Protein Scaffold and Expression Level Determine Antiviral Activity of Membrane-Anchored Antiviral Peptides

Hermann, Felix; Martinius, Holger; Egelhofer, Marc; Giroglou, Tsanan; Tonn, Torston; Roth, Stefanie; Zahn, Roland; Schult-Dietrich, Patricia; Alexandrov, A.; Dietrich, Ursula; Baum, Christopher F.; Laer, Dorothee von

doi:10.1089/hgt.2006.158

Cited by 2 publications

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“…The enhanced green fluorescent protein (eGFP) encoding vector pHR9MSIN.cPPT‐SEW (M420) has been described previously . Vesicular stomatitis virus‐G pseudotyped lentiviral particles were produced by transient triple transfection of 293T cells with calcium phosphate and titrated on PM1 cells .…”

Section: Methodsmentioning

confidence: 99%

Comparison of three humanized mouse models for adoptive T cell transfer

Volk

Hartmann

Muik

et al. 2012

The Journal of Gene Medicine

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Background Humanized mouse models for adoptive T cell transfer are important for preclinical efficacy and toxicity studies. However, common xenograft models using immunodeficient mice have so far failed to efficiently support the homing of human T cells to secondary lymphoid tissues. Methods We established a new mouse model for the adoptive transfer of genetically‐modified (gm) T cells using conditioned BALB/c mice. Conditioning involved cyclophosphamide injections, lethal irradiation and radioprotection with bone marrow from immunodeficient mice. We compared repopulation kinetics and the quality of grafts in these modified Trimera (mT3) mice with immunodeficient BALB/c Rag2−/− interleukin (IL)2 receptor gamma (rg) knockout (DKO) and NOD/LtSz‐scid IL2rg−/− (NSG) recipient mouse strains. Results DKO mice showed only marginal engraftment until onset of graft‐versus‐host disease, whereas mT3 and NSG were repopulated with comparable kinetics. However, T cell repertoire and human cytokine profiles suggest a xenoreactivity‐driven gm T cell expansion in mT3 mice, whereas NSG mice were characterized by an initial homeostatic proliferation. Morphological analysis revealed high levels of human gm T cell infiltration in the spleen and liver of all three mouse strains. However, mT3 mice provided the strongest homing of human gm T cells to mucosal sites. Additionally, mT3 mice were the only model with macroscopically visible superficial inguinal lymph nodes. These lymph nodes strongly supported the homing of gm T cells. Conclusions In the present study, we give proof‐of‐concept that wild‐type mice can accept gm T cell grafts while providing secondary lymphoid structures. Despite limitations, mT3 mice are a valid alternative for applications that specifically rely on improved secondary lymphoid structures. Copyright © 2012 John Wiley & Sons, Ltd.

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Section: Methodsmentioning

confidence: 99%

Comparison of three humanized mouse models for adoptive T cell transfer

Volk

Hartmann

Muik

et al. 2012

The Journal of Gene Medicine

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

Hermann

Egerer

Brauer

et al. 2009

J Virol

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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.

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Protein Scaffold and Expression Level Determine Antiviral Activity of Membrane-Anchored Antiviral Peptides

Cited by 2 publications

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Comparison of three humanized mouse models for adoptive T cell transfer

Comparison of three humanized mouse models for adoptive T cell transfer

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

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