Autologous engraftment of immunoengineered hematopoietic stem cells for Env-targetting broad neutralizing antibodies SECTION 1: Abstract Generating humoral immunity against HIV, particularly the difficulty of eliciting broadly neutralizing antibodies (bnAbs) through conventional vaccination remains a challenge. Current approaches rely on complex immune maturation pathways that are inefficient and often impaired in immunocompromised individuals, highlighting the need for alternative strategies. The objective here is to develop a stem cell–based immunoengineering platform capable of producing long-term, self-renewing humoral immunity by genetically programming antibody specificity. The hypothesis here is that autologous hematopoietic stem cells engineered to carry predefined anti-HIV Env bnAb heavy and light chain genes will differentiate into B-cell lineages that express functional bnAb receptors, then produce the antibodies that are predefined. The first milestone will consist of the design of a construct encoding bnAb heavy and light-chain sequences, which can be gathered from scientific literature, secondly, perform CRISPR-mediated genome editing in human CD34+ hematopoietic stem and progenitor cells, and third, evaluate differentiation into B-cell progeny and expression of the engineered receptor.