Variation in adenovirus receptors expression and adenovirus vector-mediated transgene expression at defined stages of the cell cycle

Michael A. Seidman, Suzanne M. Hogan, Rebecca L. Wendland, Stefan Worgall, Ronald Crystal, Philip L. Leopold

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Detailed investigations have addressed the infection pathway of recombinant adenovirus (Ad) gene transfer vectors, but little attention has been paid to the influence of cell physiology on the outcome of Ad infection. Based on observations that Ad infection of clonal cell populations show cell-to-cell variability in the extent of capsid binding, we hypothesized that the cell cycle may influence the outcome of Ad infection. To address this hypothesis, we evaluated Ad association with cells in both unsynchronized and pharmacologically synchronized cell populations. In unsynchronized cell populations, elevated Ad association with cells correlated with expression of cyclin B1, a marker of entry into the M phase of mitosis. The same analysis conducted on cell populations that were synchronized at M phase (using paclitaxel or nocodazole) or at S phase (using aphidicolin) confirmed that M phase cells bound three- to sixfold more capsid compared with unsynchronized cells, which are primarily in the G1 and G2 phases. The elevated association of vectors with cells translated into 2.5- to 4-fold greater transgene expression 24 hours after infection. Assessment of cell surface expression of Ad receptors demonstrated that both the high-affinity coxsackie-adenovirus receptor for Ad fiber protein and the low-affinity αv integrin receptor for Ad penton base protein showed increased cell surface expression at M phase (1.5-fold and 2- to 3-fold increases, respectively). These data demonstrate that Ad infection of a homogenous population of cells can vary depending on the cell cycle stage, with enhanced Ad binding and expression correlating with the enhanced expression of Ad receptors during M phase. These observations have relevance to understanding the mechanisms of gene transfer by Ad vectors and should help in the design of in vivo gene transfer strategies.

Original languageEnglish
Pages (from-to)13-21
Number of pages9
JournalMolecular Therapy
Volume4
Issue number1
DOIs
Publication statusPublished - 1 Jan 2001
Externally publishedYes

Fingerprint

Transgenes
Adenoviridae
Cell Cycle
Adenoviridae Infections
Cell Division
Population
Capsid
adenovirus receptor
Coxsackie and Adenovirus Receptor-Like Membrane Protein
Aphidicolin
Genes
Cyclin B1
Nocodazole
Cell Physiological Phenomena
G2 Phase
G1 Phase
Paclitaxel
Infection
S Phase
Mitosis

Keywords

  • Adenovirus
  • Cell cycle
  • Coxsackie-adenovirus receptor
  • Cyclin
  • Integrin
  • Mitosis
  • Nocodazole
  • Paclitaxel
  • Taxol

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Variation in adenovirus receptors expression and adenovirus vector-mediated transgene expression at defined stages of the cell cycle. / Seidman, Michael A.; Hogan, Suzanne M.; Wendland, Rebecca L.; Worgall, Stefan; Crystal, Ronald; Leopold, Philip L.

In: Molecular Therapy, Vol. 4, No. 1, 01.01.2001, p. 13-21.

Research output: Contribution to journalArticle

Seidman, Michael A. ; Hogan, Suzanne M. ; Wendland, Rebecca L. ; Worgall, Stefan ; Crystal, Ronald ; Leopold, Philip L. / Variation in adenovirus receptors expression and adenovirus vector-mediated transgene expression at defined stages of the cell cycle. In: Molecular Therapy. 2001 ; Vol. 4, No. 1. pp. 13-21.
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