HIV Vaccine Development

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Areas of Investigation
Our laboratory focuses on developing new and improved HIV vaccines. This work began in 1984 at Genentech and continues to this day. In 2009, the results of the RV144 clinical trial were published, which showed that immunization with a vaccine invented in our laboratory, AIDSVAX B/E, provided partial protection when combined with another vaccine named vCP1521.

Significance
The RV144 study, involving more than 16,000 Thai volunteers, was the first to show that vaccination could, in fact, prevent HIV infection. Development of a successful vaccine to protect against HIV infection would make a major impact on the worldwide spread of this deadly retroviral epidemic.

Approaches
We are trying to understand the basis of the protective immune response observed in the RV144 trial and developing improved HIV vaccine antigens to achieve even higher levels of protection. Our vaccines target the HIV envelope proteins, gp120 and gp41, that are expressed on the surface of HIV virions. These proteins are responsible for binding to cell-surface receptors and for fusion with the plasma membrane. Our vaccines are designed to stimulate broadly neutralizing antibodies (bNAbs) that neutralize viruses by interfering with receptor-binding and fusion events. HIV has evolved a number of immune escape mechanisms that reduce the immunogenicity of epitopes recognized by bNAbs. One such mechanism is conformational masking, whereby the epitopes recognized by bNAbs are exposed only after receptor binding. Currently, our laboratory is focused on identifying mutations that overcome conformational masking and expose epitopes that are normally concealed. Another immune escape mechanism involves the incorporation of protease cleavage sites at or near epitopes recognized by bNAbs. These new cleavage sites may serve to ensure that the epitopes recognized by bNAbs are rapidly degraded before the immune system can mount an effective response. We are attempting to inactivate these protease cleavage sites to create vaccine antigens more resistant to proteolysis in vivo. Finally, we continue to analyze viruses and immune responses in subjects from Thailand who participated in HIV vaccine trials. In particular, we are analyzing viral evolution and host-immune responses in a cohort of injection drug users who became infected through needle sharing. This unique sample population allows us to study the impact of host genetics on the evolution of viruses and immune responses in different individuals who became infected with the same virus inoculum at the same time.