Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells.
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.
Daniel
René
R
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
Marusich
Elena
E
Argyris
Elias
E
Zhao
Richard Y
RY
Skalka
Anna Marie
AM
Pomerantz
Roger J
RJ
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*
D018797:Cell Cycle Proteins; D002110:Caffeine