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Journal of Virology, January 2005, p. 106-115, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.106-115.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Cytoplasmic Tail Slows the Folding of Human Immunodeficiency Virus Type 1 Env from a Late Prebundle Configuration into the Six-Helix Bundle

Levon G. Abrahamyan,1 Samvel R. Mkrtchyan,1 James Binley,2 Min Lu,3 Grigory B. Melikyan,1 and Fredric S. Cohen1*

Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois,1 Torrey Pines Institute for Molecular Studies, San Diego, California,2 Department of Biochemistry, Weill Medical College of Cornell University, New York, New York3

Received 17 May 2004/ Accepted 18 August 2004

Effects of the cytoplasmic tail (CT) of human immunodeficiency virus type 1 Env on the process of membrane fusion were investigated. Full-length Env (wild type [WT]) and Env with its CT truncated ({Delta}CT) were expressed on cell surfaces, these cells were fused to target cells, and the inhibition of fusion by peptides that prevent Env from folding into a six-helix bundle conformation was measured. For both X4-tropic and R5-tropic Env proteins, {Delta}CT induced faster fusion kinetics than did the WT, and peptides were less effective at inhibiting {Delta}CT-induced fusion. We tested the hypothesis that the inhibitory peptides were less effective at inhibiting {Delta}CT-induced fusion because {Delta}CT folds more quickly into a six-helix bundle. Early and late intermediates of WT- and {Delta}CT-induced fusion were captured, and the ability of peptides to block fusion when added at the intermediate stages was quantified. When added at the early intermediate, the peptides were still less effective at inhibiting {Delta}CT-induced fusion but they were equally effective at preventing WT- and {Delta}CT-induced fusion when added at the late intermediate. We conclude that for both X4-tropic and R5-tropic Env proteins, the CT facilitates conformational changes that allow the trimeric coiled coil of prebundles to become optimally exposed. But once Env does favorably expose its coiled coil to inhibitory peptides, the CT hinders subsequent folding into a six-helix bundle. Because of this facilitation of maximal exposure and hindrance of bundle formation, the coiled coil is optimally exposed for a longer time for WT than for {Delta}CT. This accounts for the greater peptide inhibition of WT-induced fusion.

* Corresponding author. Mailing address: Department of Molecular Biophysics and Physiology, Rush University Medical Center, 1653 W. Congress Pkwy., Chicago, IL 60612. Phone: (312) 942-6753. Fax: (312) 942-8711. E-mail: fcohen{at}rush.edu.

Journal of Virology, January 2005, p. 106-115, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.106-115.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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