Engineered B cells to prevent and control viral infections

The National Institute of Allergy and Infectious Diseases awarded The Children's Hospital Corporation (Boston Children's Hospital) $159,300 on September 2, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop engineered B cells that prevent and control viral infections, beginning with HIV-1.

The research develops a scarless method to engineer B cells to express human broadly neutralizing antibodies (BNAbs) against HIV-1. The work preserves key B-cell activities in vivo, including affinity maturation—the ability to generate higher-affinity antibody variants through competition for access to antigens. Aim 1 tests whether B cells expressing human BNAbs protect against HIV-like virus challenge and can adaptively control established infection, and whether engineered B cells accelerate decay of the viral reservoir compared to standard antiretroviral therapy. Aim 2 furthers enhancement of the engineered B-cell platform.

Place of performance is Boston, Massachusetts. The period of performance runs through August 31, 2028. The award is a Project Grant, the standard NIH research grant mechanism for investigator-initiated biomedical research.

Abstract

B cells secrete antibodies that neutralize viruses and help clear infected cells. Each B cell expresses a unique B-cell receptor (BCR), a membrane-associated form of an antibody, which is diversified through somatic hypermutation (SHM). Higher affinity BCR variants are then selected by competition for access to antigens. This process of affinity maturation is central to our adaptive humoral response to vaccines and pathogens. B cells and antibodies work closely with other immune system cells, including phagocytes, T cells, and natural killer cells to coordinate a response to pathogens. The importance of B cells to our immune responses to pathogens has motivated efforts to engineer B cells to express new bcrs. These engineered B cells allow new studies of immune system function and might be used in cell-based therapies. I have recently developed a new method to engineer the BCR of mouse and macaque B cells so they express HIV-1 broadly neutralizing antibodies (BNABS). Unlike earlier approaches, our method is scarless and preserves key B-cell activities in vivo, including importantly their ability to affinity mature. Affinity maturation is critical because IT reflects the overall viability and functionality of engineered B cells, and IT enables several important applications. For example, IT facilitates adaptive control of a mutating pathogen and the study of BCR evolution as IT responds to a defined antigen epitope. My goal is to develop engineered B cells to prevent and treat infectious diseases, starting with HIV-1. Thus, in aim 1, I will employ B cells that express human BNABS to protect from a challenge with an HIV-like virus. I will then use these cells to adaptively control an established infection. These studies will also test the hypothesis that engineered B cells can accelerate the decay of the viral reservoir compared to standard antiretroviral therapy. In aim 2, I will further enhance the translational potential of these engineered B cells by applying new developments in the genome-editing fields to directly edit B cells in vivo. These studies will also explore editing strategies that can limit off-target effects and the genotoxicity associated with double-stranded breaks in the chromosome. Aim 3 addresses a major limitation of current HIV-1 vaccine research. Specifically, current animal models do not express key variable (V) and diversity (D) segments that define precursors to BNABS. I will test the hypothesis that mice expressing multiple bnab precursors can usefully anticipate human B cell responses. This model will also be used to address key open questions in B-cell biology important to development of more effective vaccines. These studies will advance HIV-1 vaccine research, address key questions in vaccinology and B-cell biology, establish the foundations for new cell-based therapies, and make these therapies safer and more accessible.