Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo

Abstract Current direct-acting antiviral therapies are highly effective in suppressing HIV-1 replication. However, mucosal inflammation undermines prophylactic treatment efficacy, and HIV-1 persists in long-lived tissue-derived dendritic cells (DCs) and CD4+ T cells of treated patients. Host-directe...

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Autores principales:	Alexandra P. M. Cloherty, Nienke H. van Teijlingen, Tracy-Jane T. H. D. Eisden, John L. van Hamme, Anusca G. Rader, Teunis B. H. Geijtenbeek, Renée R. C. E. Schreurs, Carla M. S. Ribeiro
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/747ad914bf0d46c9860d30f8766e3ccd
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spelling	oai:doaj.org-article:747ad914bf0d46c9860d30f8766e3ccd2021-12-02T15:54:05ZAutophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo10.1038/s41598-021-84081-42045-2322https://doaj.org/article/747ad914bf0d46c9860d30f8766e3ccd2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84081-4https://doaj.org/toc/2045-2322Abstract Current direct-acting antiviral therapies are highly effective in suppressing HIV-1 replication. However, mucosal inflammation undermines prophylactic treatment efficacy, and HIV-1 persists in long-lived tissue-derived dendritic cells (DCs) and CD4+ T cells of treated patients. Host-directed strategies are an emerging therapeutic approach to improve therapy outcomes in infectious diseases. Autophagy functions as an innate antiviral mechanism by degrading viruses in specialized vesicles. Here, we investigated the impact of pharmaceutically enhancing autophagy on HIV-1 acquisition and viral replication. To this end, we developed a human tissue infection model permitting concurrent analysis of HIV-1 cellular targets ex vivo. Prophylactic treatment with autophagy-enhancing drugs carbamazepine and everolimus promoted HIV-1 restriction in skin-derived CD11c+ DCs and CD4+ T cells. Everolimus also decreased HIV-1 susceptibility to lab-adapted and transmitted/founder HIV-1 strains, and in vaginal Langerhans cells. Notably, we observed cell-specific effects of therapeutic treatment. Therapeutic rapamycin treatment suppressed HIV-1 replication in tissue-derived CD11c+ DCs, while all selected drugs limited viral replication in CD4+ T cells. Strikingly, both prophylactic and therapeutic treatment with everolimus or rapamycin reduced intestinal HIV-1 productive infection. Our findings highlight host autophagy pathways as an emerging target for HIV-1 therapies, and underscore the relevancy of repurposing clinically-approved autophagy drugs to suppress mucosal HIV-1 replication.Alexandra P. M. ClohertyNienke H. van TeijlingenTracy-Jane T. H. D. EisdenJohn L. van HammeAnusca G. RaderTeunis B. H. GeijtenbeekRenée R. C. E. SchreursCarla M. S. RibeiroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alexandra P. M. Cloherty Nienke H. van Teijlingen Tracy-Jane T. H. D. Eisden John L. van Hamme Anusca G. Rader Teunis B. H. Geijtenbeek Renée R. C. E. Schreurs Carla M. S. Ribeiro Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo
description	Abstract Current direct-acting antiviral therapies are highly effective in suppressing HIV-1 replication. However, mucosal inflammation undermines prophylactic treatment efficacy, and HIV-1 persists in long-lived tissue-derived dendritic cells (DCs) and CD4+ T cells of treated patients. Host-directed strategies are an emerging therapeutic approach to improve therapy outcomes in infectious diseases. Autophagy functions as an innate antiviral mechanism by degrading viruses in specialized vesicles. Here, we investigated the impact of pharmaceutically enhancing autophagy on HIV-1 acquisition and viral replication. To this end, we developed a human tissue infection model permitting concurrent analysis of HIV-1 cellular targets ex vivo. Prophylactic treatment with autophagy-enhancing drugs carbamazepine and everolimus promoted HIV-1 restriction in skin-derived CD11c+ DCs and CD4+ T cells. Everolimus also decreased HIV-1 susceptibility to lab-adapted and transmitted/founder HIV-1 strains, and in vaginal Langerhans cells. Notably, we observed cell-specific effects of therapeutic treatment. Therapeutic rapamycin treatment suppressed HIV-1 replication in tissue-derived CD11c+ DCs, while all selected drugs limited viral replication in CD4+ T cells. Strikingly, both prophylactic and therapeutic treatment with everolimus or rapamycin reduced intestinal HIV-1 productive infection. Our findings highlight host autophagy pathways as an emerging target for HIV-1 therapies, and underscore the relevancy of repurposing clinically-approved autophagy drugs to suppress mucosal HIV-1 replication.
format	article
author	Alexandra P. M. Cloherty Nienke H. van Teijlingen Tracy-Jane T. H. D. Eisden John L. van Hamme Anusca G. Rader Teunis B. H. Geijtenbeek Renée R. C. E. Schreurs Carla M. S. Ribeiro
author_facet	Alexandra P. M. Cloherty Nienke H. van Teijlingen Tracy-Jane T. H. D. Eisden John L. van Hamme Anusca G. Rader Teunis B. H. Geijtenbeek Renée R. C. E. Schreurs Carla M. S. Ribeiro
author_sort	Alexandra P. M. Cloherty
title	Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo
title_short	Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo
title_full	Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo
title_fullStr	Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo
title_full_unstemmed	Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo
title_sort	autophagy-enhancing drugs limit mucosal hiv-1 acquisition and suppress viral replication ex vivo
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/747ad914bf0d46c9860d30f8766e3ccd
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_version_	1718385454571585536

Autophagy-enhancing drugs limit mucosal HIV-1 acquisition and suppress viral replication ex vivo

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