The Number of Toll-Like Receptor 9-Agonist Motifs in the Adenovirus Genome Correlates with Induction of Dendritic Cell Maturation by Adenovirus Immune Complexes

Abstract

Adenovirus serotype 5 (Ad5) vectors and specific neutralizing antibodies (NAbs) generate immune complexes (ICs) which are potent inducers of dendritic cell (DC) maturation. Here we show that ICs generated with rare Ad vector serotypes, such as Ad26 and Ad35, which are lead candidates in HIV vaccine development, are poor inducers of DC maturation and that their potency in inducing DC maturation strongly correlated with the number of Toll-like receptor 9 (TLR9)-agonist motifs present in the Ad vector's genome. In addition, we showed that antihexon but not antifiber antibodies are responsible for the induction of Ad IC-mediated DC maturation.

Unabated Adenovirus Replication following Activation of the cGAS/STING-Dependent Antiviral Response in Human Cells

“…Recent reports identified serotype-specific innate immune responses in the in vivo murine model (16). Suggestions that differences in immune potency correlate with genome sequence have been made (42). Our data indicate that serotypic differences in the entry and presentation of viral genomes to the cGAS PRR have a major impact on the IRF3/IFN/ISG response in human cell lines.…”

“…Phospho-IRF3 dimerizes and translocates to the nucleus (31,32), where IRF3-responsive genes, such as beta interferon (33), are transcriptionally activated. In addition to the cGAS DNA sensor, other DNA sensors (IFI16, DDx41, and Toll-like receptor 9 [TLR9]) have been characterized as general DNA sensors contributing to type I interferon induction (17,(34)(35)(36)(37)(38)(39)(40)(41)(42). TLR9 is involved in the detection of adenovirus in murine plasmacytoid DCs (pDCs) (17,39).…”

Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

“…A number of candidate PAMPs have been suggested for adenoviruses, including virally associated RNAs (47), CpG motifs (48), and the adenoviral DNA itself (21). A key finding shown here was that STING acts as a PRR for all human rAds (rAd5, rAd28, and rAd35) and most notably chAd63.…”

Alternative Serotype Adenovirus Vaccine Vectors Elicit Memory T Cells with Enhanced Anamnestic Capacity Compared to Ad5 Vectors

“…This issue is partially circumvented with the use of more rare Ad serotypes with lower baseline vectorspecific neutralizing antibody titers (1,6). Second, since the hepatic tropism of Ad5 markedly differs from that of alternativeserotype Ads (7,46,47), these different viral vectors may trigger specific innate pathways that may affect the phenotype of adaptive immune responses (48)(49)(50)(51)(52)(53). Moreover, Ad5 uses the CAR receptor, which is highly expressed on epithelial tight junctions, liver, and red blood cells, among other cell types (54), whereas Ad26, Ad35, and Ad48 utilize the complement receptor CD46 (1,7,47,55,56), which is ubiquitously expressed on all nucleated cells (55,57).…”