alexa Gene Therapy Using a Secreted Single Chain Variable Fragment Targeting CCR5 to Inhibit HIV Infection
ISSN: 1948-5964

Journal of Antivirals & Antiretrovirals
Open Access

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Research Article

Gene Therapy Using a Secreted Single Chain Variable Fragment Targeting CCR5 to Inhibit HIV Infection

Alexander Falkenhagen1 , Masoud Ameli2 , Sabah Asad3 , Stanley E Read1,3 and Sadhna Joshi1,2*

1Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Canada

2Department of Molecular Genetics, University of Toronto, Toronto, Canada

3Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada

*Corresponding Author:
Dr. Sadhna Joshi
Department of Molecular Genetics, University of Toronto
FitzGerald Building, 150 College Street, Room 210
M5S 3E2, Toronto, Ontario, Canada
Tel: 1-416-978-2499
Fax: 1-416-978-5954
E-mail: [email protected]

Received Date: July 01, 2013; Accepted Date: August 23, 2013; Published Date: August 27, 2013

Citation: Falkenhagen A, Ameli M, Asad S, Read SE, Joshi S (2013) Gene Therapy Using a Secreted Single Chain Variable Fragment Targeting CCR5 to Inhibit HIV Infection. J Antivir Antiretrovir 5: 085-091. doi: 10.4172/jaa.1000069

Copyright: © 2013 Falkenhagen A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Interaction of R5 HIV with cellular CCR5 is mandatory for entry into host cells. The humanized monoclonal antibody PRO 140 masks cell surface CCR5 and efficiently blocks R5 HIV infection. While weekly administrations of PRO 140 have been shown to drastically reduce the viral load in patients, frequent injections of purified antibodies are neither practical nor cost-effective. Engineering gene-modified cells or tissues to secrete therapeutic proteins at sites of viral replication may advantageously replace continued drug administration. We have designed a gene encoding a secreted single chain variable fragment of PRO 140, sscFvPRO140, and have used a lentiviral vector for its delivery and expression. The sscFvPRO140 was effectively secreted from gene-modified cells, remained stable in culture supernatant at 37°C, and specifically bound to CCR5-expressing cells. Single-round infection assays were performed to assess inhibition of HIV infection. sscFvPRO140 reduced R5 HIV entry in unmodified target cells, although with a lower potency compared to what has been reported for the parent monoclonal antibody. Entry of X4 HIV, which utilizes CXCR4 as a co-receptor, remained unaltered. Furthermore, viral entry was substantially reduced when gene-modified HIV target cells expressing sscFvPRO140 were infected. Gene therapy using intracellularly active molecules, such as ribozymes or Zinc finger nucleases, only confers protection to gene-modified target cells. In contrast, the proposed gene therapy strategy based on secreted anti-HIV proteins has the potential to protect the gene-modified as well as unmodified HIV target cell populations.

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