IFI44 suppresses HIV-1 LTR promoter activity and facilitates its latency

Power, Derek G.; Santoso, Netty; Dieringer, Michael; Yu, Jack; Huang, Huachao; Simpson, Sydney; Seth, Ishir; Miao, Hongyu; Zhu, Jian

doi:10.1016/j.virol.2015.02.046

Cited by 74 publications

(69 citation statements)

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“…While the role of IFI44 is not completely defined, some evidence suggests that this interferon-inducible gene acts as a suppressor of viral replication 24. In the study by Coit et al ,7 hypomethylation of this CpG site was identified when comparing SLE cases with nephritis with healthy controls and was not identified when SLE cases without nephritis were compared with healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses

et al. 2016

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ObjectivePrevious studies have shown that differential DNA methylation is associated with SLE susceptibility. How DNA methylation affects the clinical heterogeneity of SLE has not been fully defined. We conducted this study to identify differentially methylated CpG sites associated with nephritis among women with SLE.MethodsThe methylation status of 428 229 CpG sites across the genome was characterised for peripheral blood cells from 322 women of European descent with SLE, 80 of whom had lupus nephritis, using the Illumina HumanMethylation450 BeadChip. Multivariable linear regression adjusting for population substructure and leucocyte cell proportions was used to identify differentially methylated sites associated with lupus nephritis. The influence of genetic variation on methylation status was investigated using data from a genome-wide association study of SLE. Pathway analyses were used to identify biological processes associated with lupus nephritis.ResultsWe identified differential methylation of 19 sites in 18 genomic regions that was associated with nephritis among patients with SLE (false discovery rate q<0.05). Associations for four sites in HIF3A, IFI44 and PRR4 were replicated when examining methylation data derived from CD4+ T cells collected from an independent set of patients with SLE. These associations were not driven by genetic variation within or around the genomic regions. In addition, genes associated with lupus nephritis in a prior genome-wide association study were not differentially methylated in this epigenome-wide study. Pathway analysis indicated that biological processes involving type 1 interferon responses and the development of the immune system were associated with nephritis in patients with SLE.ConclusionsDifferential methylation of genes regulating the response to tissue hypoxia and interferon-mediated signalling is associated with lupus nephritis among women with SLE. These findings have not been identified in genetic studies of lupus nephritis, suggesting that epigenome-wide association studies can help identify the genomic differences that underlie the clinical heterogeneity of SLE.

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Section: Discussionmentioning

confidence: 99%

Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses

et al. 2016

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“…VSV-G pseudotyped HIV-1 NL4–3 luciferase virus (HIV-1 Luc) or retroviruses expressing HIV-1 Tat (pQCXIP-Tat) were created as described previously (Huang et al, 2015; Power et al, 2015). …”

Section: Methodsmentioning

confidence: 99%

“…Co-immunoprecipitation and western blot analysis was performed as described previously (Huang et al, 2015; Power et al, 2015). Briefly, HeLa cells stably expressing Tat-Flag were treated with levosimendan (10 μM) for 24 hr.…”

Section: Methodsmentioning

confidence: 99%

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

et al. 2017

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Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged “block and lock” approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.

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“…The multiple ifi44 zebrafish genes counts 7 ISG among 19 members, but their two human co-orthologues are induced by type I IFN. Located in the nucleus, IFI44 binds and blocks the HIV1 LTR promoter (56). However, the numerous zebrafish ifi44 probably have sub-functionalized, and mediate multiple antiviral mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Interferon-stimulated genes in zebrafish and human define an ancient arsenal of antiviral immunity

Levraud

Jouneau

Briolat

et al. 2019

Preprint

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The evolution of the interferon (IFN) system, the major innate antiviral mechanism of vertebrates, remains poorly understood. According to the detection of type I IFN genes in cartilaginous fish genomes, the system appeared 500My ago. However, the IFN system integrates many other components, most of which are encoded by IFN-stimulated genes (ISGs). To shed light on its evolution, we have used deep RNA sequencing to generate a comprehensive list of ISGs of zebrafish, taking advantage of the high quality genome annotation in this species. We analyzed larvae after inoculation of recombinant zebrafish type I IFN, or infection with chikungunya virus, a potent IFN inducer. We identified more than 400 zebrafish ISGs, defined as being either directly induced by IFN or induced by the virus in an IFN receptor-dependent manner. Their human orthologues were highly enriched in ISGs, particularly for highly-inducible genes. We identified 72 orthology groups containing ISGs in both zebrafish and human, revealing a core ancestral ISG repertoire, which includes most of the known signaling components of the IFN system. Many downstream effectors were also already present 450 My ago in the common ancestor of tetrapods and bony fish, and diversified as multi-gene families independently in the two lineages. A large proportion of the ISG repertoire is lineage-specific; around 40% of protein-coding zebrafish ISGs had no human orthologue. We identified 14 fish-specific gene families containing multiple ISGs, including finTRIMs. This work illuminates the evolution of the IFN system and provides a rich resource to explore new antiviral mechanisms.Key pointsWe established an exhaustive list of larval zebrafish ISGs.Orthologous ISGs in fish and human identify a large ancestral ISG repertoire.

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IFI44 suppresses HIV-1 LTR promoter activity and facilitates its latency

Cited by 74 publications

References 50 publications

Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses

Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Interferon-stimulated genes in zebrafish and human define an ancient arsenal of antiviral immunity

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