Elicitation of HIV Broadly Neutralizing Antibodies from Engineered B cells

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Project Summary/Abstract HIV broadly neutralizing antibodies (bnAbs) are effective against the virus, but cannot be elicited through vaccination due to genetic limitations imposed by the human repertoire of B cell antigen-receptors (BCRs). We have recently shown that mature primary B cells from wild-type mice can be engineered ex vivo to express bnAb genes as functional antigen receptors, and that these cells can be returned to the host and vaccinated to generate durable bnAb responses. Because this animal model cannot support HIV infection, therapeutic or protective efficacy of these responses have not yet been evaluated. The proposal described here: 1) Explores novel B cell targeting approaches that aim to improve how B cells are engineered and function in vivo; 2) Defines vaccine parameters and the properties of engineered cells required for reproducible elicitation of durable bnAb responses in the mouse model and; 3) Translates our successful ‘Engineered B cell Vaccine’ (EBcV) prototype to the rhesus macaque animal model for efficacy testing using chimeric HIV/SIV viruses (SHIVs). BnAbs elicited in non-human primates (NHP) will be tested for their ability to prevent heterologous tier-2 virus infection, suppress, or maintain suppression of viremia, in order to evaluate the potential for EBcVs to function as prophylactic vaccines or as an HIV functional cure. Such an approach may have significant advantages over other gene therapy strategies that aim to durably secrete bnAbs from muscle or liver cells. When elicited from modified B cells, bnAb responses should be: 1) able to mature in affinity in response to a rapidly evolving pathogen; 2) increase titers in the presence of antigen; 3) be expressed as all effector isotypes; 4) tolerated by the immune system because they originate from B cells and; 5) subject to tolerance mechanisms that should inactivate the cells expressing them if they are harmful. All studies designed in this proposal support our long-term goal, the development of safe, effective and economically feasible ‘Engineered B cell vaccines’ that would generate durable HIV bnAb responses from genome modified B cells as a strategy for prevention or HIV functional cure.