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

Schlaepfer, Erika; Fahrny, Audrey; Gruenbach, Maarja; Kuster, Stefan P.; Simon, Viviana; Schreiber, Gideon; Speck, Roberto F.

doi:10.1128/msphere.00637-18

Cited by 14 publications

(25 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data in Figs 1 and 2, as well as data from other studies [12][13][14][15], provide strong evidence for quantitative differences among the IFN-Is. To uncouple quantitative versus qualitative differences, we normalized our IFN-I treatments for ISRE-activity ( Fig 2B) for unbiased transcriptomics.…”

Section: Identification Of Novel Ifn-regulated Genes (Irgs) Based On supporting

confidence: 82%

“…Our group and others reported diverse antiviral potencies of the IFNα subtypes and IFNβ that correlated with their IFNAR binding properties. These data emphasize the contribution of quantitative differences in IFNAR signaling in controlling acute viral infection [12][13][14][15]76]. However, data from multiple in vivo studies also revealed that the IFNα subtypes may have Expression levels were based on TMM-transformed counts.…”

Section: Discussionmentioning

confidence: 90%

“…More recently, IFNα2 treatment of SIV rhesus macaques under antiretroviral therapy did not reduce the latent HIV-1 reservoir [11]. Our group and others reported that IFNα2 only moderately inhibited HIV-1 in humanized mice and primary CD4+ T cells compared to the more potent subtypes IFNα6, IFNα14 and IFNα8 [12][13][14][15]. Interestingly, the anti-HIV-1 potency of IFNα subtypes correlated with their binding affinity to IFNAR2, suggesting that the antiviral differences between the IFNα subtypes were due to quantitative differences in IFNAR signaling strength [12,15,16].…”

Section: Introductionmentioning

confidence: 77%

“…Our group and others reported that IFNα2 only moderately inhibited HIV-1 in humanized mice and primary CD4+ T cells compared to the more potent subtypes IFNα6, IFNα14 and IFNα8 [12][13][14][15]. Interestingly, the anti-HIV-1 potency of IFNα subtypes correlated with their binding affinity to IFNAR2, suggesting that the antiviral differences between the IFNα subtypes were due to quantitative differences in IFNAR signaling strength [12,15,16]. However, several human IFNα subtypes exhibit strong signals of purifying selection [17], suggesting that these IFNα subtypes may have evolved to have specific, nonredundant functions.…”

Section: Introductionmentioning

confidence: 81%

“…Recently, Schaepler et al utilized saturating concentrations of various IFNα subtypes to inhibit HIV-1 infection in activated PBMCs in vitro. Since 25 canonical ISGs were induced to similar levels at saturating IFN-I doses, the authors concluded that there were no qualitative differences between the IFNα subtypes [15]. We argue that this conclusion is premature, as there are hundreds of ISGs encompassing the interferome [5,20].…”

Section: Plos Pathogensmentioning

confidence: 88%

See 4 more Smart Citations

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

Guo

Shen²,

Kibbie

et al. 2020

PLoS Pathog

View full text Add to dashboard Cite

Section: Identification Of Novel Ifn-regulated Genes (Irgs) Based On supporting

confidence: 82%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 81%

Section: Plos Pathogensmentioning

confidence: 88%

See 3 more Smart Citations

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

Guo

Shen²,

Kibbie

et al. 2020

PLoS Pathog

View full text Add to dashboard Cite

Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection

Schuhenn

Meister

Todt

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (α) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2–infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.

show abstract

Interferon resistance of emerging SARS-CoV-2 variants

Guo

Barrett

Morrison

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis, and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive the emergence of these novel variants, studies documenting a critical role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against multiple viral lineages sampled during the course of the global outbreak, including ancestral and five major variants of concern that include the B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), B.1.617.2 (delta), and B.1.1.529 (omicron) lineages. Our data reveal that relative to ancestral isolates, SARS-CoV-2 variants of concern exhibited increased interferon resistance, suggesting that evasion of innate immunity may be a significant, ongoing driving force for SARS-CoV-2 evolution. These findings have implications for the increased transmissibility and/or lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

show abstract

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

Cited by 14 publications

References 40 publications

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection

Interferon resistance of emerging SARS-CoV-2 variants

Contact Info

Product

Resources

About