Tracking B cell:Antigen Interactions for HIV-1 Vaccine Development

Project Summary/Abstract Despite 40 years of research, no HIV-1 vaccine exists. More than 1 million people acquire HIV-1 every year and 600,000 people died in 2023 due to AIDS-related illnesses. To be effective, an HIV-1 vaccine must elicit a durable, broadly neutralizing antibody (bNAb) response that provides protection against diverse viral variants. Sequential immunization is a promising vaccination strategy for eliciting bNAbs. However, available sequential protocols have been unsuccessful at eliciting durable and high titers of bNAbs that can protect against HIV-1 infection. This proposal aims to understand how the plasma cell compartment develops during sequential immunization to inform the design of vaccines that induce long-lasting protection. Aim 1 of this proposal will use a novel, AAV- based B cell tracking technology to characterize the plasma cell compartment in the bone marrow of mice after sequential immunization. This technology tracks the antigenic history of B cells and, therefore, can provide information regarding the antigenic requirements for plasma cell development. Aim 1 will also test whether the existence of non-neutralizing plasma cells from early stages of sequential immunization inhibit the establishment of bNAb-expressing plasma cells in the bone marrow. This will deepen our understanding of how the plasma cell compartment is established and persists after HIV-1 sequential immunization. These results may be applicable to other immunization strategies that use multiple immunizations to elicit the desired antibody response. Aim 2 of this proposal seeks to uncover the mechanisms of plasma cell differentiation after immunization. B cell:antigen interactions underpin many aspects of B cell biology including activation, interaction with other lymphocytes, and selection within germinal centers. Despite its importance, it is now known how many times a B cell interacts with antigen during immunization. Aim 2 will adapt the AAV-based B cell tracking technology to quantify the number of B cell:antigen interactions a B cell experiences. In Aim 2, this approach will directly test the influence of B cell:antigen encounters on B cell fate. This will result in new information and approaches for directing B cells towards a desired fate. Altogether, this proposal will result in new knowledge about B cell fate decisions and contribute new opportunities to design immunization protocols that better elicit durable, bNAb responses for HIV- 1 vaccination.