This proposal responds to RFA DA-22-010. Progress in the treatment of HIV is undisputed with potent combined antiretroviral therapy (cART), allowing most individuals to live relatively healthy for decades while receiving treatment. Although cART can maintain plasma HIV viral suppression to undetectable levels, discontinuation of cART invariably results in a rapid rebound of plasma viremia. cART’s inability to cure HIV is due, at least in part, to persistent HIV reservoirs, such as those in the CNS, and to the limited ability of most ARTs to cross the blood-brain barrier. In addition, because of active infection in the brain, up to 50% of those infected may develop a spectrum of cognitive, motor, and/or mood problems collectively known as HIV- Associated Neurocognitive Disorder (HAND). Our long-term goal is to control HIV replication in CNS and to treat or prevent HAND in people living with HIV (PLWH). Search for new therapeutic agents with more potency and fewer adverse effects is underway. For example, broadly HIV-neutralizing antibodies (bNAbs) are a new class of therapeutics recently recognized to eliminate viremia. Still, due to their large size, these biologics are even less likely than cART to reach the brain after systemic administration. Therefore, the tools that facilitate the effective and long-lasting administration of these potent and safe drugs to the brain are urgently needed as they can solve the challenging problem of the brain’s HIV reservoir. The goal of this proposal is to control HIV replication in the brain by sustained delivery of bNAbs.Therefore, this proposal is based on the premise that the inability of cART to inhibit HIV replication in the CNS can be overcome by a complementary strategy that provides sustained release of highly efficacious bNAbs in the brain. Accordingly, we hypothesize that sustained release of genetically-encoded HIV bNAbs in the brain by ex vivo engineered and transplanted glial progenitor cells (GRPs) can suppress HIV replication and decrease HIV-induced neuropathogenesis. We assembled an interdisciplinary team with expertise in (i) modeling HIV in mice; (ii) developing HIV bNABs; (iii) stem cell-based therapy and genetic engineering of stem cells; (iv) image-guided intraarterial injection for global cell delivery to the brain. In our preliminary work, we have shown that intra-arterially delivered GRPs can cross the blood-brain barrier, potentially serving as carriers for local production of HIV bNAbs in brain parenchyma. The main advantage of using GRPs in our proposed studies is their robust engraftment, differentiation towards oligodendrocytes and astrocytes, and persistence in the brain for months and even years after transplantation. Thus, it will meet the need for long-lasting effects elicited by bNABs to prevent HIV replication in the CNS and may help eradicate the CNS reservoir of HIV. Overall, we propose an innovative cell-based strategy that addresses poor drug penetration across the blo...