Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects

ABSTRACT Type I interferons (IFNs) are key players in the antiviral immune response. Interferon alpha (IFN-α) belongs to this class of IFNs and comprises 12 subtypes that differ from each other in their binding affinities for a common receptor and, thus, in their signaling potencies. Recent data sug...

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Autores principales:	Erika Schlaepfer, Audrey Fahrny, Maarja Gruenbach, Stefan P. Kuster, Viviana Simon, Gideon Schreiber, Roberto F. Speck
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	antiviral therapy human immunodeficiency virus interferons therapeutic efficacy Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2b0b8de493bf42769700b532a2961a2c
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spelling	oai:doaj.org-article:2b0b8de493bf42769700b532a2961a2c2021-11-15T15:22:04ZDose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects10.1128/mSphere.00637-182379-5042https://doaj.org/article/2b0b8de493bf42769700b532a2961a2c2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00637-18https://doaj.org/toc/2379-5042ABSTRACT Type I interferons (IFNs) are key players in the antiviral immune response. Interferon alpha (IFN-α) belongs to this class of IFNs and comprises 12 subtypes that differ from each other in their binding affinities for a common receptor and, thus, in their signaling potencies. Recent data suggest that IFN-α6 and -α14 are the most potent IFN-α subtypes in restricting HIV replication when applied exogenously. However, in the context of antiviral therapy, IFNs are administered at high doses, which may compensate for differences in potency seen between IFN-α subtypes. In this study, we reexamined whether IFN-α subtypes induce different biological activities, with a focus on how IFN-α treatment dose affects cellular responses to HIV in primary CD4+ T cells, peripheral blood mononuclear cells (PBMCs), and macrophages. We found that the subtypes’ antiviral activities were dose dependent, with >90% inhibition of HIV replication at a high dose of all IFN-αs except the weak IFN-α/β receptor (IFNAR) binder, IFN-α1. The quality of the responses engendered by IFN-α1, -α2, -α6, and -α14 was highly comparable, with essentially the same set of genes induced by all four subtypes. Hierarchal cluster analysis revealed that the individual donors were stronger determinants for the IFN-stimulated-gene (ISG) responses than the specific IFN-α subtype used for stimulation. Notably, IFN-α2-derived mutants with substantially reduced IFNAR2 binding still inhibited HIV replication efficiently, whereas mutants with increased IFNAR1 binding potentiated antiviral activity. Overall, our results support the idea that IFN-α subtypes do not induce different biological responses, given that each subtype is exogenously applied at bioequivalent doses. IMPORTANCE Elucidating the functional role of the IFN-α subtypes is of particular importance for the development of efficacious therapies using exogenous IFN-α. Specifically, this will help define whether IFN therapy should be based on the use of pathogen-dependent IFN subtypes or, rather, IFN mutants with optimized IFNAR binding properties.Erika SchlaepferAudrey FahrnyMaarja GruenbachStefan P. KusterViviana SimonGideon SchreiberRoberto F. SpeckAmerican Society for Microbiologyarticleantiviral therapyhuman immunodeficiency virusinterferonstherapeutic efficacyMicrobiologyQR1-502ENmSphere, Vol 4, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	antiviral therapy human immunodeficiency virus interferons therapeutic efficacy Microbiology QR1-502
spellingShingle	antiviral therapy human immunodeficiency virus interferons therapeutic efficacy Microbiology QR1-502 Erika Schlaepfer Audrey Fahrny Maarja Gruenbach Stefan P. Kuster Viviana Simon Gideon Schreiber Roberto F. Speck Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects
description	ABSTRACT Type I interferons (IFNs) are key players in the antiviral immune response. Interferon alpha (IFN-α) belongs to this class of IFNs and comprises 12 subtypes that differ from each other in their binding affinities for a common receptor and, thus, in their signaling potencies. Recent data suggest that IFN-α6 and -α14 are the most potent IFN-α subtypes in restricting HIV replication when applied exogenously. However, in the context of antiviral therapy, IFNs are administered at high doses, which may compensate for differences in potency seen between IFN-α subtypes. In this study, we reexamined whether IFN-α subtypes induce different biological activities, with a focus on how IFN-α treatment dose affects cellular responses to HIV in primary CD4+ T cells, peripheral blood mononuclear cells (PBMCs), and macrophages. We found that the subtypes’ antiviral activities were dose dependent, with >90% inhibition of HIV replication at a high dose of all IFN-αs except the weak IFN-α/β receptor (IFNAR) binder, IFN-α1. The quality of the responses engendered by IFN-α1, -α2, -α6, and -α14 was highly comparable, with essentially the same set of genes induced by all four subtypes. Hierarchal cluster analysis revealed that the individual donors were stronger determinants for the IFN-stimulated-gene (ISG) responses than the specific IFN-α subtype used for stimulation. Notably, IFN-α2-derived mutants with substantially reduced IFNAR2 binding still inhibited HIV replication efficiently, whereas mutants with increased IFNAR1 binding potentiated antiviral activity. Overall, our results support the idea that IFN-α subtypes do not induce different biological responses, given that each subtype is exogenously applied at bioequivalent doses. IMPORTANCE Elucidating the functional role of the IFN-α subtypes is of particular importance for the development of efficacious therapies using exogenous IFN-α. Specifically, this will help define whether IFN therapy should be based on the use of pathogen-dependent IFN subtypes or, rather, IFN mutants with optimized IFNAR binding properties.
format	article
author	Erika Schlaepfer Audrey Fahrny Maarja Gruenbach Stefan P. Kuster Viviana Simon Gideon Schreiber Roberto F. Speck
author_facet	Erika Schlaepfer Audrey Fahrny Maarja Gruenbach Stefan P. Kuster Viviana Simon Gideon Schreiber Roberto F. Speck
author_sort	Erika Schlaepfer
title	Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects
title_short	Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects
title_full	Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects
title_fullStr	Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects
title_full_unstemmed	Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects
title_sort	dose-dependent differences in hiv inhibition by different interferon alpha subtypes while having overall similar biologic effects
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/2b0b8de493bf42769700b532a2961a2c
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Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects

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