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Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner

HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to pu...

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Autores principales: Mehla, Rajeev, Bivalkar-Mehla, Shalmali, Zhang, Ruonan, Handy, Indhira, Albrecht, Helmut, Giri, Shailendra, Nagarkatti, Prakash, Nagarkatti, Mitzi, Chauhan, Ashok
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886842/
https://www.ncbi.nlm.nih.gov/pubmed/20585398
http://dx.doi.org/10.1371/journal.pone.0011160
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author Mehla, Rajeev
Bivalkar-Mehla, Shalmali
Zhang, Ruonan
Handy, Indhira
Albrecht, Helmut
Giri, Shailendra
Nagarkatti, Prakash
Nagarkatti, Mitzi
Chauhan, Ashok
author_facet Mehla, Rajeev
Bivalkar-Mehla, Shalmali
Zhang, Ruonan
Handy, Indhira
Albrecht, Helmut
Giri, Shailendra
Nagarkatti, Prakash
Nagarkatti, Mitzi
Chauhan, Ashok
author_sort Mehla, Rajeev
collection PubMed
description HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC) -α and -δ, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC) involving stress induced AMP Kinase (AMPK) inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs.
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spelling pubmed-28868422010-06-22 Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner Mehla, Rajeev Bivalkar-Mehla, Shalmali Zhang, Ruonan Handy, Indhira Albrecht, Helmut Giri, Shailendra Nagarkatti, Prakash Nagarkatti, Mitzi Chauhan, Ashok PLoS One Research Article HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC) -α and -δ, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC) involving stress induced AMP Kinase (AMPK) inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs. Public Library of Science 2010-06-16 /pmc/articles/PMC2886842/ /pubmed/20585398 http://dx.doi.org/10.1371/journal.pone.0011160 Text en Mehla et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Mehla, Rajeev
Bivalkar-Mehla, Shalmali
Zhang, Ruonan
Handy, Indhira
Albrecht, Helmut
Giri, Shailendra
Nagarkatti, Prakash
Nagarkatti, Mitzi
Chauhan, Ashok
Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner
title Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner
title_full Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner
title_fullStr Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner
title_full_unstemmed Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner
title_short Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner
title_sort bryostatin modulates latent hiv-1 infection via pkc and ampk signaling but inhibits acute infection in a receptor independent manner
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886842/
https://www.ncbi.nlm.nih.gov/pubmed/20585398
http://dx.doi.org/10.1371/journal.pone.0011160
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