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Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy
BACKGROUND: Unlike CD4+ T cells, HIV-1 infected macrophages exhibit extended life span even upon stress, consistent with their in vivo role as long-lived HIV-1 reservoirs. RESULTS: Here, we demonstrate that PI3K/Akt inhibitors, including clinically available Miltefosine, dramatically reduced HIV-1 p...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265748/ https://www.ncbi.nlm.nih.gov/pubmed/18237430 http://dx.doi.org/10.1186/1742-4690-5-11 |
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author | Chugh, Pauline Bradel-Tretheway, Birgit Monteiro-Filho, Carlos MR Planelles, Vicente Maggirwar, Sanjay B Dewhurst, Stephen Kim, Baek |
author_facet | Chugh, Pauline Bradel-Tretheway, Birgit Monteiro-Filho, Carlos MR Planelles, Vicente Maggirwar, Sanjay B Dewhurst, Stephen Kim, Baek |
author_sort | Chugh, Pauline |
collection | PubMed |
description | BACKGROUND: Unlike CD4+ T cells, HIV-1 infected macrophages exhibit extended life span even upon stress, consistent with their in vivo role as long-lived HIV-1 reservoirs. RESULTS: Here, we demonstrate that PI3K/Akt inhibitors, including clinically available Miltefosine, dramatically reduced HIV-1 production from long-living virus-infected macrophages. These PI3K/Akt inhibitors hyper-sensitize infected macrophages to extracellular stresses that they are normally exposed to, and eventually lead to cell death of infected macrophages without harming uninfected cells. Based on the data from these Akt inhibitors, we were able to further investigate how HIV-1 infection utilizes the PI3K/Akt pathway to establish the cytoprotective effect of HIV-1 infection, which extends the lifespan of infected macrophages, a key viral reservoir. First, we found that HIV-1 infection activates the well characterized pro-survival PI3K/Akt pathway in primary human macrophages, as reflected by decreased PTEN protein expression and increased Akt kinase activity. Interestingly, the expression of HIV-1 or SIV Tat is sufficient to mediate this cytoprotective effect, which is dependent on the basic domain of Tat – a region that has previously been shown to bind p53. Next, we observed that this interaction appears to contribute to the downregulation of PTEN expression, since HIV-1 Tat was found to compete with PTEN for p53 binding; this is known to result in p53 destabilization, with a consequent reduction in PTEN protein production. CONCLUSION: Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs. |
format | Text |
id | pubmed-2265748 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-22657482008-03-08 Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy Chugh, Pauline Bradel-Tretheway, Birgit Monteiro-Filho, Carlos MR Planelles, Vicente Maggirwar, Sanjay B Dewhurst, Stephen Kim, Baek Retrovirology Research BACKGROUND: Unlike CD4+ T cells, HIV-1 infected macrophages exhibit extended life span even upon stress, consistent with their in vivo role as long-lived HIV-1 reservoirs. RESULTS: Here, we demonstrate that PI3K/Akt inhibitors, including clinically available Miltefosine, dramatically reduced HIV-1 production from long-living virus-infected macrophages. These PI3K/Akt inhibitors hyper-sensitize infected macrophages to extracellular stresses that they are normally exposed to, and eventually lead to cell death of infected macrophages without harming uninfected cells. Based on the data from these Akt inhibitors, we were able to further investigate how HIV-1 infection utilizes the PI3K/Akt pathway to establish the cytoprotective effect of HIV-1 infection, which extends the lifespan of infected macrophages, a key viral reservoir. First, we found that HIV-1 infection activates the well characterized pro-survival PI3K/Akt pathway in primary human macrophages, as reflected by decreased PTEN protein expression and increased Akt kinase activity. Interestingly, the expression of HIV-1 or SIV Tat is sufficient to mediate this cytoprotective effect, which is dependent on the basic domain of Tat – a region that has previously been shown to bind p53. Next, we observed that this interaction appears to contribute to the downregulation of PTEN expression, since HIV-1 Tat was found to compete with PTEN for p53 binding; this is known to result in p53 destabilization, with a consequent reduction in PTEN protein production. CONCLUSION: Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs. BioMed Central 2008-01-31 /pmc/articles/PMC2265748/ /pubmed/18237430 http://dx.doi.org/10.1186/1742-4690-5-11 Text en Copyright © 2008 Chugh et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Chugh, Pauline Bradel-Tretheway, Birgit Monteiro-Filho, Carlos MR Planelles, Vicente Maggirwar, Sanjay B Dewhurst, Stephen Kim, Baek Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy |
title | Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy |
title_full | Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy |
title_fullStr | Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy |
title_full_unstemmed | Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy |
title_short | Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy |
title_sort | akt inhibitors as an hiv-1 infected macrophage-specific anti-viral therapy |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265748/ https://www.ncbi.nlm.nih.gov/pubmed/18237430 http://dx.doi.org/10.1186/1742-4690-5-11 |
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