Hepatic HMOX1 Expression Positively Correlates with Bach-1 and miR-122 in Patients with HCV Mono and HIV/HCV Coinfection

Jabłonowska, Elżbieta; Wójcik, Kamila; Szymańska, Bożena; Omulecka, Aleksandra; Ćwiklińska, Hanna; Piekarska, Anna

doi:10.1371/journal.pone.0095564

Cited by 9 publications

(11 citation statements)

References 29 publications

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“…These findings are consistent with an immune-modulatory role for HO-1 in HIV-1 infection. Additionally, HIV/HCV-coinfected individuals have lower liver HO-1 expression than that observed in HCV-monoinfected individuals; this loss of liver HO-1 is particularly evident in subjects with high HIV loads and low CD4 ϩ T lymphocyte counts (44). These findings, in conjunction with our observation of HO-1 deficiency in brain tissue from HIV-infected subjects, suggest that HIV infection modulates HO-1 expression in the CNS and in peripheral tissues (3).…”

Section: Discussionsupporting

confidence: 56%

“…An antiviral effect of HO-1 induction has been observed in infection studies of hepatitis C virus (HCV) (36), hepatitis B virus (HBV) (37), Ebola virus (38), enterovirus 71 (EV71) (39), vaccinia virus (40), and porcine reproductive and respiratory syndrome virus (41). Interestingly, HCV has been reported to downregulate HO-1 protein expression (42,43), although contrasting studies report HO-1 induction by HCV (44,45).…”

Section: Discussionmentioning

confidence: 99%

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Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

Gill

Kovacsics

Vance

et al. 2015

J Virol

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Expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIVpositive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses. In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genes nef, vpr, or vpu but rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIVinfected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis. IMPORTANCEThe continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART. H eme oxygenase-1 (HO-1) is a highly inducible phase II d...

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

Gill

Kovacsics

Vance

et al. 2015

J Virol

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“…It plays crucial role in suppressing inflammation and protecting against oxidative stress. Upregulation of HMOX-1 is an indication of oxidative stress [ 33 ]. We have previously shown that Nef expression in monocytic cells induces the expression of proinflammatory cytokines and thus acts like a cellular stress signal.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis of mRNAs in Human Monocytic Cells Expressing the HIV-1 Nef Protein and Their Exosomes

Aqil

Mallik

Bandyopadhyay

et al. 2015

BioMed Research International

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The Nef protein of human immunodeficiency virus (HIV) promotes viral replication and progression to AIDS. Besides its well-studied effects on intracellular signaling, Nef also functions through its secretion in exosomes, which are nanovesicles containing proteins, microRNAs, and mRNAs and are important for intercellular communication. Nef expression enhances exosome secretion and these exosomes can enter uninfected CD4 T cells leading to apoptotic death. We have recently reported the first miRNome analysis of exosomes secreted from Nef-expressing U937monocytic cells. Here we show genome-wide transcriptome analysis of Nef-expressing U937 cells and their exosomes. We identified four key mRNAs preferentially retained in Nef-expressing cells; these code for MECP2, HMOX1, AARSD1, and ATF2 and are important for chromatin modification and gene expression. Interestingly, their target miRNAs are exported out in exosomes. We also identified three key mRNAs selectively secreted in exosomes from Nef-expressing U937 cells and their corresponding miRNAs being preferentially retained in cells. These are AATK, SLC27A1, and CDKAL and are important in apoptosis and fatty acid transport. Thus, our study identifies selectively expressed mRNAs in Nef-expressing U937 cells and their exosomes and supports a new mode on intercellular regulation by the HIV-1 Nef protein.

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“… 68 In addition, higher HMOX1 expression was correlated with higher expression of Bach1 and miR-122 in chronic HCV patients. 69 Several miRNA profiling studies have demonstrated alterations in miRNAs expression and identified miRNA-mRNA regulatory networks during HCV infection. 51 , 70 , 71 , 72 Differential upregulation of hsa-miR-130a, hsa-miR-130b, hsa-miR-298, hsa-miR-193a-5p and hsa-miR-371-5p were observed in HCV Con1 replicon in comparison to control cells.…”

Section: Cellular Mirnas In Hcv Mediated Liver Disease Progressionmentioning

confidence: 99%

MicroRNAs: Role in hepatitis C virus pathogenesis

2015

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Hepatitis C virus (HCV) is a global health burden with an estimated 170–200 million peoples chronically infected worldwide. HCV infection remains as an independent risk factor for chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, and a major reason for liver transplantation. Discovery of direct acting antiviral (DAA) drugs have shown promising results with more than 90% success rate in clearing the HCV RNA in patients, although long-term consequences remain to be evaluated. microRNAs (miRNAs) are important players in establishment of HCV infection and target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Altered expression of miRNAs is involved in the pathogenesis associated with HCV infection by controlling signaling pathways such as immune response, proliferation and apoptosis. miRNA is emerging as a means of communication between various cell types inside the liver. There is likely possibility of developing circulating miRNAs as biomarkers of disease progression and can also serve as diagnostic tool with potential of early therapeutic intervention in HCV associated end stage liver disease. This review focuses on recent studies highlighting the contribution of miRNAs in HCV life cycle and their coordinated regulation in HCV mediated liver disease progression.

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Hepatic HMOX1 Expression Positively Correlates with Bach-1 and miR-122 in Patients with HCV Mono and HIV/HCV Coinfection

Cited by 9 publications

References 29 publications

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

Transcriptomic Analysis of mRNAs in Human Monocytic Cells Expressing the HIV-1 Nef Protein and Their Exosomes

MicroRNAs: Role in hepatitis C virus pathogenesis

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