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Viruses 2013, 5(11), 2898-2919; doi:10.3390/v5112898
Article

Development of Hematopoietic Stem Cell Based Gene Therapy for HIV-1 Infection: Considerations for Proof of Concept Studies and Translation to Standard Medical Practice

1,* , 1
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1 Department of Virology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA 2 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA 3 Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
* Author to whom correspondence should be addressed.
Received: 18 October 2013 / Revised: 15 November 2013 / Accepted: 18 November 2013 / Published: 22 November 2013
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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Abstract

Over the past 15 years we have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). We propose that the expression of selected RNA-based HIV-1 inhibitors in the CD4+ cells derived from GM-HSPC will protect them from HIV-1 infection and results in a sufficient immune repertoire to control HIV-1 viremia resulting in a functional cure for HIV-1/AIDS. Additionally, it is possible that the subset of protected T cells will also be able to facilitate the immune-based elimination of latently infected cells if they can be activated to express viral antigens. Thus, a single dose of disease resistant GM-HSPC could provide an effective treatment for HIV-1+ patients who require (or desire) an alternative to lifelong antiretroviral chemotherapy. We describe herein the results from several pilot clinical studies in HIV-1 patients and our strategies to develop second generation vectors and clinical strategies for HIV-1+ patients with malignancy who require ablative chemotherapy as part of treatment and others without malignancy. The important issues related to stem cell source, patient selection, conditioning regimen and post-infusion correlative studies become increasingly complex and are discussed herein.
Keywords: HIV-1; stem cells; gene therapy; non-ablative conditioning; transplantation HIV-1; stem cells; gene therapy; non-ablative conditioning; transplantation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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DiGiusto, D.L.; Stan, R.; Krishnan, A.; Li, H.; Rossi, J.J.; Zaia, J.A. Development of Hematopoietic Stem Cell Based Gene Therapy for HIV-1 Infection: Considerations for Proof of Concept Studies and Translation to Standard Medical Practice. Viruses 2013, 5, 2898-2919.

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