Head of the Laboratory / The Rockefeller University
The Rockefeller University 1230 York Avenue New York, NY 10065
Dr. Nussenzweig studies molecular aspects of the immune system’s adaptive and innate responses, using a combination of biochemistry, molecular biology, and genetics. He is also a Howard Hughes Medical Institute investigator.
The first interest of the Nussenzweig lab is antibody maturation in germinal centers. Professor Nussenzweig’s laboratory determined that the germinal center is a dynamic environment where B cells circulate between zones of cell division and undergo somatic mutation and selection. The lab found that selection is mediated by T cell help, and that T cells dictate the amount of B cell division.
The Nussenzweig lab’s second research interest revolves around somatic mutation and the genesis of lymphoma-associated chromosome translocations. In addition to antibody gene mutation, B cells suffer off target mutations during the germinal center because AID, the enzyme that mediates mutation is not sequence specific. The Nussenzweig lab determined that the translocations that initiate many B cell cancers are the product of off target activity by AID. The lab found that AID off target genes are those regulated by super-enhancers where polymerase is delayed. This is caused by a polymerase stalling factor called Spt5.
The third research focus of the Nussenzweig lab is discovery, characterization, preclinical and clinical testing of potent HIV-neutralizing antibodies. The lab developed methods for cloning antibodies from antigen specific B cells and applied these methods to cloning HIV-1 specific antibodies. The cloning revealed that the antibodies are highly mutated, leading to the hypothesis that vaccines to elicit them will require the use of multiple sequential immunogens.
This idea was tested and proven to be correct by Nussenzweig working collaboratively as a member of the CHAVD. The cloning methods have been widely adapted and led to the discovery of broad and potent antibodies that can protect against and treat active HIV-1 infection in animal models. The lab also performed clinical studies and determined that the antibodies are safe and effective in humans, and are exploring their role for therapy and prevention in humans.