly neutralizing antibodies by flow cytometry (middle). Antibodies are rescued by PCR cloning and expression (right) and analysed for their ability to mediate neutralization of diverse viral strains.