Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation

ABSTRACT Monocytes from HIV-infected patients produce increased levels of inflammatory cytokines, which are associated with chronic immune activation and AIDS progression. Chronic immune activation is often not restored even in patients showing viral suppression under ART. Therefore, new therapeutic...

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Autores principales:	Flávio Lemos Matassoli, Ihid Carneiro Leão, Bruno Braz Bezerra, Richard B. Pollard, Dieter Lütjohann, James E. K. Hildreth, Luciana Barros de Arruda
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	HIV beta-cyclodextrin monocytes inflammation human immunodeficiency virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d81caf87eda14d1c85c5475fff01ff38
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spelling	oai:doaj.org-article:d81caf87eda14d1c85c5475fff01ff382021-11-15T15:22:21ZHydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation10.1128/mSphere.00497-182379-5042https://doaj.org/article/d81caf87eda14d1c85c5475fff01ff382018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00497-18https://doaj.org/toc/2379-5042ABSTRACT Monocytes from HIV-infected patients produce increased levels of inflammatory cytokines, which are associated with chronic immune activation and AIDS progression. Chronic immune activation is often not restored even in patients showing viral suppression under ART. Therefore, new therapeutic strategies to control inflammation and modulate immune activation are required. Hydroxypropyl-beta-cyclodextrin (HP-BCD) is a cholesterol-sequestering agent that has been reported to be safe for human use in numerous pharmaceutical applications and that has been shown to inactivate HIV in vitro and to control SIV infection in vivo. Since cellular cholesterol content or metabolism has been related to altered cellular activation, we evaluated whether HP-BCD treatment could modulate monocyte response to inflammatory stimuli. Treatment of monocytes isolated from HIV-positive and HIV-negative donors with HP-BCD inhibited the expression of CD36 and TNF-α after LPS stimulation, independent of raft disruption. Accordingly, HP-BCD-treated cells showed significant reduction of TNF-α and IL-10 secretion, which was associated with lower mRNA expression. LPS-induced p38MAPK phosphorylation was dampened by HP-BCD treatment, indicating this pathway as a target for HP-BCD-mediated anti-inflammatory response. The expression of HLA-DR was also reduced in monocytes and dendritic cells treated with HP-BCD, which could hinder T cell activation by these cells. Our data suggest that, besides its well-known antiviral activity, HP-BCD could have an immunomodulatory effect, leading to decreased inflammatory responses mediated by antigen-presenting cells, which may impact HIV pathogenesis and AIDS progression. IMPORTANCE Chronic immune activation is a hallmark of HIV infection and is often not controlled even in patients under antiretroviral therapy. Indeed, chronic diseases with inflammatory pathogenesis are being reported as major causes of death for HIV-infected persons. Hydroxypropyl-beta cyclodextrin (HP-BCD) is a cholesterol-sequestering drug that inhibits HIV replication and infectivity in vitro and in vivo. Recent studies have demonstrated the importance of cholesterol metabolism and content in different inflammatory conditions; therefore, we investigated the potential of HP-BCD as an immunomodulatory drug, regulating the activation of cells from HIV-infected patients. Treatment of monocytes with HP-BCD inhibited the expression and secretion of receptors and mediators that are usually enhanced in HIV patients. Furthermore, we investigated the molecular mechanisms associated with the immunomodulatory effect of HP-BCD. Our results indicate that, besides reducing viral replication, HP-BCD treatment may contribute to modulation of chronic immune activation associated with AIDS.Flávio Lemos MatassoliIhid Carneiro LeãoBruno Braz BezerraRichard B. PollardDieter LütjohannJames E. K. HildrethLuciana Barros de ArrudaAmerican Society for MicrobiologyarticleHIVbeta-cyclodextrinmonocytesinflammationhuman immunodeficiency virusMicrobiologyQR1-502ENmSphere, Vol 3, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV beta-cyclodextrin monocytes inflammation human immunodeficiency virus Microbiology QR1-502
spellingShingle	HIV beta-cyclodextrin monocytes inflammation human immunodeficiency virus Microbiology QR1-502 Flávio Lemos Matassoli Ihid Carneiro Leão Bruno Braz Bezerra Richard B. Pollard Dieter Lütjohann James E. K. Hildreth Luciana Barros de Arruda Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation
description	ABSTRACT Monocytes from HIV-infected patients produce increased levels of inflammatory cytokines, which are associated with chronic immune activation and AIDS progression. Chronic immune activation is often not restored even in patients showing viral suppression under ART. Therefore, new therapeutic strategies to control inflammation and modulate immune activation are required. Hydroxypropyl-beta-cyclodextrin (HP-BCD) is a cholesterol-sequestering agent that has been reported to be safe for human use in numerous pharmaceutical applications and that has been shown to inactivate HIV in vitro and to control SIV infection in vivo. Since cellular cholesterol content or metabolism has been related to altered cellular activation, we evaluated whether HP-BCD treatment could modulate monocyte response to inflammatory stimuli. Treatment of monocytes isolated from HIV-positive and HIV-negative donors with HP-BCD inhibited the expression of CD36 and TNF-α after LPS stimulation, independent of raft disruption. Accordingly, HP-BCD-treated cells showed significant reduction of TNF-α and IL-10 secretion, which was associated with lower mRNA expression. LPS-induced p38MAPK phosphorylation was dampened by HP-BCD treatment, indicating this pathway as a target for HP-BCD-mediated anti-inflammatory response. The expression of HLA-DR was also reduced in monocytes and dendritic cells treated with HP-BCD, which could hinder T cell activation by these cells. Our data suggest that, besides its well-known antiviral activity, HP-BCD could have an immunomodulatory effect, leading to decreased inflammatory responses mediated by antigen-presenting cells, which may impact HIV pathogenesis and AIDS progression. IMPORTANCE Chronic immune activation is a hallmark of HIV infection and is often not controlled even in patients under antiretroviral therapy. Indeed, chronic diseases with inflammatory pathogenesis are being reported as major causes of death for HIV-infected persons. Hydroxypropyl-beta cyclodextrin (HP-BCD) is a cholesterol-sequestering drug that inhibits HIV replication and infectivity in vitro and in vivo. Recent studies have demonstrated the importance of cholesterol metabolism and content in different inflammatory conditions; therefore, we investigated the potential of HP-BCD as an immunomodulatory drug, regulating the activation of cells from HIV-infected patients. Treatment of monocytes with HP-BCD inhibited the expression and secretion of receptors and mediators that are usually enhanced in HIV patients. Furthermore, we investigated the molecular mechanisms associated with the immunomodulatory effect of HP-BCD. Our results indicate that, besides reducing viral replication, HP-BCD treatment may contribute to modulation of chronic immune activation associated with AIDS.
format	article
author	Flávio Lemos Matassoli Ihid Carneiro Leão Bruno Braz Bezerra Richard B. Pollard Dieter Lütjohann James E. K. Hildreth Luciana Barros de Arruda
author_facet	Flávio Lemos Matassoli Ihid Carneiro Leão Bruno Braz Bezerra Richard B. Pollard Dieter Lütjohann James E. K. Hildreth Luciana Barros de Arruda
author_sort	Flávio Lemos Matassoli
title	Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation
title_short	Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation
title_full	Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation
title_fullStr	Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation
title_full_unstemmed	Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation
title_sort	hydroxypropyl-beta-cyclodextrin reduces inflammatory signaling from monocytes: possible implications for suppression of hiv chronic immune activation
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/d81caf87eda14d1c85c5475fff01ff38
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Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation

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