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. 2018 Aug 24;14(8):e1007246.
doi: 10.1371/journal.ppat.1007246. eCollection 2018 Aug.

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

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Free PMC article

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

Krystelle Nganou-Makamdop et al. PLoS Pathog. .
Free PMC article

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.

Conflict of interest statement

AS and MS are shareholders of XL-protein GmbH. Otherwise, the authors declare no conflict of interest.

Figures

Fig 1
Fig 1. Experimental design.
35 rhesus macaques received intrarectal challenge with SIVMAC251 at baseline. At week 8 post-infection (p.i.), 25 animals received ART and 10 animals remained untreated. From week 16 to week 24 p.i., ART untreated SIV-infected animals received placebo saline (group 1, n = 4) and PASylated IFN-1ant 3 times per week (group 2, n = 6). ART-treated SIV-infected macaques received placebo saline (group 3, n = 9), PASylated IFN-1ant 2 times per week (group 4, n = 11) or 3 times per week (group 5, n = 5) from week 16 to week 24 p.i.. About 25 weeks after IFN-1ant, ART was interrupted and all animals monitored for an additional 15 weeks.
Fig 2
Fig 2. Effect of PASylated IFN-1ant on ISG expression levels.
Expression of ISGs assessed by RNA sequencing in ART-treated and ART-untreated macaques from SIV challenge at baseline throughout administration of PASylated IFN-1ant (3x weekly or 2x weekly) or placebo saline from weeks 16 to 24 p.i. (a) Heatmap colors represent log2 transformed library size normalized read counts scaled to unit variance across transcript vectors (rows), and normalized to the baseline median sample value of each transcript. Line plots (b) represent the median log2 transformed gene expression estimates for each ISG at week 14 and week 19. Box-whisker plots (c) summarize the differences between weeks 14 and 19 median gene expression estimates for each gene. Error bars indicate lower and upper quartiles. P values were calculated by unpaired t test.
Fig 3
Fig 3. Plasma cytokines.
Plasma concentration of IL-1β, IL-1ra, IL-6 and IL-8 before (open circles; week 13) and after (filled circles; week 25) antagonist administration in ART-untreated and ART-treated SIV infected macaques.
Fig 4
Fig 4. Effect of PASylated IFN-1ant on plasma virus loads.
Log10 Plasma SIV RNA levels measured from SIV challenge at baseline up to 25 weeks after administration of PASylated IFN-1ant. ART-untreated animals (a) received placebo saline (n = 4) or 3 times weekly IFN-1ant injections (n = 6) from week 16 to week 24 p.i. In ART-treated animals (b), antiretroviral treatment was initiated at week 8 p.i. and animals received placebo saline (n = 9), IFN-1ant injections 2 times weekly (IFN-1ant2x; n = 11) or 3 times weekly (IFN-1ant3x; n = 5). Shading indicates IFN-1ant treatment period from week 16 to week 24 p.i. Error bars indicate geometric SD and a dotted line indicates the LLQ (lower limit of quantification). Individual plasma virus loads of ART-untreated and ART-treated animals are presented in lower panels. (c) Log10 Plasma SIV RNA levels measured in macaques challenged with SIV at baseline followed by ART start at week 8 p.i. and finally 3 times weekly administration of PASylated IFN-1ant from week 16 to 24 p.i. (n = 5) or from week 35 to 43 p.i. (n = 5). Shadings indicate IFN-1ant treatment period. Error bars indicate geometric SD and a dotted line indicates the LLQ (lower limit of quantification).
Fig 5
Fig 5. Effect of PASylated IFN-1ant on cell-associated virus.
(a) PBMC-associated SIV gag DNA at week 8 p.i., week 16 p.i. (pre-IFN-1ant) and week 24 p.i. (post-IFN-1ant) in sorted CD4 T cell subsets (CCR5+, central memory: CM, effector memory: EM and total) from macaques treated with placebo saline, PASylated IFN-1ant injected 2 times weekly (IFN-1ant2x) or 3 times weekly (IFN-1ant3x). Animals receiving ART starting week 8 p.i. are presented in the lower panel. Horizontal bars represent median values. P values were calculated by Mann–Whitney U test. (b) LN-associated SIV gag DNA at week 7 p.i., week 15 p.i. (pre-IFN-1ant) and week 23 p.i. (post-IFN-1ant) in sorted CD4 T cell subsets (effector memory: EM, central memory: CM, germinal center T follicular helper: GC Tfh; non-GC Tfh and total) from macaques treated with placebo saline, IFN-1ant injections 2 times weekly (IFN-1ant2x) or 3 times weekly (IFN-1ant3x). Animals receiving ART starting week 8 p.i. are presented in the lower panel. Horizontal bars represent median values. P values were calculated by Mann–Whitney U test. (c) PBMC and (d) LN subset percentages of total SIV gag DNA before and after 2 or 3 times weekly IFN-1ant administration in macaques with ART-untreated or ART-treated SIV infection.
Fig 6
Fig 6. T cell activation/exhaustion and subsets frequencies.
(a) Peripheral blood frequency of CD38+, HLA-DR+ and Ki67+ CD8 memory T cells, (b) Frequency of LAG3+, PD-1+ and TIGIT+ CD8 memory T cells and (c) Peripheral blood CD4:CD8 ratio and frequency of peripheral blood CCR5+ memory CD4 T cells in ART-untreated or ART-treated macaques that received placebo saline, IFN-1ant injections 2 times weekly (IFN-1ant2x) or 3 times weekly (IFN-1ant3x). Error bars represent IQR. P values were calculated between groups by Mann–Whitney U test.
Fig 7
Fig 7. Effect of PASylated IFN-1ant on plasma VL rebound upon ART interruption.
Log10 Plasma SIV RNA levels measured up to 15 weeks after ART interruption (25 weeks after PASylated IFN-1ant/placebo) in macaques previously treated from weeks 16–24 p.i. with placebo saline (n = 9), IFN-1ant injections 2 times weekly (IFN-1ant2x; n = 11) or 3 times weekly (IFN-1ant3x; n = 5). Delayed IFN-1ant 3x macaques (n = 5) received antagonist treatment from 35–43 p.i. Error bars indicate geometric SD and a dotted line indicates the LLQ (lower limit of quantification).

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