Rational design of vaccines for AIDS and influenza

Abstract

Successful immunization against challenging infectious diseases requires novel approaches to vaccine design. To control diseases of high human health impact such as AIDS and influenza by vaccination requires an understanding of the mechanisms of viral entry and identification of highly conserved vulnerable regions of the virus to which immune responses are not normally directed. Structural biology has provided important information about the three-dimensional organization and chemical structure of the HIV-1 and influenza glycoproteins. By harnessing structural biology, monoclonal antibody specificity, genomics, and informatics, we have been able to define neutralizing antibodies of exceptional breadth and potency against circulating strains of HIV-1, and we have begun to develop immunogens to elicit such antibodies. Similarly, for influenza, understanding of this target has led to structural and genetic approaches to the development of new immunogens that provide a proof of concept for universal influenza vaccination.

Fig. 1

Structure of the HIV-1 Envelope viral glycoprotein. A ribbon diagram representation of the stabilized core region of the gp120 subunit from the HIV-1 viral spike depicts its molecular geography, including an outer domain (red), inner domain (gray) and bridging sheet (blue). Adapted by permission from Macmillan Publishers Ltd. (3)

Fig. 2

Resurfaced stabilized core HIV-1 Env proteins define antibodies to the CD4 binding site and serve as prototype vaccines. Modification of surface exposed residues of the HIV-1 Env (left) and substitution with divergent amino acids (red) allow development of a defined protein (right) that can be used to analyze sera and isolate monoclonal antibodies, as well as a prototype that can serve as an immunogen to elicit similar antibody responses. Reprinted from Figure 2 of (1) with permission from The Royal Society, 6-9 Carlton House Terrace, London SW1Y 5AG, United Kingdom.

Fig. 3

Molecular representation of the influenza virus spike and two highly conserved regions of vulnerability. The spike is composed of a trimeric HA with an upper (head) and lower (stem) region that together are required for entry into respiratory tract cells. The location of the highly conserved sites in the receptor binding region and stem are highlighted (yellow).