Co-delivered PD-L1 rescues the protective efficacy mediated by an AAV-expressed HIV-1 bNAb

Kuipa, M.; Koroma, A. A.; Leguizamo, I.; Dhole, P.; Barot, Y.; Lee, M. Y.- H.; Tharp, G. K.; Liang, S.; Chouinard, M.; Ehnert, S.; Weissman, S.; Whitehead, C.; Stammen, R. L.; Wood, J. S.; Curran, E. H.; Machiah, D.; Dessasau, E. D.; Nishimura, Y.; Xie, J.; Gao, G.; Verma, S.; Kulpa, D. A.; Moore, I. N.; Bosinger, S. E.; Gardner, M. R.

doi:10.64898/2026.05.29.728706

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bioRxiv · 10.64898/2026.05.29.728706

Co-delivered PD-L1 rescues the protective efficacy mediated by an AAV-expressed HIV-1 bNAb

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Abstract

Adeno-associated virus (AAV)-delivered anti-HIV-1 broadly neutralizing antibodies (bNAbs) could prevent and treat HIV-1 infection but are limited by host immune responses, specifically anti-drug antibodies (ADA). We tested whether PD-L1-mediated immune shielding could improve the consistency of AAV-delivered bNAb expression from muscle tissue in rhesus macaques. AAV9.PD-L1 co-delivery with AAV9.3BNC117 reduced the occurrence of ADA and T cell responses and improved the durability of 3BNC117 expression for one year post administration. Importantly, 5 of 6 macaques that received co-delivered AAV9.PD-L1 vectors were protected against ten repeated SHIVAD8-EO challenges. Histopathological and spatial transcriptomic profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation, muscle injury, and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a strategy to prolong transgene expression from muscle-directed AAV-delivered biologics.

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Kuipa, M., Koroma, A. A., Leguizamo, I., Dhole, P., Barot, Y., Lee, M. Y.- H., Tharp, G. K., Liang, S., Chouinard, M., Ehnert, S., Weissman, S., Whitehead, C., Stammen, R. L., Wood, J. S., Curran, E. H., Machiah, D., Dessasau, E. D., Nishimura, Y., Xie, J., Gao, G., Verma, S., Kulpa, D. A., Moore, I. N., Bosinger, S. E., Gardner, M. R.. 2026-06-01. Co-delivered PD-L1 rescues the protective efficacy mediated by an AAV-expressed HIV-1 bNAb. https://doi.org/10.64898/2026.05.29.728706

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