Biology subjects

Barot, Y.

Publications and source records attributed to Barot, Y..

3 recordsLinked to original sources

bioRxiv2026

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

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.

immunology↗

bioRxiv2026

Overcoming host immune responses to an AAV-delivered HIV-1 bNAb in rhesus macaques mediated by co-delivery of PD-L1

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.

immunology↗

bioRxiv2026

Characterization of expression elements for an AAV delivered antibody in nonhuman primates when co-delivered with PD-L1

Successful AAV-expressed antibody therapy for HIV-1 requires broadly neutralizing antibody (bNAbs) concentrations and reduced immune responses to sustain viral suppression without ART. We have previously demonstrated that co-delivery of AAV-expressed PD-L1 reduces immune responses against HIV-1 bNAbs in rhesus macaques. Here we systematically evaluated six AAV9 transgene cassettes encoding 10-1074 with different promoter/intron combinations (CMV, CMV/R, CBA, CASI, CB7, EF1) across in vitro systems, immune-deficient mice, and in rhesus macaques. We show that both promoter and species selection, leads to differences in 10-1074 concentrations with the CB7 promoter leading to greatest expression in mice and CMV/R promoter in macaques. In addition to differences observed, loss of 10-1074 serum concentrations in macaques resulted in higher anti-drug antibody responses and antigen specific IFN-y T cell responses were focused on the 10-1074 heavy-chain variable region. Furthermore, inclusion of the WPRE greatly impacted 10-1074 expression leading to higher concentrations in both mice and nonhuman primates. Lastly, circulating 10-1074 in macaques retained neutralizing activity against diverse HIV-1 pseudovirus isolates. Together these results demonstrate how expression elements influence AAV-expressed antibodies in the context of co-delivery and highlight the need for further improvements to AAV transgene cassettes when co-delivered with AAV expressed PD-L1.

microbiology↗