期刊
JOURNAL OF VIROLOGY
卷 80, 期 21, 页码 10407-10418出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01212-06
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资金
- NCI NIH HHS [R01 CA045234] Funding Source: Medline
- NIAID NIH HHS [K08 AI001866, R01 AI049057] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007464] Funding Source: Medline
The human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) causes cell cycle arrest in G(2). 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 G, 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 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)-immunoreactivecells. 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.
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