Polycyclic aromatic hydrocarbons and cytochrome P450 in HIV pathogenesis

Rao, P.S.S.; Kumar, Santosh

doi:10.3389/fmicb.2015.00550

Cited by 30 publications

(22 citation statements)

References 83 publications

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“…Exacerbation of viral infection may be related to the fact that AhR activation constrains the type-I interferon response 19 . Other studies have reported that TCDD triggers AhR-dependent HIV-1 gene expression in cell lines, but there has been conflicting data on which HIV-1 promoter elements are responsible (reviewed by Rao and Kumar, 2015).…”

Section: Discussionmentioning

confidence: 99%

The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

Bieniasz

Kueck

Cassella

et al. 2018

Preprint

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activation induces the expression of numerous genes, with many effects on cells.However, AhR activation is not known to affect the replication of viruses. We show that AhR activation in macrophages causes a block to HIV-1 and HSV-1 replication. We find that AhR activation transcriptionally represses cyclin-dependent kinase (CDK)1/2 and their associated cyclins, thereby reducing SAMHD1 phosphorylation, cellular dNTP levels and both HIV-1 and HSV-1 replication. Remarkably, a different antiviral stimulus, interferon gamma (IFN-g), that induces a largely non-overlapping set of genes, also transcriptionally represses CDK1, CDK2 and their associated cyclins, resulting in similar dNTP depletion and antiviral effects. Concordantly, the SIV Vpx protein provides complete and partial resistance to the antiviral effects of AhR and IFN-g, respectively.Thus, distinct antiviral signaling pathways converge on CDK/cyclin repression, causing inhibition of viral DNA synthesis and replication. KEYWORDSAryl hydrocarbon receptor, interferon gamma, human immunodeficiency virus, herpes simplex virus, cyclin-dependent kinase, SAMHD1

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Section: Discussionmentioning

confidence: 99%

The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

Bieniasz

Kueck

Cassella

et al. 2018

Preprint

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“…In fact, CYP1A-mediated metabolism and activation of PAHs, commonly found in cigarette smoke, has been implicated in development of cancer [ 54 ]. The role of PAHs in enhancing HIV pathogenesis is bolstered by the fact that CYP1 enzyme catalyzed metabolic activation of PAH results in increased production of ROS and oxidative stress [ 55 ]. The CYP1A1 subtype is widely distributed in extrahepatic tissues and its expression is regulated by AHR [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Cigarette Smoke Condensate on Oxidative Stress, Apoptotic Cell Death, and HIV Replication in Human Monocytic Cells

Rao¹,

Ande²,

Sinha³

et al. 2016

PLoS ONE

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While cigarette smoking is prevalent amongst HIV-infected patients, the effects of cigarette smoke constituents in cells of myeloid lineage are poorly known. Recently, we have shown that nicotine induces oxidative stress through cytochrome P450 (CYP) 2A6-mediated pathway in U937 monocytic cells. The present study was designed to examine the effect of cigarette smoke condensate (CSC), which contains majority of tobacco constituents, on oxidative stress, cytotoxicity, expression of CYP1A1, and/or HIV-1 replication in HIV-infected (U1) and uninfected U937 cells. The effects of CSC on induction of CYP1 enzymes in HIV-infected primary macrophages were also analyzed. The results showed that the CSC-mediated increase in production of reactive oxygen species (ROS) in U937 cells is dose- and time-dependent. Moreover, CSC treatment was found to induce cytotoxicity in U937 cells through the apoptotic pathway via activation of caspase-3. Importantly, pretreatment with vitamin C blocked the CSC-mediated production of ROS and induction of caspase-3 activity. In U1 cells, acute treatment of CSC increased ROS production at 6H (>2-fold) and both ROS (>2 fold) and HIV-1 replication (>3-fold) after chronic treatment. The CSC mediated effects were associated with robust induction in the expression of CYP1A1 mRNA upon acute CSC treatment of U937 and U1 cells (>20-fold), and upon chronic CSC treatment to U1 cells (>30-fold). In addition, the CYP1A1 induction in U937 cells was mediated through the aromatic hydrocarbon receptor pathway. Lastly, CSC, which is known to increase viral replication in primary macrophages, was also found to induce CYP1 enzymes in HIV-infected primary macrophages. While mRNA levels of both CYP1A1 and CYP1B1 were elevated following CSC treatment, only CYP1B1 protein levels were increased in HIV-infected primary macrophages. In conclusion, these results suggest a possible association between oxidative stress, CYP1 expression, and viral replication in CSC-treated cells of myeloid lineage. This study warrants a closer examination of the role of CYP1B1 in smoking-mediated enhanced HIV replication.

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“…Of the 5000 compounds that are present in CSC, polyaryl hydrocarbons (PAHs) are a class of carcinogenic compounds that are implicated by several studies for their potential to induce oxidative stress 10 – 12 . Benzo(a)pyrene (BaP) is a prototype PAH, which has been widely studied for its carcinogenicity, genotoxicity, and mutagenicity 13 – 16 .…”

Section: Introductionmentioning

confidence: 99%

Benzo(a)pyrene in Cigarette Smoke Enhances HIV-1 Replication through NF-κB Activation via CYP-Mediated Oxidative Stress Pathway

Ranjit

Sinha

Kodidela

et al. 2018

Sci Rep

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Smoking aggravates HIV-1 pathogenesis and leads to decreased responses to antiretroviral therapy. In this study, we aim to find a molecular mechanism that would explain smoking-induced HIV-1 replication. Benzo(a)pyrene (BaP), a major carcinogen in cigarette, requires metabolic activation through cytochrome P450s (CYPs) to exert its toxic effects. We hypothesized that CYP-mediated BaP metabolism generates reactive oxygen species (ROS), and the resultant oxidative stress aggravates HIV-1 replication. As expected, we observed ~3 to 4-fold increase in HIV-1 replication in U1 cells and human primary macrophages after chronic BaP exposure. We also observed ~30-fold increase in the expression of CYP1A1 at mRNA level, ~2.5-fold increase in its enzymatic activity as well as elevated ROS and cytotoxicity in U1 cells. The knock-down of the CYP1A1 gene using siRNA and treatment with selective CYP inhibitors and antioxidants significantly reduced HIV-1 replication. Further, we observed a nuclear translocation of NF-κB subunits (p50 and p65) after chronic BaP exposure, which was reduced by treatment with siRNA and antioxidants/CYP inhibitors. Suppression of NF-κB pathway using specific NF-κB inhibitors also significantly reduced HIV-1 replication. Altogether, our results suggest that BaP enhances HIV-1 replication in macrophages by a CYP-mediated oxidative stress pathway followed by the NF-κB pathway.

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Polycyclic aromatic hydrocarbons and cytochrome P450 in HIV pathogenesis

Cited by 30 publications

References 83 publications

The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

Effects of Cigarette Smoke Condensate on Oxidative Stress, Apoptotic Cell Death, and HIV Replication in Human Monocytic Cells

Benzo(a)pyrene in Cigarette Smoke Enhances HIV-1 Replication through NF-κB Activation via CYP-Mediated Oxidative Stress Pathway

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