The changing face of HIV vaccine research

Abstract

While there has been remarkable progress in understanding the biology of HIV-1 and its recognition by the human immune system, we have not yet developed an efficacious HIV-1 vaccine. Vaccine challenges include the genetic diversity and mutability of HIV-1 which create a plethora of constantly changing antigens, the structural features of the viral envelope glycoprotein that disguise conserved receptor-binding sites from the immune system, and the presence of carbohydrate moieties that shield potential epitopes from antibodies. Despite these challenges, there has been significant scientific progress in recent years. In 2009, a large-scale clinical trial known as RV144 demonstrated that a HIV-1 vaccine could modestly reduce the incidence of HIV-1 infection. Further, the identification of broadly neutralizing monoclonal antibodies (such as VRC01, a human monoclonal antibody capable of neutralizing over 90% of natural HIV-1 isolates, as well as PG and PGT antibodies that recognize conserved glycopeptide epitopes) has revealed new opportunities for vaccine design. Our ability to understand HIV-1 structure and antibody epitopes at the atomic level, the rapid advance of computational and bioinformatics approaches to immunogen design, and our newly acquired knowledge that it is possible for a vaccine to reduce the risk of HIV-1 infection, have all opened up new and promising pathways towards the development of an urgently needed effective HIV-1 vaccine. This article summarizes challenges to the development of an HIV-1 vaccine, lessons learned from scientific investigation and completed vaccine trials, and promising developments in HIV-1 vaccine design.

Figure 1

Broadly neutralizing antibodies against HIV-1. The VRC01 antibody is capable of near pan-neutralization of HIV-1, which it achieves by recognition of the initial contact site of the CD4 receptor on HIV-1 gp120. (a) Neutralization dendrogram of VRC01. Strains of HIV-1 are displayed according to their genetic distance and coloured red, green and black according to their sensitivity to neutralization by VRC01 (Reproduced with permission from AAAS; Wu et al. [23]). (b) Recognition by VRC01. The surface of the gp120 glycoprotein is coloured grey for inner domain, red for outer domain and blue for bridging sheet region. The initial contact surface for CD4 is highlighted by yellow cross-hatching, and the recognition surface of VRC01 is shown in green. Note the concordance between VRC01 recognition and CD4 contact (Reproduced with permission from AAAS; Zhou et al. [26]).

Figure 2

Maturation of broadly neutralizing HIV-1 immunity. VRC01-like antibodies mature from the human VH1-2*02 germline (grey ribbon at left) and acquire over 50 somatic mutations while evolving to effectively recognize HIV-1 gp120 (red ribbon at right). The gp120-interactive surface of antibody VRC01 corresponds to the “top” of the domain in this orientation, with the binding surface for the light chain, on the surface facing the reader. Shown are variable heavy chain domains from three lineages of maturing antibodies (green, orange and yellow), with somatic mutations in each lineage highlighted in amino acid-surface representation coloured according to lineage, with fully saturated colours corresponding to charged changes and less saturated colours corresponding to hydrophobic changes.