The Interaction between the Fiber Knob Domain and the Cellular Attachment Receptor Determines the Intracellular Trafficking Route of Adenoviruses

Adenovirus 5 vector genetically re-targeted by an Affibody molecule with specificity for tumor antigen HER2/neu

“…47 In addition to cellular binding, the fiber and its knob domain have been suggested to carry several functions important for intracellular trafficking, membrane lysis and virus maturation. [20][21][22][23][24][25] Fiber content of FibDCAR-HI-Link-ZHZH viruses was 12-29% of WT, which is an improvement from earlier studies where knobless virions have had fiber content of 2-10%. 10 Another improvement of Ad5/FibDCAR-HI-Link-ZHZH was the PP-to-PFU ratio, which was 140, as compared to 70 for the WT virus.…”

“…12,40 These growth defects can be explained by a low-fiber content caused by the lack of the fiber knob hampering virus entry and intracellular trafficking and a loss of other growth -or viral assembly functions carried by the fiber knob. [20][21][22][23][24][25] Only in the de-knobbed virus Ad5/R7-C2C2, containing the Ig binding C2 domain from Streptococcal protein G, we found a normal fiber content indicating that this fiber somehow compensates, as far as fiber content of the virus is concerned, for the loss of the fiber knob. 40 Therefore, a novel approach was also employed in the present study.…”

“…10,12 The poor performance of viruses with de-knobbed fibers is due to the fact that the knob has other important functions in the life cycle of the virus than just binding to the cellular receptor. [20][21][22][23][24][25] These facts make such viruses difficult to use for gene therapeutic purposes.…”

Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells

“…Shayakhmetov et al 40 demonstrated that a fiber-substituted Ad vector containing the Ad35 fiber protein showed an intracellular trafficking pattern different from that of a conventional Ad5 vector. Replication of a chimeric CRAd possessing the fiber knob of Ad serotype-3, which belongs to species-B, was enhanced in multiple steps, including nuclear transport of the virus genome and E1A transcription, compared with a conventional CRAd.…”

Chick embryo lethal orphan virus can be polymer-coated and retargeted to infect mammalian cells

“…Miyazawa et al 50 demonstrated that the intracellular trafficking of Ad7 (subgroup B virus), which accumulates in late endosomes and Ad5 (subgroup C virus), which rapidly escapes early endosomes, varies due to differences in fibre structure involved in triggering pH-dependent membrane lysis and endosomal escape. More recently, Shayakhmetov et al 51 demonstrated that virus binding of the chimeric Ad5/35L vector (an Ad5 vector expressing Ad35 fibre knob domains) to the Ad35 receptor caused the virus to remain in late endosomes for longer resulting in a large proportion being recycled back to the surface and ultimately less transgene expression than Ad5. Adenoviruses are susceptible to neutralization from preexisting immunity present in the majority of the human population limiting their use for systemic delivery.…”