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Journal of Virology, April 2005, p. 4774-4781, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4774-4781.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus (HIV) gp41 Escape Mutants: Cross-Resistance to Peptide Inhibitors of HIV Fusion and Altered Receptor Activation of gp120

Emmanuel Desmezieres,¹ Nidhi Gupta,¹ Russell Vassell,¹ Yong He,¹ Keith Peden,¹ Lev Sirota,² Zhongning Yang,³ Paul Wingfield,⁴ and Carol D. Weiss^1*

Division of Viral Products,¹ Division of Biostatistics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration,² Protein Expression Lab, National Institute of Arthritis and Musculoskeletal Diseases, National Institutes of Health, Bethesda,⁴ 12 Lodge Place, Rockville, Maryland³

Received 28 September 2004/ Accepted 3 December 2004

Human immunodeficiency virus (HIV) infects cells by fusing with cellular membranes. Fusion occurs when the envelope glycoprotein (Env) undergoes conformational changes while binding to cellular receptors. Fusogenic changes involve assembly of two heptad repeats in the ectodomain of the gp41 transmembrane subunit to form a six-helix bundle (6HB), consisting of a trimeric N heptad repeat (N-HR) coiled-coil core with three antiparallel C heptad repeats (C-HRs) that pack in the coiled-coil grooves. Peptides corresponding to the N-and C-HRs (N and C peptides, respectively) interfere with formation of the 6HB in a dominant-negative manner and are emerging as a new class of antiretroviral therapeutics for treating HIV infection. We generated an escape mutant virus with resistance to an N peptide and show that early resistance involved two mutations, one each in the N- and C-HRs. The mutations conferred resistance not only to the selecting N peptide but also to C peptides, as well as other types of N-peptide inhibitors. Moreover, the N-HR mutation altered sensitivity to soluble CD4. Biophysical studies suggest that the 6HB with the resistance mutations is more stable than the wild-type 6HB and the 6HB formed by inhibitor binding to either wild-type or mutant C-HR. These findings provide new insights into potential mechanisms of resistance to HIV peptide fusion inhibitors and dominant-negative inhibitors in general. The results are discussed in the context of current models of Env-mediated membrane fusion.

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* Corresponding author. Mailing address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-466, Bldg. 29, Room 532, 8800 Rockville Pike, Bethesda, MD 20892-4555. Phone: (301) 402-3190. Fax: (301) 496-1810. E-mail: cdweiss{at}helix.nih.gov.

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Journal of Virology, April 2005, p. 4774-4781, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4774-4781.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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