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Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.

Rebetz, Johan; Na, Manli LU ; Su, Changqing; Holmqvist, Bo LU ; Edqvist, Anna LU ; Nyberg, Cecilia; Widegren, Bengt LU ; Salford, Leif LU ; Sjögren, Hans Olov LU and Arnberg, Niklas, et al. (2009) In PLoS ONE 4(12).
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... (More)
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. (Less)
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PLoS ONE
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4
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12
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Public Library of Science
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  • wos:000273105200016
  • pmid:20041185
  • scopus:77954078795
ISSN
1932-6203
DOI
10.1371/journal.pone.0008484
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English
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yes
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c11878f2-83b1-4cce-84d9-6d39761e1e09 (old id 1523210)
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http://www.ncbi.nlm.nih.gov/pubmed/20041185?dopt=Abstract
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2010-01-11 14:18:44
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@article{c11878f2-83b1-4cce-84d9-6d39761e1e09,
  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.},
  articleno    = {e8484},
  author       = {Rebetz, Johan and Na, Manli and Su, Changqing and Holmqvist, Bo and Edqvist, Anna and Nyberg, Cecilia and Widegren, Bengt and Salford, Leif and Sjögren, Hans Olov and Arnberg, Niklas and Qian, Qijun and Fan, Xiaolong},
  issn         = {1932-6203},
  language     = {eng},
  number       = {12},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0008484},
  volume       = {4},
  year         = {2009},
}