This Article Full Text (PDF) Other Versions of this Article: JVI.01212-06v1 80/21/10407    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zimmerman, E. S. Articles by Planelles, V. Search for Related Content PubMed PubMed Citation Articles by Zimmerman, E. S. Articles by Planelles, V.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.01212-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

"HIV-1 Vpr induces DNA replication stress in vitro and in vivo"

Division of Cellular Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132; The Gladstone Institute of Virology and Immunology, San Francisco, CA 94158; The Positive Health Program, San Francisco General Hospital, San Francisco, CA 94110; Program in Human Molecular Biology and Genetics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132

^* To whom correspondence should be addressed. Email: vicente.planelles{at}path.utah.edu.

	Abstract

The human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) causes cell cycle arrest in G₂. Vpr-expressing cells display the hallmarks of certain forms of DNA damage, specifically activation of the Ataxia telangiectasia-mutated and Rad3-related kinase, ATR. However, evidence that Vpr function is relevant in vivo, or in the context of viral infection is still lacking. In the present study, we demonstrate that HIV-1 infection of primary, human CD4+ lymphocytes causes G₂ arrest in a Vpr-dependent manner, and that this response requires ATR, as shown by RNA interference. The event leading to ATR activation in CD4+ lymphocytes is the accumulation of replication protein A (RPA) in nuclear foci, an indication that Vpr likely induces stalling of replication forks. Primary macrophages are refractory to ATR activation by Vpr, a finding that is consistent with the lack of detectable ATR, Rad17 and Chk1 protein expression in these nondividing cells. These observations begin to explain the remarkable resilience of macrophages to HIV-1-induced cytopathicity. To study the in vivo consequences of Vpr function, we isolated CD4+ lymphocytes from HIV-1-infected individuals and interrogated the cell cycle status of anti p24^Gag immunoreactive cells. We report that infected cells in vivo display an aberrant cell cycle profile whereby a majority of cells have a 4n DNA content, consistent with the onset of G₂ arrest.

This article has been cited by other articles:

• DeHart, J. L., Bosque, A., Harris, R. S., Planelles, V. (2008). Human Immunodeficiency Virus Type 1 Vif Induces Cell Cycle Delay via Recruitment of the Same E3 Ubiquitin Ligase Complex That Targets APOBEC3 Proteins for Degradation. J. Virol. 82: 9265-9272 [Abstract] [Full Text]  
• DeHart, J. L., Planelles, V. (2008). Human Immunodeficiency Virus Type 1 Vpr Links Proteasomal Degradation and Checkpoint Activation. J. Virol. 82: 1066-1072 [Full Text]  
• Schrofelbauer, B., Hakata, Y., Landau, N. R. (2007). HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1. Proc. Natl. Acad. Sci. USA 104: 4130-4135 [Abstract] [Full Text]