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HIV gp120 immunogen engineering.

Following vaccination, the immune system generates a mixture of antibodies with multiple specificities to the target protein. This polyclonal response provides protection against many pathogens, but is insufficient against others like HIV. HIV mutates rapidly enough that the antibodies raised against the immunizing strain of the virus do not recognize the infecting strain, which largely explains the failure of HIV vaccines to date.

Recent research indicates that conserved sites on the HIV's protein coat are required for viral fitness, and a growing number of "broadly-neutralizing antibodies" specific for these key epitopes have been isolated from patients. Our aim is to elicit these broadly-neutralizing antibodies prophylactially via vaccination; that is, to coax the immune system into generating antibodies with a single effective specificity rather than multiple irrelevant ones.

To achieve this goal, we apply the tools of protein engineering by yeast surface display developed in the Wittrup lab to make novel gp120-based immunogens. In close collaboration with Darrell Irvine's group at MIT, we test the engineered vaccines in animal models with cutting-edge adjuvants and formulations. As part of this effort, we have developed novel tools that let us analyze the humoral response in immunized animals, and track the quantity and specificity of antibodies in real-time. The project is generously supported by a grant from the Ragon Institute of MGH, MIT and Harvard.