Project Summary / Abstract This proposal describes the framework of a DP1 grant for Alejandro B. Balazs, PhD. Dr. Balazs is currently an assistant professor at Harvard Medical School and a principal investigator at the Ragon Institute of MGH, MIT & Harvard. Dr. Balazs' research is focused on engineering the immune system via gene transfer as a novel means of creating protection against infectious disease. This proposal represents an entirely new research direction for his laboratory and is focused on the creation of vectors capable of producing multi-specific polyclonal antibodies in vivo which can neutralize both the highly-mutable HIV-1 virus as well as addictive substances. These will test the hypothesis that engineered polyclonal immune responses can permanently suppress HIV-1 infection more effectively than separate antibodies. The proposal aims to test this concept by first comparing multiple designs of vectors engineered to produce multi-specific antibodies that can both neutralize HIV in a series of cell-based assays. Designs with optimal activity will advance to testing in both mouse and non-human primate models to identify those with maximal expression potential in vivo. Optimal designs will be tested in animal models of HIV- infection. These experiments aim to determine whether polyclonal engineered immune responses can more effectively control HIV replication than multiple individual antibodies while resisting the emergence of escape mutants to achieve a functional cure of HIV infection in people with substance use disorders. Such a finding would have profound implications for treatment of HIV in the context of substance use disorder offering an improved therapeutic intervention against HIV, particularly for people who are unable to comply with existing antiretroviral drug regimens. Moreover, this technology will also test the development of a single therapeutic intervention targeting both HIV and addictive substances, to improve health outcomes for people living with HIV with underlying substance use disorders, consistent with the mission of NIDA and the NIH.