HIV-1 immunogen design
HIV-1, the causative agent of AIDS has on its surface a protein called envelope (env). Env is a trimeric glycoprotein in which each monomer consists of two non-covalently associated subunits gp120 and gp41. This protein binds to a receptor molecule called CD4 that is found on cells in the immune system. Env is responsible for the entry of virus into these cells. Most antibodies in people infected with HIV are directed against the env protein. Antibodies which can prevent viral entry into cells are called neutralizing antibodies. However, very few antibodies in HIV infected people are neutralizing and many of them react with segments exposed only in unfolded or misfolded viral env protein molecules. The low stability of the env protein coupled with the high mutation rate of the virus are two important reasons for the difficulty in producing an effective HIV vaccine. Conventional approaches of using inactivated or weakened virus as a vaccine cannot be used for HIV because humans do not naturally develop immunity to the virus.
Our laboratory is attempting to stabilize env through mutation, fragment design and nanoparticle display. The idea is that such molecules (called immunogens), when injected into small animals, will result in the production of neutralizing antibodies that will bind to conserved structures present on the surface of HIV and therefore block viral entry into immune cells. Potential immunogens are first characterized biophysically. In collaborative studies, these immunogens are next injected into small animals and the resulting sera are characterized for neutralizing activity. In recent collaborative work with the Amara lab at Emory, one of our immunogens, in combination with a viral vector prime, was shown to protect rhesus macaques against pathogenic viral challenge. Finding immunogens capable of generating neutralizing antibodies is a particularly difficult and challenging problem which must be overcome if an HIV vaccine is to become a reality.