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Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication

BACKGROUND: Existing highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy...

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Autores principales: Miller, Leia K, Kobayashi, Yoshifumi, Chen, Chiann-Chyi, Russnak, Timothy A, Ron, Yacov, Dougherty, Joseph P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015732/
https://www.ncbi.nlm.nih.gov/pubmed/24156270
http://dx.doi.org/10.1186/1742-4690-10-120
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author Miller, Leia K
Kobayashi, Yoshifumi
Chen, Chiann-Chyi
Russnak, Timothy A
Ron, Yacov
Dougherty, Joseph P
author_facet Miller, Leia K
Kobayashi, Yoshifumi
Chen, Chiann-Chyi
Russnak, Timothy A
Ron, Yacov
Dougherty, Joseph P
author_sort Miller, Leia K
collection PubMed
description BACKGROUND: Existing highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART. RESULTS: A preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells. CONCLUSIONS: These results represent a proof-of-concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance.
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spelling pubmed-40157322014-05-10 Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication Miller, Leia K Kobayashi, Yoshifumi Chen, Chiann-Chyi Russnak, Timothy A Ron, Yacov Dougherty, Joseph P Retrovirology Research BACKGROUND: Existing highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART. RESULTS: A preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells. CONCLUSIONS: These results represent a proof-of-concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance. BioMed Central 2013-10-24 /pmc/articles/PMC4015732/ /pubmed/24156270 http://dx.doi.org/10.1186/1742-4690-10-120 Text en Copyright © 2013 Miller 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
Miller, Leia K
Kobayashi, Yoshifumi
Chen, Chiann-Chyi
Russnak, Timothy A
Ron, Yacov
Dougherty, Joseph P
Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication
title Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication
title_full Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication
title_fullStr Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication
title_full_unstemmed Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication
title_short Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication
title_sort proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015732/
https://www.ncbi.nlm.nih.gov/pubmed/24156270
http://dx.doi.org/10.1186/1742-4690-10-120
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