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Induction of Cell-Cycle Arrest in Cervical Cancer Cells by the Human Immunodeficiency Virus Type 1 Viral Protein R

From the Departments of Obstetrics and Gynecology, Microbiology and Immunology, Biochemistry, and Medicine, University of Rochester Cancer Center, Rochester, New York

Address reprint requests to: Vicente Planelles, PhD, Departments of Medicine and Microbiology and Immunology, University of Rochester Cancer Center, 601 Elmwood Avenue, Box #704, Rochester, NY 14642, E-mail: vicente_planelles{at}urmc.rochester.edu

Objective: To determine the ability of the human immunodeficiency virus type 1 (HIV-1) gene vpr to induce cell-cycle arrest in cervical cancer cells with or without human papillomavirus (HPV) type 16 E6 or E7 expression.

Methods: High- and low-level expression vectors for vpr (designated pVPR_HIGH and pVPR_LOW, respectively) were used in conjunction with HPV-16 E6 or E7 vectors to transfect HPV-negative C33A cervical cancer cells. Vpr expression vectors encode a cell surface marker gene, murine Thy-1, for specific detection of transfected cells. Dual staining for the surface molecule Thy-1 and DNA content was used to determine cell-cycle profile and G₂-phase arrest.

Results: C33A cells not expressing HPV-16 E6 showed some but not maximal G₂-phase arrest when transfected with pVPR_HIGH alone (43.2% of cells in the phase). Addition of HPV-16 E6 or E6 plus E7 to pVPR_HIGH substantially increased the percentages of cells in the G2 phase (51.3% and 53.0%, respectively). Cotransfection with pVPR_HIGH and HPV-16 E7 did not increase significantly the

percentage of cells in the G₂ phase compared with pVPR_HIGH alone (40.6% versus 43.2%). In transfections involving pVPR_LOW, a slight degree of G₂-phase arrest was observed when Vpr was expressed alone (29.0% of cells in the G₂ phase) or in cotransfection with HPV-16 E7 (33.2% of cells), and G₂-phase arrest was augmented with the addition of HPV-16 E6 (41.7%) or E6 plus E7 (45.7%).

Conclusion: Cervical cancer cells are susceptible to cell-cycle arrest induced by HIV-1 vpr. This effect is exacerbated by coexpression of HPV-16 E6, although E6 alone is incapable of inducing any detectable G₂-phase arrest, suggesting that E6 and VPR share links in cell-cycle signaling pathways.

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