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J. Biol. Chem., Vol. 277, Issue 50, 48816-48826, December 13, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/50/48816    most recent M207982200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yao, X.-J. Articles by Cohen, E. A. Search for Related Content PubMed PubMed Citation Articles by Yao, X.-J. Articles by Cohen, E. A. Social Bookmarking                      What's this?

Genetic Selection of Peptide Inhibitors of Human Immunodeficiency Virus Type 1 Vpr^*

Xiao-Jian Yao, Julie Lemay, Nicole Rougeau, Martin Clément^§, Steve Kurtz^¶, Pierre Belhumeur, and Éric A. Cohen

From the Laboratoire de Rétrovirologie Humaine, Département de Microbiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada and ^¶ Northwest Neurologic Inc., Portland, Oregon 97210

Human immunodeficiency virus 1 (HIV-1) encodes a gene product, Vpr, that facilitates the nuclear uptake of the viral pre-integration complex in non-dividing cells and causes infected cells to arrest in the G₂ phase of the cell cycle. Vpr was also shown to cause mitochondrial dysfunction in human cells and budding yeasts, an effect that was proposed to lead to growth arrest and cell killing in budding yeasts and apoptosis in human cells. In this study, we used a genetic selection in Saccharomyces cerevisiae to identify hexameric peptides that suppress the growth arrest phenotype mediated by Vpr. Fifteen selected glutathione S-transferase (GST)-fused peptides were found to overcome to different extents Vpr-mediated growth arrest. Amino acid analysis of the inhibitory peptide sequences revealed the conservation of a di-tryptophan (diW) motif. DiW-containing GST-peptides interacted with Vpr in GST pull-down assays, and their level of interaction correlated with their ability to overcome Vpr-mediated growth arrest. Importantly, Vpr-binding GST-peptides were also found to alleviate Vpr-mediated apoptosis and G₂ arrest in HIV-1-producing CD4⁺ T cell lines. Furthermore, they co-localized with Vpr and interfered with its nuclear translocation. Overall, this study defines a class of diW-containing peptides that inhibit HIV-1 Vpr biological activities most likely by interacting with Vpr and interfering with critical protein interactions.

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