title: Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells.
abstract: Caffeine is an efficient inhibitor of DNA repair and DNA damage-activated checkpoints. We have shown recently that caffeine inhibits retroviral transduction of dividing cells, most likely by blocking postintegration repair. This effect may be mediated at least in part by a cellular target of caffeine, the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. In this study, we present evidence that caffeine also inhibits efficient transduction of nondividing cells. We observed reduced transduction in caffeine-treated growth-arrested cells as well as caffeine-treated terminally differentiated human neurons and macrophages. Furthermore, this deficiency was observed with a human immunodeficiency virus type 1 (HIV-1) vector lacking Vpr, indicating that the effect is independent of the presence of this viral protein in the infecting virion. Finally, we show that HIV-1 transduction of nocodazole-arrested cells is reduced in cells that express an ATR dominant-negative protein (kinase-dead ATR [ATRkd]) and that the residual transduction of ATRkd-expressing cells is relatively resistant to caffeine. Taken together, these data suggest that the effect(s) of caffeine on HIV-1 transduction is mediated at least partly by the inhibition of the ATR pathway but is not dependent on the caffeine-mediated inhibition of cell cycle checkpoints.
authors.affiliation: Thomas Jefferson University, Division of Infectious Diseases and Environmental Medicine, Department of Medicine, JAH Suite 321, 1020 Locust St., Philadelphia, PA 19107, USA. Rene.Daniel@jefferson.edu
authors.forename: René
authors.initials: R
authors.lastname: Daniel
authors.forename: Elena
authors.initials: E
authors.lastname: Marusich
authors.forename: Elias
authors.initials: E
authors.lastname: Argyris
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Zhao
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Skalka
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Pomerantz
mesh_terms: D002110:Caffeine / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D005822:Genetic Vectors; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D014161:Transduction, Genetic; D016662:Virus Integration / Q000187:drug effects*
chemical_list: D018797:Cell Cycle Proteins; D002110:Caffeine