Type I IFN signaling blockade by a PASylated antagonist during chronic SIV infection suppresses specific inflammatory pathways but does not alter T cell activation or virus replication

Abstract

Chronic activation of the immune system in HIV infection is one of the strongest predictors of morbidity and mortality. As such, approaches that reduce immune activation have received considerable interest. Previously, we demonstrated that administration of a type I interferon receptor antagonist (IFN-1ant) during acute SIV infection of rhesus macaques results in increased virus replication and accelerated disease progression. Here, we administered a long half-life PASylated IFN-1ant to ART-treated and ART-naïve macaques during chronic SIV infection and measured expression of interferon stimulated genes (ISG) by RNA sequencing, plasma viremia, plasma cytokines, T cell activation and exhaustion as well as cell-associated virus in CD4 T cell subsets sorted from peripheral blood and lymph nodes. Our study shows that IFN-1ant administration in both ART-suppressed and ART-untreated chronically SIV-infected animals successfully results in reduction of IFN-I-mediated inflammation as defined by reduced expression of ISGs but had no effect on plasma levels of IL-1β, IL-1ra, IL-6 and IL-8. Unlike in acute SIV infection, we observed no significant increase in plasma viremia up to 25 weeks after IFN-1ant administration or up to 15 weeks after ART interruption. Likewise, cell-associated virus measured by SIV gag DNA copies was similar between IFN-1ant and placebo groups. In addition, evaluation of T cell activation and exhaustion by surface expression of CD38, HLA-DR, Ki67, LAG-3, PD-1 and TIGIT, as well as transcriptome analysis showed no effect of IFN-I blockade. Thus, our data show that blocking IFN-I signaling during chronic SIV infection suppresses IFN-I-related inflammatory pathways without increasing virus replication, and thus may constitute a safe therapeutic intervention in chronic HIV infection.

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

“…Neutralization of (most) IFNα subtypes in SIV-infected rhesus macaques prior to infection increased viral loads as expected, but also decreased subsequent immune activation profiles [24]. By contrast, blockade of IFN-I signaling in chronic SIVtreated and untreated rhesus macaques decreased inflammation profiles associated with ISGs but did not reverse T cell exhaustion or activation [33].…”

“…We next determined the expression levels in the colon biopsies in vivo of the 266 'core IRGs' that were similarly regulated by the 5 IFNα subtypes and IFNβ in gut CD4+ T cells in b Plasma viral loads were based on copies/ml, whereas colon HIV RNA levels were based on copies per CD4 T cell [40] c Plasma levels of IL6 and LPS were based on pg/ml. d Colon IFNα and IFNβ mRNA levels (copies per 10 4 x GAPDH) were quantified by qPCR as described [33] e Illumina Sequence Read Counts for each colon biopsy sample following quality control (this study)…”

Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

“…( c ) REACTOME_NEUTROPHIL_DEGRANULATION (MSIDB #M27620) ( d ) GSEA line plot of HALLMARK_TNFA_SIGNALING_VIA_NFKB pathway (MSIGDB # M5890). ( e ) GSEA line plot of HALLMARK_IL6_JAK_STAT3_SIGNALING (MSIGDB# M5897) ( f ) a custom geneset of ISGs from prior NHP studies ( Nganou-Makamdop et al, 2018 ; Palesch et al, 2018 ; Sandler et al, 2014 ); ( g-h ) Heat maps of top-scoring (i.e. leading edge) from the untreated 4 DPI vs 2 DPI GSEA analyses.…”

Role of cytokine agonists and immune checkpoint inhibitors toward HIV remission

“…This indicates that the overall timing of IFN induced innate responses during acute infection plays a major role in the course of disease progression and dwarfs the detrimental effects of a hyperactive inflammatory response. The administration of an IFN-1ant during chronic SIV infection of ART-naïve and ARTsuppressed RMs resulted in the reduction of IFN-I mediated inflammation, a reduction in expression of ISGs, but no significant effect on plasma levels of IL-1β, IL-1Ra, IL-6, and IL-8 (64). Contrary to what was seen during acute SIV infection, there was no significant increase in plasma viremia up to 25 weeks post IFN-1ant administration and no difference was seen in levels of cell-associated SIV-DNA (64).…”

“…The administration of an IFN-1ant during chronic SIV infection of ART-naïve and ARTsuppressed RMs resulted in the reduction of IFN-I mediated inflammation, a reduction in expression of ISGs, but no significant effect on plasma levels of IL-1β, IL-1Ra, IL-6, and IL-8 (64). Contrary to what was seen during acute SIV infection, there was no significant increase in plasma viremia up to 25 weeks post IFN-1ant administration and no difference was seen in levels of cell-associated SIV-DNA (64). Another recent study using pegylated IFN-α2a (pIFN-α2a) in conjunction with suppressive ART showed upregulation of ISGs, but the treatment failed to significantly reduce the size of the reservoir (65).…”