Development of prophylactic vaccines against HIV-1

Abstract

The focus of most current HIV-1 vaccine development is on antibody-based approaches. This is because certain antibody responses correlated with protection from HIV-1 acquisition in the RV144 phase III trial, and because a series of potent and broad spectrum neutralizing antibodies have been isolated from infected individuals. Taken together, these two findings suggest ways forward to develop a neutralizing antibody-based vaccine. However, understanding of the correlates of protection from disease in HIV-1 and other infections strongly suggests that we should not ignore CTL-based research. Here we review recent progress in the field and highlight the challenges implicit in HIV-1 vaccine design and some potential solutions.

Figure 1

Model of HIV-1 envelope glycoprotein gross structure and broadly neutralizing antibody binding surfaces. The functional HIV-1 envelope glycoproteins are made up of two subunits, the outer (surface) receptor binding subunit gp120, and the membrane-spanning, fusion-mediating subunit, gp41. The viral envelope is represented in beige, and the intraviral portion of gp41 is not represented. These subunits are non-covalently linked into a trimer of heterodimers. Glycans are not shown, but there are on average 25 N-linked glycan sites that represent 50% of the total mass of gp120. Broadly neutralizing monoclonal antibody epitope clusters are represented as follows: the gp120 CD4 binding surface (green); an epitope cluster of at the tip of the trimer that depends upon conservation of Env quaternary folding (mauve); the gp120 epitope cluster of glycopeptide-reactive antibodies (pink); the gp41 membrane proximal external region (MPER) cluster (blue). The antibodies listed are non-exhaustive examples of a growing collection. Broadly neutralizing antibodies isolated pre-2009 are lettered in grey, post-2009 in black.