This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hermann, F. G. Articles by von Laer, D. Search for Related Content PubMed PubMed Citation Articles by Hermann, F. G. Articles by von Laer, D.

 Previous Article  |  Next Article 

Journal of Virology, May 2009, p. 4844-4853, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.00666-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mutations in gp120 Contribute to the Resistance of Human Immunodeficiency Virus Type 1 to Membrane-Anchored C-Peptide maC46 ^,

Felix G. Hermann,¹ Lisa Egerer,¹ Frances Brauer,¹ Christian Gerum,² Harald Schwalbe,² Ursula Dietrich,¹ and Dorothee von Laer^1*

Georg Speyer Haus, Paul Ehrlich Strasse 42-44, 60596 Frankfurt am Main, Germany,¹ Institut für Organische Chemie und Chemische Biologie, Zentrum für Biomolekulare Magnetische Resonanz, Johann Wolfgang Goethe Universität, Max von Laue Strasse 7, 60438 Frankfurt am Main, Germany²

Received 26 March 2008/ Accepted 24 February 2009

Binding of the human immunodeficiency virus (HIV) envelope glycoprotein (Env) to the cellular CD4 receptor and a chemokine coreceptor initiates a series of conformational changes in the Env subunits gp120 and gp41. Eventually, the trimeric gp41 folds into a six-helix bundle, thereby inducing fusion of the viral and cellular membranes. C peptides derived from the C-terminal heptad repeat (CHR) of gp41 are efficient entry inhibitors as they block the six-helix bundle formation. Previously, we developed a membrane-anchored C peptide (maC46) expressed from a retroviral vector that also shows high activity against virus strains resistant to enfuvirtide (T-20), an antiviral C peptide approved for clinical use. Here, we present a systematic analysis of mutations in Env that confer resistance of HIV type 1 (HIV-1) to maC46. We selected an HIV-1 BaL strain with 10-fold reduced sensitivity to maC46 (BaL_C46) by passaging virus for nearly 200 days in the presence of gradually increasing concentrations of maC46. In comparison to wild-type BaL, BaL_C46 had five mutations at highly conserved positions in Env, three in gp120, one in the N-terminal heptad-repeat (NHR), and one in the CHR of gp41. No mutations were found in the NHR domain around the GIV motif that are known to cause resistance to enfuvirtide. Instead, maC46 resistance was found to depend on complementary mutations in the NHR and CHR that considerably favor binding of the mutated NHR to the mutated CHR over binding to maC46. In addition, resistance was highly dependent on mutations in gp120 that accelerated entry. Taken together, resistance to maC46 did not develop readily and required multiple cooperating mutations at conserved positions of the viral envelope glycoproteins gp120 and gp41.

---

* Corresponding author. Mailing address: Georg Speyer Haus, Paul Ehrlich Strasse 42-44, 60596 Frankfurt am Main, Germany. Phone: 49 172 4069569. Fax: 49 69 63395297. E-mail: Laer{at}em.uni-frankfurt.de

Published ahead of print on 11 March 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

---

Journal of Virology, May 2009, p. 4844-4853, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.00666-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.