Overcoming host immune responses to an AAV-delivered HIV-1 bNAb in rhesus macaques mediated by co-delivery of PD-L1
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.
Show abstract
Adeno-associated virus (AAV)-delivered anti-HIV-1 broadly neutralizing antibodies (bNAbs) have demonstrated promise for preventing and treating HIV-1 infection in preclinical models. However, host immune responses, specifically anti-drug antibodies (ADA), limit sustained bNAb expression. We have previously shown that PD-L1-mediated immune shielding improves the consistency of AAV-delivered bNAb 3BNC117 expression from muscle tissue in rhesus macaques. Here, we test the breadth of this approach with another bNAb, 10-1074. We show that AAV9.PD-L1 co-delivery with AAV9.10-1074 reduced the occurrence of ADA responses and improved the durability of bNAb expression for one year post administration. Notably 12 of 12 macaques that received AAV9.10-1074 vectors were protected against ten repeated SHIVAD8-EO challenges. Histopathological profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a broad strategy to prolong transgene expression from muscle-directed AAV-delivered biologics.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.