Tristetraprolin expression and microRNA-mediated regulation during simian immunodeficiency virus infection of the central nervous system
© Liu et al.; licensee BioMed Central Ltd. 2013
Received: 15 July 2013
Accepted: 28 August 2013
Published: 2 September 2013
The RNA-binding protein tristetraprolin (TTP) participates in normal post-transcriptional control of cytokine and chemokine gene expression, dysregulation of which contributes to the HIV-associated neurocognitive disorders. Transcriptional and post-transcriptional regulation of TTP has been described, including regulation by microRNA-29a. In the simian immunodeficiency virus (SIV) model of HIV CNS disease, control of cytokine/chemokine expression coincides with the end of acute phase infection. This control is lost during progression to disease. In this study, we assessed TTP regulation and association with cytokine regulation in the brain during SIV infection.
Quantitation of TTP expression over the course of SIV infection revealed downregulation of TTP during acute infection, maintenance of relatively low levels during asymptomatic phase, and increased expression only during late-stage CNS disease, particularly in association with severe disease. The ability of miR-29a to regulate TTP was confirmed, and evidence for additional miRNA targeters of TTP was found. However, increased miR-29a expression in brain was not found to be significantly negatively correlated with TTP. Similarly, increased TTP during late-stage disease was not associated with lower cytokine expression.
TTP expression is regulated during SIV infection of the CNS. The lack of significant negative correlation of miR-29a and TTP expression levels suggests that while miR-29a may contribute to TTP regulation, additional factors are involved. Reduced TTP expression during acute infection is consistent with increased cytokine production during this phase of infection, but the increases in TTP observed during late-stage infection were insufficient to halt runaway cytokine levels. While antisense inhibitors of the post-transcriptional targeters of TTP identified here could conceivably be used further to augment TTP regulation of cytokines, it is possible that high levels of TTP are undesirable. Additional research is needed to characterize members of the miRNA/TTP/cytokine regulatory network and identify nodes that may be best targeted therapeutically to ameliorate the effects of chronic inflammation in retrovirus-associated CNS disease.
KeywordsCytokine RNA-binding protein Tristetraprolin microRNA Human immunodeficiency virus HIV-associated neurocognitive disorder
The advent of effective antiretroviral therapy for HIV-1 in the mid-1990s dramatically improved life expectancy and quality . However, as individuals live longer with HIV, the HIV-associated neurocognitive disorders (HAND) remain a growing problem [2, 3]. HAND severity ranges from asymptomatic neurocognitive impairment to minor motor/cognitive disorder to HIV-associated dementia , and its effects span several neurocognitive domains, including attention/working memory, motor skills, and executive functions [5, 6].
The growing prevalence of HAND dictates a need to understand the underlying disease mechanism, which have not been fully elucidated but are likely multifactorial. Neurotoxicity of viral products [7, 8] and prolonged exposure to inflammatory cytokines/chemokines are probable causes [9–11]. Innate immune responses during acute phase infection may also cause damage or influence predisposition to disease [12, 13]. Because longitudinal monitoring of the central nervous system (CNS) is difficult or impossible in human cohorts, our group developed a simian immunodeficiency virus (SIV) macaque model of HIV CNS pathogenesis [14, 15]. In this model, pigtailed macaques (Macaca nemestrina) are dual inoculated with SIV/17E-Fr, a neurovirulent clone, and SIV/ΔB670, an immunosuppressive swarm. An initial acute phase, like that seen in HIV, lasts for the first 10-14 days post infection (dpi), with many measures of innate immune response peaking around 7 dpi . This is followed by a latent or “asymptomatic” phase. Pronounced CD4+ T cell depletion and motor deficits appear by approximately 35 days dpi and are monitored until 84 dpi, by which time more than 90% of infected macaques have developed CNS disease and AIDS . Patterns of cytokine expression during SIV infection suggest that, at terminal stages of disease, high and sustained cytokine levels contribute to neurodegenerative pathologies. Transient acute phase cytokine expression may itself cause lasting damage or set the stage for neurodegeneration. Accordingly, brain cytokine regulation is of central importance in CNS disease progression.
Tristetraprolin (TTP, also known as zinc finger protein 36 homolog, ZFP36) has been characterized as an anti-inflammatory and anticarcinogenic protein that is also involved in differentiation processes [16, 17]. TTP is thought to act primarily through post-transcriptional regulation of messenger RNA [18, 19]. TTP binds to and destabilizes transcripts with 3′ untranslated regions (3′ UTRs) that contain AU-rich elements (AREs) [20–22], including those of CCL2, IL-6, IL-10, TNF-α, iNOS, and many other inflammatory mediators. Post-transcriptionally, TTP activity is regulated by post-translational phosphorylation, and a cellular microRNA (miRNA) has been reported to modulate TTP abundance [23, 24]. miRNAs are short, single-stranded RNA molecules—often 22-23 nucleotides in length—that regulate host and viral gene expression [25–28]. Incorporated into the cytosolic RNA-induced silencing complex, miRNAs bind transcripts through partially complementary sequences known as miRNA recognition elements (MRE), usually located in the 3′ UTR of the target transcript [25, 26]. Subsequent regulation can be achieved by transcript cleavage and degradation, inhibition of translation, and cellular sequestration of transcripts.
Because TTP has been reported to regulate many cytokines that we previously observed to be coordinately regulated in SIV infection , and since miRNAs have various associations with CNS disease [13, 29–32], we investigated the expression of TTP and potentially related miRNAs in our HIV CNS disease model. We then queried the role of TTP in cytokine regulation during SIV disease, as well as the influence of miRNA expression on TTP levels. We report here that TTP is differentially regulated during the course of SIV infection and that acute phase downregulation of TTP is mechanistically consistent with increased cytokine levels recorded during this phase. However, during the general dysregulation of late-stage disease, increased expression of TTP is apparently insufficient to halt damaging levels of cytokine production. We also confirm that miR-29a can indeed regulate the TTP 3′ UTR, but that consideration of other factors is needed to explain TTP modulation in the CNS. Finally, we present evidence for several additional miRNA members of a complex interaction network governing TTP, miRNA, and cytokine expression.
TTP mRNA is differentially expressed during viral pathogenesis
miR-29a targets the 3′UTR of TTP
Transfection of microRNAs into human macrophages affects TTP levels
We next characterized the effects of miR-29a mimics and inhibitors on TTP expression in cells of the monocyte/macrophage lineage. Monocyte-derived macrophages were chosen for two reasons. First, macrophages are central actors in immune responses and viral replication and entry into to the brain in our SIV encephalitis model as well as in HIV-1 infection of brain. Second, previous work indicated the involvement of macrophage TTP in regulation of cytokines such as TNF-alpha [34–36]. Third, miR-29 species are upregulated in macrophages during differentiation  and in early SIV infection . Flow cytometry of macrophages that were co-transfected with the GFP-TTP 3′UTR reporter vector and small RNA molecules showed that a miR-29a mimic, but not a control RNA, reduced mean fluorescence intensity by 20-70%, i.e. consistently, but with considerable inter-donor variability (Figure 2B). As with the HEK-293 T experiments, however, only a slight increase in fluorescence was seen upon transfection with a miR-29a antagonist, suggesting redundancy of 3′ UTR-binding sites in macrophages. We also performed an experiment in which mimics and inhibitors of miR-29a were transfected into primary macrophages without a reporter vector to assess the effects of the miRNA on native protein. Semi-quantitative analysis of Western immunoblots for native TTP protein revealed that transfection of miR-29a inhibited TTP production, whereas anti-miR-29a resulted in a 4-fold increase of protein (Additional file 1: Figure S1). We thus confirmed that miR-29a is a regulator of TTP, including in the disease-relevant setting of the macrophage.
Fluctuation of thalamic miR-29a levels during progression to SIV CNS disease
Relationship of miR-29a and TTP mRNA levels
An inverse correlation of miR-29a and TTP expression might be expected in the case of an exclusive, classic regulatory relationship of the miRNA with its target. However, no significant correlation was found in our model across time points (data not shown). Analyses focused on specific phases of infection (acute, persistent/asymptomatic, and late-stage disease) similarly found no negative correlations of miR-29a with TTP. As noted, miR-29a and TTP levels were highest in late stage disease, and a positive correlation (R = 0.58, data not shown) was in fact observed between the two analytes at 84 dpi.
Novel miRNA regulators of TTP
We sought to identify additional miRNA candidates for TTP 3′ UTR regulation for three reasons. First, although exogenous miR-29a inhibitors allowed greater production of native TTP protein in macrophages (Additional 1: Figure S1), our reporter experiments in both 293 T and primary macrophage culture indicated that miR-29a was not the only regulator of the TTP 3′ UTR. Second, as described, we did not observe an inverse relationship of TTP and miR-29a levels in vivo, as one might expect if miR-29a were a major physiologically relevant regulator of TTP during SIV infection in brain. Third, relationships of TTP with additional miRNAs in more complicated regulatory networks have been proposed in the recent literature [39, 40]. Three target prediction algorithms were used to generate a list of candidate miRNAs, which were ranked based upon the number of predicting algorithms and the number of predicted MREs in the 3′ UTR for each miRNA.
We selected four miRNAs for transfection into macrophages along with the TTP 3′UTR reporter construct: miRs-145, -155, -361-3p, and -608. Despite numerous predicted binding sites in the TTP 3′ UTR, miR-361-3p did not occasion control of the 3′ UTR-containing reporter (Figure 4B). In contrast, transfection of miRs-608-, 155, and -145 reduced mean fluorescence intensity of the 3′ UTR construct compared with GFP alone by approximately 70%, 50%, and 40%, respectively (Figure 4B); this reduction was significant for miR-608.
Differential expression of putative TTP-targeting miRNAs in vivo
Tristetraprolin transcript was generally downregulated over the course of SIV infection and CNS disease development. Downregulation of TTP mRNA in the acute stage of infection is consistent with the contemporaneous upregulation of numerous cytokines. However, control of cytokine production at the end of acute phase infection  appears to involve mechanisms other than TTP upregulation, since TTP levels remained comparatively low during acute and latent infection. On average, during late stage infection, TTP mRNA levels returned to the levels found in uninfected control subjects, but this result was driven largely by large increases of TTP transcript in brain of subjects with the most severe CNS disease.
The mechanism of TTP downregulation likely involves miRNAs. However, our confirmation and extension in primary cells of a previous report that miR-29a exerted regulation through the TTP 3′UTR was not accompanied by observable negative correlations of miR-29a and TTP expression in brain. Indeed, with the exception of increased abundance in several late-stage subjects, particularly those with severe CNS disease, miR-29a expression did not change drastically during the course of infection. We would like to note, however, that we could not perform longitudinal sampling on the same individuals; because of interindividual variation, it remains possible that changes within the individual brain occurred but could be observed only with much larger numbers of subjects.
Since differences in miR-29a levels did not appear to account for TTP regulation during SIV infection, several additional miRNAs were investigated that, out of multiple candidates, exerted regulatory effects through the TTP 3′ UTR. Quantitation of miRs-145, 155, 361-3p, and -608 in brain and comparison of their abundance with that of TTP indicated that miR-145 should be investigated further as a candidate for natural regulation of TTP during SIV infection. The evidence did not support a consistent role for miRs-155, -361-3p, or the very low-abundance miR-608 in TTP regulation. miR-608 did, however, appear to be a potentially effective regulator of TTP in supraphysiologic quantitites.
It may be important to stress that absolute abundance of a miRNA is not the only determinant of its involvement in regulatory processes [41, 42]. In addition to factors such as sequestration and differential binding partners, the balance of all targeting miRNAs and all affected target—not simply the level of a single miRNA—may be decisive in determining the magnitude of observed regulation. Numerous miRNAs with predicted MREs in the TTP 3′ UTR are also predicted to target cytokines that are differentially expressed during stages of infection in our model: miR-145 (IL6, TNF-alpha, IFN-beta, and the chemokine CCL2); miR-361-3p (IL10 and MIP1-alpha); miR-29 family members (IFN-gamma, IL12p40); and miR-608 (IL6, TNF-alpha, IL12p35 and -40, IL10, MIP1-alpha and -beta, and CCL2).
We thus posit the following model. During acute infection, TTP transcript abundance is slightly reduced. This likely occurs at the transcriptional level, since ERK activation, which occurs during early viral replication , including in our model , downregulates TTP ; however, a post-transcriptional component such as increased turnover of the TTP mRNA cannot be ruled out. At the same time, miRNA-mediated control of TTP translation is relieved by a combination of mechanisms in the broader context of antiviral innate immune responses. These may include both downregulation of some targeting miRNAs and greatly increased transcription of mRNAs of cytokines and other factors produced during the innate immune responses. These transcripts would act as “sponges” for miRNAs that also target TTP. As a result, TTP protein levels could be maintained or even rise despite lower levels of transcript, and this situation would be exacerbated with increasing transcription. The overall abundance of all mRNA targets of TTP-targeting miRNAs would determine the extent to which miRNA levels could affect TTP production. The explosion of dysregulated cytokine transcripts during progression to CNS disease would thus explain why even greatly increased levels of TTP targeters such as miR-155—or, in some individuals, miR-29a—would have little or no effect on TTP. Carefully integrated systems biology experiments and new approaches for detecting miRNA-target antagonism patterns [46–48] will help to address these issues in future studies.
Apart from the remaining questions regarding mechanisms of TTP regulation, our results show that TTP transcript abundance alone cannot explain changes in cytokine mRNA levels during progression to lentiviral CNS disease, and that increases in TTP are in fact associated with disease development. During late-stage SIV CNS disease in our model, both TTP and its targets, including inflammatory cytokines, are upregulated in brain of individuals with severe encephalitis. It would thus appear that although TTP may influence cytokine levels during early infection, and while the protein likely continues to exert a dampening effect throughout infection, increases in TTP are insufficient to control inflammation during late stage disease. Preliminary results indicate that this may be due to a marked increase in phosphorylated TTP  during progression to disease (JL and KWW, unpublished observations). Since phosphorylated forms of the protein are known to have impaired ability to cause mRNA decay [36, 50], the prevalent form of the protein during late-stage infection may not effectively regulate transcripts of inflammatory mediators.
The finding of upregulated but partly ineffective TTP in disease is also consistent with reports on TTP in several diseases and models. In an interesting recent study with some parallels to this work, Zhang et al reported that TTP was upregulated in endothelial cells in contact with atherosclerotic lesions . Also, in rheumatoid arthritis upregulated TTP is found in cells involved in pathogenesis  and may be a marker of severe disease , in part because of production stimulated by the TTP target TNF. Although the complete absence of TTP (knockout mice) is associated with uncontrolled inflammatory responses [20, 54–56] and TTP influences cytokine levels in cell culture models, there are conflicting reports on whether TTP and TNF levels are correlated in rheumatoid arthritis patient samples [34, 53]. Exposure of mouse brain to hypertonic insult resulted in upregulation of both TTP and TNF . In some cases, then, the normal TTP anti-inflammatory mechanism, although duly activated, cannot completely or on its own stem the rising inflammatory tide of disease- or injury-related dysregulation.
Indeed, TTP can promote apoptosis independently of its effects on mRNA stability, an effect that has prompted the label of “anti-oncogene” [35, 58, 59]. Thus, the high levels of TTP observed in macaque brain during late stage lentiviral infection may not be protective, but may instead contribute to CNS disease. Increasing the levels of TTP to enable the mRNA-destabilizing activity of this RNA binding protein—for example, through the use of inhibitors of anti-TTP miRNAs —is an attractive therapeutic possibility in cancers , atherosclerosis , and perhaps other conditions. Models such as ours may play an important role in investigating the possibly deleterious effects of increased TTP in the CNS during lentiviral infection.
TTP mRNA levels were modulated during SIV infection, but large fold upregulation of TTP was insufficient to control dysregulated CNS cytokine expression during late-stage disease. We also confirmed TTP as a target of miR-29a, but found that higher miR-29a expression in brain was not associated with reduced TTP abundance. The results presented here are consistent with targeting of TTP by additional miRNAs and the existence of a complex interaction network governing TTP, miRNA, and cytokine expression. Additional research is needed to characterize this network more fully, including the contributions of protein levels and post-translational modifications of TTP. Finally, the possibly deleterious effects of increased levels of TTP should be assessed carefully along with any investigation of TTP-altering therapies as a strategy to control cytokine deregulation in retrovirus-associated CNS disease.
Animal studies and ethics statement
No new animal studies were conducted for this project. Archived samples were from previous studies involving dual-inoculation of Macaca nemestrina with an immunosuppressive SIV swarm and a neurotropic clone . All animal studies were approved by the Johns Hopkins University Institutional Animal Care and Use Committee and conducted in accordance with the Weatherall Report, the Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23, revised 1996), and the USDA Animal Welfare Act.
HEK-293 T cells were cultured in D10 media (DMEM, 10% fetal bovine serum, 2 mM L-Glutamine, 10 mM HEPES. Cells were passaged upon reaching 80% confluency, approximately every 3 days.
Human macrophages were differentiated from monocytes in peripheral blood mononuclear cells (PBMCs) that were isolated by standard Percoll protocol, as described previously . PBMCs were cultured in macrophage differentiation medium with 20% serum [MDM20: Dulbecco’s modified Eagle’s medium (DMEM, Invitrogen), 20% human serum (GemCell), 2 mM L-Glutamine (Sigma), 10 mM HEPES (Gibco), 10 mM sodium pyruvate (Sigma), 50 ng/ml M-CSF (R&D), and 2 mg/ml Gentamicin (Gibco)] for one week, with a half-volume re-feeding at three days post-plating. After seven days, supernatants were removed and adherent macrophages were washed with PBS. Medium was replaced with MDM10 (MDM with 10% human serum).
Reporter plasmid cloning
The TTP 3′UTR was amplified from cDNA using primers 5′-GGA CTC AGA TCT CGA GCA AAG TGA C 3′ and 5′ – GAT CCC GGG CCC GCG GTA CCG ATC C-3′ that contained Kpn1 and XhoI restriction sites, respectively. The PCR product was sequenced (GeneWiz), verified against the Ensembl Genome database, and cloned by TOPO cloning kit (Invitrogen). The pEGFP-TTP UTR construct was made by subcloning the TTP3′ UTR into the pEGFP-C1 plasmid (Clontech) using the same restriction enzymes.
HEK-293 T cells were reverse transfected by seeding in antibiotic-free medium onto 96-well plates containing Lipofectamine 2000 (Invitrogen) complexes containing 50 nM synthetic miRNA mimics, miRNA antagonists, or control RNAs (Qiagen) and 150 ng reporter plasmid DNA. Medium was removed, cells were washed with PBS, and fresh medium was added after four hours.
Human monocyte-derived macrophages were transfected with 100 nM synthetic RNAs using Lipofectamine 2000 in medium without antibiotics. Transfection complexes were removed, and cells were washed with PBS and re-fed with fresh MDM10 after 4 hours.
RNA was isolated from cells using TRIzol reagent (Invitrogen) per manufacturer’s protocol. Macaque thalamus tissue was homogenized using bead Lysing Matrix D (MP Biomedicals) and TRIzol.
HEK-293 T cells transfected with GFP-containing plasmid DNA, RFP transfection normalization control, and synthetic RNAs were harvested 24 hours post-transfection via trypsinization. Flow cytometry was performed with a BD FACSCalibur instrument. Analysis was performed with Flowjo 9.1 software (Flowjo).
Reverse transcription quantitative real-time PCR for TTP messenger RNA was performed using macaque brain RNA. Random primers were used to reverse transcribe RNA into cDNA. TTP cDNA was then amplified using the primers 5′-GGC GAC TCC CCA TCT TCA AT-3′ and 5′CAG TGC AAC AGA CGT GGC TC-3′. Amplification was monitored in real time with a HEX-conjugated probe (5′-TCT GAG TGA CAA GTG ACT GCC CGG TCA G-3′). All primers and probes were from IDT. Fold changes in induction were analyzed using the delta-delta-C(t) method with comparison to 18S rRNA as described previously . Cytokine measurements for the same samples were retrieved from our database and were made as described previously .
MicroRNA RT-qPCR was performed using the stem-loop RT primer/Taqman microRNA PCR system (Applied Biosystems) . The suggested protocol was followed as previously described  with the following alterations. Reverse transcription primer amount was reduced to 1.5 ul per reaction, and reverse transcription reactions were multiplexed. Real-time probe volume was reduced to 0.5 ul per reaction. Fold changes in induction were analyzed using the delta-delta-C(t) method with comparison to the small RNA U6 (as depicted) or, with similar results, to the geometric mean of six relatively invariant small RNAs (data not shown). For both mRNA and miRNA RT-qPCR, amplification reactions were performed on either the iQ5 or the Chromo4 optical system (BioRad).
A Perl program described previously  was used to combine the RNAhybrid , TargetScan , and MiRanda  target prediction algorithms, assigning a score to candidate macaque miRNA/3′ UTR pairs by the number of programs predicting interaction and the number of calls per 3′ UTR.
Human immunodeficiency virus
Simian immunodeficiency virus
Central nervous system
Aquired immunodeficiency syndrome
HIV-associated neurocognitive disorder
- 3′ UTR:
3′ untranslated region
microRNA recognition element
Peripheral blood mononuclear cell
Green fluorescent protein.
The authors would like to acknowledge the expert technical assistance of Brandon T. Bullock and thank all members of the Molecular and Comparative Pathobiology Retrovirus Laboratory for helpful discussions. The authors thank Cameron Ward for initial characterization of anti-TTP antibodies. This project was supported by the Johns Hopkins Brain Science Institute; the National Institutes of Health through grants R01 NS076357, P01 MH070306, and U19 AI096113 (to JEC) and R21 AI102659 and P30 MHO75673 (NIMH Center pilot grant to KWW); and by the National Center for Research Resources and the Office of Research Infrastructure Programs (ORIP) and the National Institutes of Health through Grant Number P40 OD013117.
Jonathan Liu contributed to this study while working at The Johns Hopkins University. He is now a student at The California Institute of Technology, Pasadena, California, USA.
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