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C Peptides as Entry Inhibitors for Gene Therapy

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Gene Therapy for HIV and Chronic Infections

Part of the book series: Advances in Experimental Medicine and Biology ((ASGCT,volume 848))

Abstract

Peptides derived from the C-terminal heptad repeat 2 region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very potent HIV-1 fusion inhibitors. Antiviral genes encoding either membrane-anchored (ma) or secreted (iSAVE) C peptides have been engineered and allow direct in vivo production of the therapeutic peptides by genetically modified host cells. Membrane-anchored C peptides expressed in the HIV-1 target cells by T-cell or hematopoietic stem cell gene therapy efficiently prevent virus entry into the modified cells. Such gene-protection confers a selective survival advantage and allows accumulation of the genetically modified cells. Membrane-anchored C peptides have been successfully tested in a nonhuman primate model of AIDS and were found to be safe in a phase I clinical trial in AIDS patients transplanted with autologous gene-modified T-cells. Secreted C peptides have the crucial advantage of not only protecting genetically modified cells from HIV-1 infection, but also neighboring cells, thus suppressing virus replication even if only a small fraction of cells is genetically modified. Accordingly, various cell types can be considered as potential in vivo producer cells for iSAVE-based gene therapeutics, which could even be modified by direct in vivo gene delivery in future. In conclusion, C peptide gene therapeutics may provide a strong benefit to AIDS patients and could present an effective alternative to current antiretroviral drug regimens.

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Abbreviations

AAV:

Adeno-associated virus

BCNU:

Bis-chloroethylnitrosourea

HIV-1:

Human immunodeficiency virus type 1

HPC:

Hematopoietic stem/progenitor cells

HR:

Heptad repeat

IC50 :

Inhibitory concentration 50

iSAVE:

In vivo secreted antiviral entry inhibitor

ma:

Membrane-anchored

MGMT:

O6-Methylguanine-DNA Methyltransferase

O6-BG:

O6-benzylguanine

SIN:

Self-inactivating

SIV:

Simian immunodeficiency virus

wPRE:

Woodchuck hepatitis virus posttranscriptional regulatory element

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Author information

Authors and Affiliations

  1. Division of Virology, Department of Hygiene, Microbiology and Social Medicine, Medical University of Innsbruck, Peter Mayr-Str. 4b, Innsbruck, 6020, Austria

    Lisa Egerer & Dorothee von Laer M.D.

  2. Fred Hutchinson Cancer Research Center, 19024, M/S D1-100, 1100 Fairview Ave N, Seattle, WA, 98109-1024, USA

    Hans-Peter Kiem M.D., Dr.med.

Authors
  1. Lisa Egerer
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  2. Hans-Peter Kiem M.D., Dr.med.
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  3. Dorothee von Laer M.D.
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Correspondence to Dorothee von Laer M.D. .

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Editors and Affiliations

  1. University of Amsterdam, Amsterdam, The Netherlands

    Ben Berkhout

  2. The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Hildegund C.J. Ertl

  3. University of the Witwatersrand, Johannesburg, South Africa

    Marc S. Weinberg

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© 2015 American Society of Gene and Cell Therapy

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Egerer, L., Kiem, HP., von Laer, D. (2015). C Peptides as Entry Inhibitors for Gene Therapy. In: Berkhout, B., Ertl, H., Weinberg, M. (eds) Gene Therapy for HIV and Chronic Infections. Advances in Experimental Medicine and Biology(), vol 848. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2432-5_10

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