Biology

Prof. Raghavan Varadarajan
Molecular Biophysics Unit, Indian Institute of Science, Bangalore

Human immunodeficiency virus 1 (HIV-1) is an important human pathogen which causes over a million deaths annually. Despite extensive efforts for several decades, we are far from an HIV-1 vaccine. The surface envelope glycoprotein of HIV-1 is composed of two polypeptide chains, gp120 and gp41, which are present on the surface of the virus as a trimer of heterodimers. gp120 remains largely exposed on the virus. However, the virus has evolved various mechanisms to evade the antibody immune response towards gp120. A very high rate of mutation, large conformational flexibility and the coverage of the surface by carbohydrates are some of the important ways by which the virus has evaded a neutralizing antibody response. The outer domain (OD) of the HIV-1 envelope glycoprotein gp120 is an important target for vaccine design since it contains a number of conserved epitopes, including a large fraction of the CD4 binding site. Structure guided design of gp120 derived immunogens that successfully elicited neutralizing antibodies will be described. Influenza is another important pathogen that can cause millions of deaths during a pandemic. In contrast to HIV-1, there are good vaccines against seasonal influenza but these need to be updated annually. In another series of studies, the design of   conserved influenza immunogens was attempted. A protein minimization approach was used to express the conserved stem domain of the influenza surface protein, hemagglutinin (HA). The resulting molecules from  H3 and H1 and H5 influenza subtypes  are highly immunogenic in mice, elicit neutralizing antibodies, and are able to confer protection to homologous and heterologous lethal challenge. Targeting the highly conserved HA stem domain with a bacterially produced immunogen is a novel vaccine strategy which may play a role in pandemic preparedness.