Passive administration of antibodies is an important treatment for select infectious diseases, cancers, and inflammatory diseases. While direct engagement of the target epitope by the antibody is important for a therapeutic effect, secondary effects on both the innate and adaptive immune responses, including T and B cell responses may be important in obtaining the maximal benefit. HIV-1 immunotherapy with a potent, broadly neutralizing human monoclonal antibody to HIV-1 that targets the CD4 binding site on the viral envelope spike (3BNC117) impacts host serum antibody responses in viremic subjects. Untreated controls showed little change in their serum IgG HIV-1 neutralizing activity over a six-month period. In comparison to that, 14/15 patients receiving an infusion of 3BNC117 demonstrated increases in their serum IgG responses to heterologous tier 2 viruses. Despite these observations, and similar ones in the field of cancer immunotherapy, no molecular analysis has been performed to account for these ?vaccine-like, or vaccinal? effects of antibody infusion. T cell help is required for T-dependent B cell responses, in this proposal, we will molecularly and phenotypically analyze if and what B and T cell responses are induced after broadly neutralizing antibody therapy. This could inform our therapeutic strategies and provide important insights into the development of effective combination therapies and/or HIV-1 vaccines. I am currently an Instructor of Clinical Investigation and a graduate student in the Laboratory of Molecular Immunology with Michel Nussenzweig at The Rockefeller University. My overall career ambition is to become an independent investigator and an expert in steering immune responses to the benefit of humans. For this my goal is to establish a research program using novel techniques on clinical samples to make observations at a systems level, and then to dissect mechanisms underlying those observations at the cellular and molecular levels. I am particularly interested, at present, in identifying how therapeutic antibody treatment influences the host immune response, to identify, in the future ideal combination therapies that could improve the therapeutic effects. My plan for transition to independence is detailed in the attached application. Briefly, during the K phase of the award I will complete my PhD and clinical master training (anticipated date: summer 2017), I will complete projects in progress of aim 1, I will expand my technical, leader and mentoring skills and submit research manuscripts for publication. Importantly, with the current proposal I will lay the grounds for hypothesis driven research questions for my future career. I will identify and apply for independent research positions with an anticipated start date in 2017 or 2018. In the R00 phase I will integrate the techniques I have learned, initiate my own clinical trials, submit research manuscripts and apply for funding (R01, R03), as well as the NIH New Innovator Award.
The main barrier to prevent HIV-1 infection is the absence of a vaccine that provides broad protection against antigenically distinct viruses. Broadly neutralizing antibody therapy used in recent HIV-1 clinical trials induced a serological immune response in treated infected patients. T cell help is required for T-dependent B cell responses, in this proposal we will molecularly and phenotypically analyze if and what B and T cell responses are induced after broadly neutralizing antibody therapy.
