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Journal of Virology, September 2007, p. 8878-8890, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00122-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Vpr Cytopathicity Independent of G₂/M Cell Cycle Arrest in Human Immunodeficiency Virus Type 1-Infected CD4⁺ T Cells

Diane L. Bolton and Michael J. Lenardo^*

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892

Received 18 January 2007/ Accepted 30 May 2007

The mechanism of CD4⁺ T-cell depletion in human immunodeficiency virus type 1 (HIV-1)-infected individuals remains unknown, although mounting evidence suggests that direct viral cytopathicity contributes to this loss. The HIV-1 Vpr accessory protein causes cell death and arrests cells in the G₂/M phase; however, the molecular mechanism underlying these properties is not clear. Mutation of hydrophobic residues on the surface of its third alpha-helix disrupted Vpr toxicity, G₂/M arrest induction, nuclear localization, and self-association, implicating this region in multiple Vpr functions. Cytopathicity by virion-delivered mutant Vpr protein correlated with G₂/M arrest induction but not nuclear localization or self-association. However, infection with whole virus encoding these Vpr mutants did not abrogate HIV-1-induced cell killing. Rather, mutant Vpr proteins that are impaired for G₂/M block still prevented infected cell proliferation, and this property correlated with the death of infected cells. Chemical agents that inhibit infected cells from entering G₂/M also did not reduce HIV-1 cytopathicity. Combined, these data implicate Vpr in HIV-1 killing through a mechanism involving inhibiting cell division but not necessarily in G₂/M. Thus, the hydrophobic region of the third alpha-helix of Vpr is crucial for mediating G₂/M arrest, nuclear localization, and self-association but dispensable for HIV-1 cytopathicity due to residual cell proliferation blockade mediated by a separate region of the protein.

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* Corresponding author. Mailing address: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Rm. 11N311, 10 Center Dr., Bethesda, MD 20892-1892. Phone: (301) 496-6753. Fax: (301) 402-8350. E-mail: lenardo{at}nih.gov

Published ahead of print on 6 June 2007.

Present address: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

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Journal of Virology, September 2007, p. 8878-8890, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00122-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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