Cell-based therapy for HIV brain reservoirs: glial progenitors delivering broadly neutralizing antibodies

Objective Despite the success of combination antiretroviral therapy (cART) in suppressing HIV replication, viral reservoirs persist in a latent state in resting memory CD4+ T-cells, lymphoid tissue and spleen, as well as in glia within the central nervous system (CNS), necessitating lifelong treatment. Persistent viral reservoirs in the brain are partly due to limited drug penetration across the blood–brain barrier, which contributes to HIV-associated neurocognitive disorders. To address this challenge, we developed a regenerative, cell-based strategy for sustained, localized delivery of broadly neutralizing antibodies (bNAbs) within the brain. Method Mouse glial progenitor cells (mGRPs) were genetically engineered to express and secrete a near pan-neutralizing anti-HIV bNAb targeting the conserved CD4-binding site of gp120. Results Engineered mGRPs retained progenitor viability and phenotype while producing antibodies that bound gp120 and neutralized up to 97% of HIV pseudovirus in vitro. Following intracerebral transplantation or minimally invasive intra-arterial administration, mGRPs survived, migrated across the blood–brain barrier, and engrafted within brain parenchyma, without evidence of immune rejection. In vivo, locally released bNAbs effectively bound gp120-expressing target cells within the CNS. Conclusion These findings establish proof-of-concept for glial progenitors as living bioreactors capable of sustained biologic delivery. Notably, current data for the detection of mGRPs is limited to seven days post-implantation. Continuation of this study by longitudinal follow-up will provide a greater understanding of long-term cell survival and functionality. This approach offers a complementary strategy to systemic cART, with the potential to suppress viral persistence, reduce neuroinflammation, and advance toward a durable functional cure for HIV.