Protective efficacy of AAV-expressed bNAbs co-delivered with PD-L1

ABSTRACT: Adeno-associated virus (AAV)-delivered anti-HIV-1 broadly neutralizing antibodies (bNAbs) have demonstrated promise for preventing1-8 and treating HIV-1 infection in preclinical models9,10. However, host immune responses, specifically anti-drug antibodies (ADA), limit sustained bNAb expression11-17. Here, we tested whether PD-L1-mediated immune shielding could improve the consistency of AAV-delivered bNAb expression from muscle tissue in rhesus macaques. We show that AAV9.PD-L1 co-delivery with AAV9.10-1074 or AAV9.3BNC117 reduced the occurrence of ADA responses and improved the durability of bNAb expression for one year post administration. Macaques with sustained serum bNAb concentrations were protected against ten repeated SHIVAD8-EO challenges. In macaques that received AAV9.PD-L1 vectors, we observed reduced inflammation in muscle tissue harvested over one year post-AAV administration. In contrast, in macaques that did not receive AAV9.PD-L1, we detected greater severity of inflammation including the formation of tertiary lymphoid structures (TLSs), which was associated with higher ADA responses and diminished serum bNAb concentrations. Furthermore, spatial transcriptomics confirmed TLS gene signatures, along with muscle fibrosis signatures, when AAV9.PD-L1 was not administered. These findings uncover a role for local immune activation in sustaining ADA and promoting muscle deterioration. Thus, an immune shielding approach could serve as an optimal strategy to prolong transgene expression from muscle-directed AAV-delivered biologics.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE314035 | GEO | 2026/08/11

REPOSITORIES: GEO