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Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo
Highly active antiretroviral therapy (HAART) has greatly reduced the morbidity and mortality from HIV infection, but AIDS continues to be a serious health problem worldwide. Despite enormous efforts to develop a vaccine, there is still no cure, and alternative approaches including gene therapy shoul...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162371/ https://www.ncbi.nlm.nih.gov/pubmed/19741733 http://dx.doi.org/10.1038/gt.2009.118 |
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author | Kiem, Hans-Peter Wu, Robert A. Sun, Guihua von Laer, Dorothee Rossi, John J. Trobridge, Grant D. |
author_facet | Kiem, Hans-Peter Wu, Robert A. Sun, Guihua von Laer, Dorothee Rossi, John J. Trobridge, Grant D. |
author_sort | Kiem, Hans-Peter |
collection | PubMed |
description | Highly active antiretroviral therapy (HAART) has greatly reduced the morbidity and mortality from HIV infection, but AIDS continues to be a serious health problem worldwide. Despite enormous efforts to develop a vaccine, there is still no cure, and alternative approaches including gene therapy should be explored. Here we developed and compared combinatorial foamy virus (FV) anti-HIV vectors that also express a mutant methylguanine methyltransferase (MGMTP140K) transgene to increase the percentage of gene modified cells after transplantation. These FV vectors inhibit replication of HIV-1 and also the simian immunodeficiency virus/HIV-1 (SHIV) chimera that can be used in monkey AIDS gene therapy studies. We identified a combinatorial FV vector that expresses 3 anti-HIV transgenes and inhibits viral replication by over 4 logs in a viral challenge assay. This FV anti-HIV vector expresses an HIV fusion inhibitor and two shRNAs targeted to HIV-1 tat and rev, and can be produced at high titer (3.8×10(7) transducing units/ml) using improved helper plasmids suitable for clinical use. Using a competitive repopulation assay, we show that human CD34(+) cells transduced with this combinatorial FV vector efficiently engraft in a mouse xenotransplantation model, and that the percentage of transduced repopulating cells can be increased after transplantation. |
format | Online Article Text |
id | pubmed-3162371 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
record_format | MEDLINE/PubMed |
spelling | pubmed-31623712011-08-26 Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo Kiem, Hans-Peter Wu, Robert A. Sun, Guihua von Laer, Dorothee Rossi, John J. Trobridge, Grant D. Gene Ther Article Highly active antiretroviral therapy (HAART) has greatly reduced the morbidity and mortality from HIV infection, but AIDS continues to be a serious health problem worldwide. Despite enormous efforts to develop a vaccine, there is still no cure, and alternative approaches including gene therapy should be explored. Here we developed and compared combinatorial foamy virus (FV) anti-HIV vectors that also express a mutant methylguanine methyltransferase (MGMTP140K) transgene to increase the percentage of gene modified cells after transplantation. These FV vectors inhibit replication of HIV-1 and also the simian immunodeficiency virus/HIV-1 (SHIV) chimera that can be used in monkey AIDS gene therapy studies. We identified a combinatorial FV vector that expresses 3 anti-HIV transgenes and inhibits viral replication by over 4 logs in a viral challenge assay. This FV anti-HIV vector expresses an HIV fusion inhibitor and two shRNAs targeted to HIV-1 tat and rev, and can be produced at high titer (3.8×10(7) transducing units/ml) using improved helper plasmids suitable for clinical use. Using a competitive repopulation assay, we show that human CD34(+) cells transduced with this combinatorial FV vector efficiently engraft in a mouse xenotransplantation model, and that the percentage of transduced repopulating cells can be increased after transplantation. 2009-09-10 2010-01 /pmc/articles/PMC3162371/ /pubmed/19741733 http://dx.doi.org/10.1038/gt.2009.118 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Kiem, Hans-Peter Wu, Robert A. Sun, Guihua von Laer, Dorothee Rossi, John J. Trobridge, Grant D. Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo |
title | Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo |
title_full | Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo |
title_fullStr | Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo |
title_full_unstemmed | Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo |
title_short | Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo |
title_sort | foamy combinatorial anti-hiv vectors with mgmtp140k potently inhibit hiv-1 and shiv replication and mediate selection in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162371/ https://www.ncbi.nlm.nih.gov/pubmed/19741733 http://dx.doi.org/10.1038/gt.2009.118 |
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