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Type I IFN responses in rhesus macaques prevent SIV transmission and slow disease progression

ABSTRACT: In acute HIV infection immune activation may provide target cells and drive virus replication, which innate immunity may limit. Thus, the net effects of inflammatory mediators, including type I interferon (IFN-I), are unclear. Here, we block IFN-I signaling during pathogenic acute SIV infection with an IFN-I receptor antagonist. Delayed antiviral gene expression, increased SIV reservoir, increased CD4 T cell depletion and accelerated progression to AIDS and death ensue despite decreased T cell activation. In contrast, IFNα2a treatment initially upregulates antiviral genes and prevents systemic SIV infection after rectal challenge. Antiviral gene expression normalizes, and infection ensues with fewer transmitted/founder variants. Continued IFNα2a treatment causes delayed antiviral gene expression, increased SIV reservoir and increased CCR5+ CD4 T cell loss. Thus, the precise timing of antiviral gene expression has a profound impact on disease course. The benefits of early antiviral activity outweigh the harms of increased immune activation in acute SIV infection.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE53690 | GEO | 2014/07/23

REPOSITORIES: GEO

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Type I IFN responses in rhesus macaques prevent SIV transmission and slow disease progression

Project description:In acute HIV infection immune activation may provide target cells and drive virus replication, which innate immunity may limit. Thus, the net effects of inflammatory mediators, including type I interferon (IFN-I), are unclear. Here, we block IFN-I signaling during pathogenic acute SIV infection with an IFN-I receptor antagonist. Delayed antiviral gene expression, increased SIV reservoir, increased CD4 T cell depletion and accelerated progression to AIDS and death ensue despite decreased T cell activation. In contrast, IFNα2a treatment initially upregulates antiviral genes and prevents systemic SIV infection after rectal challenge. Antiviral gene expression normalizes, and infection ensues with fewer transmitted/founder variants. Continued IFNα2a treatment causes delayed antiviral gene expression, increased SIV reservoir and increased CCR5+ CD4 T cell loss. Thus, the precise timing of antiviral gene expression has a profound impact on disease course. The benefits of early antiviral activity outweigh the harms of increased immune activation in acute SIV infection. SRA Study accession: SRP034563, BioProject ID:PRJNA231884

2014-07-23 | E-GEOD-53690 | biostudies-arrayexpress

Transcription profiling of rhesus monkeys through HIV disease progression and impact on neuroAIDS.

Project description:The virus/host interactions during the acute phase of human immunodeficiency virus (HIV) infection help determine the course of disease. During this time period, virus enters the brain. Here, we report clusters of genes whose transcripts are significantly upregulated in the frontal lobe of the brain during acute simian immunodeficiency virus (SIV) infection of rhesus monkeys. Many of these genes are involved in interferon (IFN) and/or interleukin (IL)-6 pathways. Although neither IFNa nor IFN? are elevated in the brain, IL6 is increased. Both IFNa and IL6 are elevated in plasma during this acute phase. The upregulation of STAT1, verified by immunohistochemical staining, can be due to both central nervous system (CNS) (SIV and IL6) and peripheral (IFNa and IL6) causes, and can itself drive the expression of many of these genes. Examination of the levels of expression of the upregulated genes in the post-acute and long-term phases of infection, as well as in SIV encephalitis, reveals increased expression throughout SIV infection, which may serve to protect the brain, but can have untoward long-term consequences.

2008-06-12 | E-GEOD-2393 | biostudies-arrayexpress

Tissue-specific transcriptional profiling of plasmacytoid dendritic cells reveals a hyperactivated state in chronic SIV infection

Project description:HIV associated immune activation (IA) is associated with increased morbidity in people living with HIV (PLWH) on antiretroviral therapy, and remains a barrier for strategies aimed at reducing the HIV reservoir. The underlying mechanisms of IA have not been definitively elucidated, however, persistent production of Type I IFNs and expression of ISGs is considered to be one of the primary factors. Plasmacytoid DCs (pDCs) are a major producer of Type I IFN during viral infections, and are highly immunomodulatory in acute HIV and SIV infection, however their role in chronic HIV/SIV infection has not been firmly established. Here, we performed a detailed transcriptomic characterization of pDCs in chronic SIV infection in rhesus macaques, and in sooty mangabeys, a natural host non-human primate (NHP) species that undergoes non-pathogenic SIV infection. We also investigated the immunostimulatory capacity of lymph node homing pDCs in chronic SIV infection by contrasting gene expression of pDCs isolated from lymph nodes with those from blood. We observed that pDCs in LNs, but not blood, produced high levels of IFN transcripts, and upregulated gene expression programs consistent with T cell activation and exhaustion. We apply a novel strategy to catalogue uncharacterized surface molecules on pDCs, and identified the lymphoid exhaustion markers TIGIT and LAIR1 as highly expressed in SIV infection. pDCs from SIV-infected sooty mangabeys lacked the activation profile of ISG signatures observed in infected macaques. These data demonstrate that pDCs are a primary producer of Type I IFN in chronic SIV infection. Further, this study demonstrated that pDCs trafficking to LNs persist in a highly activated state well into chronic infection. Collectively, these data identify pDCs as a highly immunomodulatory cell population in chronic SIV infection, and a putative therapeutic target to reduce immune activation.

2021-06-15 | GSE178225 | GEO

Expression patterns throughout disease progression and impact on neuroAIDS.

2005-03-10 | GSE2393 | GEO

Reduced chronic lymphocyte activation following Interferon-α blockade in the acute phase of SIV infection in rhesus macaques

Project description:Pathogenic HIV/SIV infection of humans and rhesus macaques (RMs) induces persistently high production of type-I interferon (IFN-I) which is thought to contribute to disease progression. To elucidate the specific role of IFN in SIV pathogenesis, 12 RMs were treated prior to i.v. SIVmac239 infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN subtypes, and compared with six mock-infused, SIV-infected controls. Plasma viremia was measured post infection to assess the effect of IFNα blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypical staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute phase viral loads vs. controls. 4 out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4+ T cell counts which was associated with progression to AIDS. Interestingly, 50% of animals treated with AGS-009 (6/12) developed AIDS within one year of infection, compared with 17% (1/6) of untreated controls. Finally, blockade of IFN decreased the levels of activated CD4+ and CD8+ T cells, as well as B-cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-blockade animals supports the hypothesis that IFN signaling contributes to lymphocyte activation during SIV infection, and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential anti-inflammatory effect of IFN blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals.

2018-02-19 | GSE110617 | GEO

Gene expression profiling data from sooty mangabeys treated with interferon alpha

Project description:In contrast to pathogenic HIV and SIV infection of humans and macaques, SIV infection of sooty mangabeys (SMs) is typically non-pathogenic despite high virus replication. A key feature of primary SIV infection of SMs is a strong type I interferon (IFN-I) response, characterized by massive up-regulation of interferon-stimulated genes (ISG), followed by rapid resolution during the acute-to-chronic phase transition and establishment of an immune quiescent state that persists throughout the chronic infection. Based on these observations we hypothesized that low levels of IFN-I signaling may be instrumental in preventing chronic immune activation and disease progression in SIV-infected SMs. We used microarrays to characterize gene expression changes induced by IFNalpha treatment. To directly assess the effects of an experimentally-induced augmentation of IFN-I signaling in chronically SIV-infected SMs, we administered recombinant rhesus macaque IFNalpha2-IgFc (rmIFNα2) to eight naturally SIV-infected SMs weekly for 16 weeks and longitudinally monitored viral load, lymphocyte counts, immune activation, SIV-specific CD8+ T-cell responses, and gene expression profile. Administration of rmIFNα2 was bioactive in vivo with gene expression profiling revealing a strong upregulation of numerous ISGs in the blood of treated animals.

2012-07-09 | E-GEOD-35460 | biostudies-arrayexpress

Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation

Project description:Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity is restricting viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by mRNA deep sequencing (mRNA-seq) at 3 and 12 days post inoculation (DPI) in 4 animals for each time point. The eight RMs were intrarectally challenged with SIVmac251 using 1 mL of a high-dose inoculum (6000 TCID50/mL). SIV inoculates were deposited at a rectal depth of 25 mm from the anus. Baseline rectal samples were obtained 14 days prior to viral challenge by pinch biopsy.

2014-04-17 | E-GEOD-56845 | biostudies-arrayexpress

IFNalpha-blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health

Project description:The induction of type I interferons during acute viral infections drives local and systemic anti-viral responses. However, in chornic virus infection these type I interferon driven responses can be detrimental and can be characterized impaired immune responses (greater T cell exhaustion) and an overall decline in health outcomes. To parse out the role of type I IFN and assess the therapeutic impact of blocking type I IFN, we administered IFN-a blocking antibody to a cohort of SIV-infected ART treated Maccaca mulata. After 9 weeks of treatment (1 injection per week), we observed a significant reduction in the SIV-DNA levels in the lymphnode. This reduced SIV reservoir was seem with a systemic increase in immune cell subset signatures associated with better CD8 T cell function and lower plasma levels of TGF-beta. In addition, upon interruption of ART (16 weeks after ART initiation and after 16 rounds of anti-IFNa infusion), we observed that the non-human primates that underwent type I interferon blockade maintained better overall health and hemoglobin levels.

2021-09-27 | GSE184495 | GEO

Gene expression profiling data from sooty mangabeys treated with interferon alpha

2012-07-10 | GSE35460 | GEO

Paracrine IFN response limits ZIKV infection in human Sertoli cells

Project description:Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. The testes have been implicated as sites of long-term ZIKV replication, and our previous studies have identified Sertoli cells (SC), the nurse cells of the seminiferous epithelium that govern spermatogenesis, as major targets of ZIKV infection. To improve our understanding of the host-ZIKV interaction within human testicular cells, we analyzed ZIKV-induced proteome changes in SC and mixed seminiferous tubule cells (STC) using high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that ZIKV infection in SC and STC induced distinct IFN-stimulated proteins and impacted pathways and functional networks associated with innate antiviral defense. IFN signaling was the most significantly enriched pathway and MX1 was the most abundant IFN-stimulated protein in both SC and STC. Increased levels of MX1 at later time points of infection coincided with diminished propagation of ZIKV in SC, whereas silencing of MX1 and IFIT1 enhanced peak ZIKV titers in SC. Furthermore, although downstream IFN-I signaling was found to be functional and restricted ZIKV replication in SC, in comparison to A549 cells, SC exhibited dampened expression of IFN-I/III-stimulated genes despite higher levels of virus progeny and IFN-I/III transcripts. Together, this study highlights the IFN-I/III response as a driver of the antiviral state that limits ZIKV infection in SC and suggests that delayed and reduced robustness of innate antiviral defense in SC may contribute to ZIKV persistence in the testes.

2021-09-10 | PXD025133 | Pride

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