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We aim to develop an hematopoietic stem cell (HSC) gene therapy approach for the prevention and control of HIV-1 infection. Toward this goal, we engineered helper-dependent adenovirus (HDAd) 6/3+ vectors to directly transduce HSCs , enabling progeny cells to secrete eCD4-Ig, a decoy protein that broadly neutralizes HIV/simian immunodeficiency virus (SIV) isolates by mimicking the primary viral receptor CD4 and coreceptors such as CCR5. In rhesus macaques, the HDAd 6/3+ platform achieved long-term expression of an enhanced eCD4-Ig variant ("eCD4-Ig-Emm06") that retained potent neutralization efficacy . Transduced HSCs differentiated into lymphoid and myeloid lineages and trafficked to systemic tissues, with B cells emerging as a major source of eCD4Ig-Emm06. HDAd-eCD4Ig-Emm06-treated animals had significantly reduced splenic viral reservoirs, and the animal with the highest circulating levels of eCD4Ig-Emm06 exhibited fewer founder viruses, delayed onset to viremia, and lower plasma viral loads, demonstrating promise within this proof-of-concept study. Further improvements in protective efficacy may be achieved through approaches identified in this study, including lineage-specific expression, reduced immunogenicity, and efficient selection. These findings validate HDAd 6/3+ as a promising platform for durable gene-based delivery of biologic therapeutics and guide advancement of HSC gene therapy for HIV and other chronic infections.