Virginia and D. K. Ludwig Professor of Biochemistry, Stanford UniversityView Slides
Developing an HIV vaccine remains an important, unanswered challenge: one in 200 people on earth are infected with HIV. In order for HIV to infect a cell, the membrane surrounding the virus needs to fuse with the membrane surrounding the cell. Our approach to HIV vaccine development is to target this membrane-fusion process.
Studies of the membrane-fusion proteins from several viruses, particularly the influenza hemagglutinin protein and the HIV-1 envelope glycoprotein, reveal a general mechanism for enveloped-virus membrane fusion. In this “spring-loaded” mechanism, a major conformational change results in the formation of a transient “pre-hairpin” intermediate in which the membrane-fusion protein spans both the viral and cellular membranes. This pre-hairpin intermediate is vulnerable to inhibition. Previously, a monoclonal antibody was identified that binds to the HIV gp-41 pre-hairpin intermediate and inhibits the replication of HIV-1 clinical isolates, providing proof-of-principle for our vaccine approach.
Because the pre-hairpin intermediate is transient, a stable mimetic is required to elicit an immune response. We have designed peptide mimetics of the gp41 pre-hairpin intermediate. The polyclonal antibody responses to these mimetics in preclinical experiments will be discussed.