title: Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.
abstract: The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.
authors.affiliation: The Rausing Lab, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Rebetz
authors.forename: Manli
authors.initials: M
authors.lastname: Na
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
authors.forename: Bo
authors.initials: B
authors.lastname: Holmqvist
authors.forename: Anna
authors.initials: A
authors.lastname: Edqvist
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nyberg
authors.forename: Bengt
authors.initials: B
authors.lastname: Widegren
authors.forename: Leif G
authors.initials: LG
authors.lastname: Salford
authors.forename: Hans Olov
authors.initials: HO
authors.lastname: Sjögren
authors.forename: Niklas
authors.initials: N
authors.lastname: Arnberg
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Fan
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000378:metabolism; D000818:Animals; D024201:Bystander Effect; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D011991:Receptors, Virus / Q000378:metabolism*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D011991:Receptors, Virus; C085301:adenovirus receptor