Differential expression of HIV-1 interfering factors in monocyte-derived macrophages stimulated with polarizing cytokines or interferons

Jiménez, Viviana Cobos; Booiman, Thijs; Taeye, Steven W. de; Dort, Karel A. van; Rits, Maarten A N; Hamann, Jörg; Kootstra, Neeltje A.

doi:10.1038/srep00763

Cited by 86 publications

(74 citation statements)

References 64 publications

(110 reference statements)

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“…Examination of cellular expression revealed high levels of Trex1 in immune cells, which were highly induced by proinflammatory stimuli and not by anti-inflammatory cytokines or growth factors in macrophages. This is concurrent with the observation made in human monocyte-derived macrophages in which Trex1 was also upregulated after proinflammatory stimuli (29). Additionally, it has also been reported that Trex1 is upregulated by genotoxic drugs (30,31), indicating that Trex1 is needed for both pathogen DNA degradation and also small strands of nuclear DNA originated from genotoxicity.…”

Section: Discussionsupporting

confidence: 85%

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Pereira-Lopes

Celhar

Sans-Fons

et al. 2013

The Journal of Immunology

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The three-prime repair exonuclease 1 (TREX1) is the most abundant exonuclease in mammalian cells. Mutations in Trex1 gene are being linked to the development of Aicardi–Goutières syndrome, an inflammatory disease of the brain, and systemic lupus erythematosus. In clinical cases and in a Trex1-deficient murine model, chronic production of type I IFN plays a pathogenic role. In this study, we demonstrate that Trex1−/− mice present inflammatory signatures in many different organs, including the brain. Trex1 is highly induced in macrophages in response to proinflammatory stimuli, including TLR7 and TLR9 ligands. Our findings show that, in the absence of Trex1, macrophages displayed an exacerbate proinflammatory response. More specifically, following proinflammatory stimulation, Trex1−/− macrophages exhibited an increased TNF-α and IFN-α production, higher levels of CD86, and increased Ag presentation to CD4+ T cells, as well as an impaired apoptotic T cell clearance. These results evidence an unrevealed function of the Trex1 as a negative regulator of macrophage inflammatory activation and demonstrate that macrophages play a major role in diseases associated with Trex1 mutations, which contributes to the understanding of inflammatory signature in these diseases.

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Section: Discussionsupporting

confidence: 85%

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Pereira-Lopes

Celhar

Sans-Fons

et al. 2013

The Journal of Immunology

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“…We focused the analysis of restriction factors to HIV, based on the work of Cobos Jimenez et al (26). We observed that triggering of MDMs by the TLR3 and -4 agonists poly(I·C) and LPS, respectively, resulted in the upregulation of all restriction factors examined and in the suppression of cyclophilin, a cellular factor that is incorporated into viral particles.…”

Section: Resultsmentioning

confidence: 99%

“…We also investigated the role of anti-HIV-active IFN-␣ (34) and well-known HIV restriction factors (26). Neutralizing the IFN axis reversed the anti-HIV effects only modestly when triggering the TLR2 pathway; this occurred to a greater extent when triggering the TLR3 and -4 pathways but only minimally when triggering the TLR8 pathway.…”

Section: Figmentioning

confidence: 99%

“…A lack of incorporation of cyclophilin A into viral particles in the presence of cyclosporine results in attenuated viral replication (35). All these restriction factors are encoded by IFN-stimulated genes (26) and may contribute to the TLR3-and TLR4-induced HIV-inhibitory effects. Surprisingly, IFN-␣ was not increased in response to the various TLR agonists; however, we observed a quite impressive increase of IFN-␤ in response to poly(I·C), as reported by Gendelman et al (23).…”

Section: Figmentioning

confidence: 99%

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Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV

Schlaepfer

Rochat

et al. 2014

J Virol

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Macrophages must react to a large number of pathogens and their effects. In chronic HIV infection, the microenvironment changes with an influx of microbial products that trigger Toll-like receptors (TLRs). That dynamic nature can be replicated ex vivo by the proinflammatory (M1-polarized) and alternatively activated (M2-polarized) macrophages. Thus, we determined how polarized macrophages primed by various TLR agonists support HIV replication. Triggering of TLR2, -3, -4, -5, and -8 reinforced the low level of permissiveness in polarized macrophages. HIV was inhibited even more in M1-polarized macrophages than in macrophages activated only by TLR agonists. HIV was inhibited before its integration into the host chromosome. Polarization and triggering by various TLR agonists resulted in distinct cytokine profiles, endocytic activity, and distinct upregulation of restriction factors of HIV. Thus, different mechanisms likely contribute to the HIV-inhibitory effects. In chronic HIV infection, macrophages might become less permissive to HIV due to changes in the microenvironment. The high level of reactivity of polarized macrophages to TLR triggering may be exploited for immunotherapeutic strategies. IMPORTANCEMacrophages are a major target of HIV-1 infection. Different cell types in this very heterogeneous cell population respond differently to stimuli. In vitro, the heterogeneity is mimicked by their polarization into proinflammatory and alternatively activated macrophages. Here we explored the extent to which agonists triggering the TLR family affect HIV replication in polarized macrophages. We found that a number of TLR agonists blocked HIV replication substantially when given before infection. We also report the mechanisms of how TLR agonists exert their inhibitory action. Our findings may advance our understanding of which and how TLR agonists block HIV infection in polarized macrophages and may facilitate the design of novel immunotherapeutic approaches.

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“…These observations prompted us to examine whether endogenous APOL1 expressed in differentiated and IFN-␥-stimulated U937 cells contributes to anti-HIV-1 activity. However, interferon-stimulated macrophages express a multitude of restriction factors and microRNA (miRNAs) that affect HIV-1 replication (63), and thus, it may be challenging to elucidate the contribution of APOL1 under such conditions. Nevertheless, we have established U937 cell lines that stably express APOL1 shRNA.…”

Section: Discussionmentioning

confidence: 99%

The Innate Immune Factor Apolipoprotein L1 Restricts HIV-1 Infection

Taylor

Khatua

Popik

2014

J Virol

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b Apolipoprotein L1 (APOL1) is a major component of the human innate immune response against African trypanosomes. Although the mechanism of the trypanolytic activity of circulating APOL1 has been recently clarified, the intracellular function(s) of APOL1 in human cells remains poorly defined. Like that of many genes linked to host immunity, APOL1 expression is induced by proinflammatory cytokines gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). Additionally, IFN-␥-polarized macrophages that potently restrict HIV-1 replication express APOL1, which suggests that APOL1 may contribute to HIV-1 suppression. Here, we report that APOL1 inhibits HIV-1 replication by multiple mechanisms. We found that APOL1 protein targeted HIV-1 Gag for degradation by the endolysosomal pathway. Interestingly, we found that APOL1 stimulated both endocytosis and lysosomal biogenesis by promoting nuclear localization of transcription factor EB (TFEB) and expression of TFEB target genes. Moreover, we demonstrated that APOL1 depletes cellular viral accessory protein Vif, which counteracts the host restriction factor APOBEC3G, via a pathway involving degradation of Vif in lysosomes and by secretion of Vif in microvesicles. As a result of Vif depletion by APOL1, APOBEC3G was not degraded and reduced infectivity of progeny virions. In support of this model, we also showed that endogenous expression of APOL1 in differentiated U937 monocytic cells stimulated with IFN-␥ resulted in a reduced production of virus particles. This finding supports the hypothesis that induction of APOL1 contributes to HIV-1 suppression in differentiated monocytes. Deciphering the precise mechanism of APOL1-mediated HIV-1 restriction may facilitate the design of unique therapeutics to target HIV-1 replication.

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Differential expression of HIV-1 interfering factors in monocyte-derived macrophages stimulated with polarizing cytokines or interferons

Cited by 86 publications

References 64 publications

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV

The Innate Immune Factor Apolipoprotein L1 Restricts HIV-1 Infection

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