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Journal of Virology, October 2009, p. 10075-10084, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01700-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Small Molecule Targets Env for Endoplasmic Reticulum-Associated Protein Degradation and Inhibits Human Immunodeficiency Virus Type 1 Propagation {triangledown}

Alenka Jejcic,1 Robert Daniels,2 Laura Goobar-Larsson,1 Daniel N. Hebert,2 and Anders Vahlne1*

Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, SE-141 86, Sweden,1 Department of Biochemistry and Molecular Biology, Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, Massachusetts 010032

Received 10 August 2008/ Accepted 16 July 2009

Human immunodeficiency virus type 1 (HIV-1) is dependent on its envelope glycoprotein (Env) to bind, fuse, and subsequently infect a cell. We show here that treatment of HIV-1-infected cells with glycyl-prolyl-glycine amide (GPG-NH2), dramatically reduced the infectivity of the released viral particles by decreasing their Env incorporation. The mechanism of GPG-NH2 was uncovered by examining Env expression and maturation in treated cells. GPG-NH2 treatment was found to affect Env by significantly decreasing its steady-state levels, its processing into gp120/gp41, and its mass by inducing glycan removal in a manner dependent on its native signal sequence and the proteasome. Therefore, GPG-NH2 negatively impacts Env maturation, facilitating its targeting for endoplasmic reticulum-associated protein degradation, where Env is deglycosylated en route to its degradation. These findings illustrate that nontoxic drugs such as GPG-NH2, which can selectively target glycoproteins to existing cellular degradation pathways, may be useful for pathogen therapy.

* Corresponding author. Mailing address: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, SE-141 86, Sweden. Phone: 46 8 5858 1313. Fax: 46 8 5858 7933. E-mail: anders.vahlne{at}ki.se

{triangledown} Published ahead of print on 29 July 2009.

Journal of Virology, October 2009, p. 10075-10084, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01700-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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