Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of mouse trigeminal ganglia by herpes simplex virus induces cytokine expression that persists long after infectious virus or viral antigens become undetectable. To examine mechanisms underlying this phenomenon, we used a thymidine kinase mutant, dlsptk, which fails to replicate in ganglia and does not reactivate upon ganglionic explant. Using quantitative reverse transcriptase-polymerase chain reaction assays, we found that levels of interferon-gamma and tumor necrosis factor-alpha transcripts in dlsptk-infected ganglia were lower than those in wild type-infected ganglia, but were significantly (eight- to 10-fold) higher than those in mock-infected ganglia from Day 3 to Day 100 postinfection. We also studied latency-associated transcript (LAT) negative mutants that exhibit increased expression of productive cycle transcripts in ganglia. Ganglia infected with these mutants contained levels of cytokine transcripts similar to those in wild type-infected ganglia; any increases in viral antigen expression mediated by the LAT deletion were not accompanied by increased cytokine expression. Thus, neither viral replication, the ability to reactivate, nor LAT expression in ganglia is required for persistent elevated cytokine expression. The results provide indirect evidence that low-level expression of viral productive cycle genes in neurons can provide signals that elicit cytokine expression.
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PMID:Persistent elevated expression of cytokine transcripts in ganglia latently infected with herpes simplex virus in the absence of ganglionic replication or reactivation. 1111 95

The various alphaherpesviruses, including Marek's disease virus (MDV), have both common and unique features of gene content and expression. The entire MDV U(s) region has been sequenced in our laboratory (P. Brunovskis and L. F. Velicar, Virology 206:324-338, 1995). Genes encoding the MDV glycoprotein D (gD), glycoprotein I (gI), and glycoprotein E (gE) homologs have been found in this region, although no gG homolog was found. In this work, transcription of the tandem MDV gD, gI, and gE genes was studied and found to have both unique characteristics and also features in common with other alphaherpesviruses. MDV gD could not be immunoprecipitated from MDV GA-infected duck embryo fibroblast cells by antisera reactive to its TrpE fusion proteins, while gI and gE could be. When the gD gene was subjected to in vitro-coupled transcription-translation, the precursor polypeptide was produced and could be immunoprecipitated by anti-gD. Northern blot, reverse transcriptase PCR, and RNase protection analyses have shown that (i) no mRNA initiating directly from the gD gene could be detected; (ii) a large but low-abundance 7.5-kb transcript spanning five genes, including the one encoding gD, was seen on longer exposure; and (iii) transcription of the gI and gE genes formed an abundant bicistronic 3.5-kb mRNA, as well as an abundant 2.0-kb gE-specific mRNA. Therefore, the MDV gD gene expression is down-regulated at the transcription level in MDV-infected cell culture, which may be related to the cell-associated nature of MDV in fibroblast cells. Compared to the highly gD-dependent herpes simplex virus and the other extreme of the varicella-zoster virus which lacks the gD gene, MDV is an intermediate type of alphaherpesvirus.
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PMID:Transcriptional analysis of Marek's disease virus glycoprotein D, I, and E genes: gD expression is undetectable in cell culture. 1116 Jul 11

In the search of effective and selective chemotherapeutic agents for the treatment of viral infections, my "Odyssey" brought me to explore a variety of approaches, encompassing interferon and interferon inducers, suramin and other polyanionic substances, S-adenosylhomocysteine hydrolase inhibitors, inosine 5'-monophosphate dehydrogenase inhibitors, 5-substituted 2'-deoxyuridines such as (E)-5-(2-bromovinyl)-2'-deoxyuridine, acyclovir (esters) and other acyclic guanosine analogues, 2',3'-dideoxynucleoside analogues, non-nucleoside reverse transcriptase inhibitors (NNRTIs), bicyclams, and acyclic nucleoside phosphonates. This had led to the identification of a number of compounds, efficacious against such important viral pathogens as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), and other herpesviruses, pox-, adeno-, polyoma-, and papillomaviruses, and hemorrhagic fever viruses.
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PMID:Hamao Umezawa Memorial Award Lecture: "An Odyssey in the Viral Chemotherapy Field". 1169 63

Therapy of HIV infection has undergone significant changes since the introduction of highly-active antiretroviral therapy (HAART). Mortality and the appearance of opportunistic infections have significantly been reduced. Diseases of the skin and adjacent mucous membranes often provide the first signs for HIV infection. The spectrum of dermatologic findings related to HIV includes a variety of cutaneous and mucocutaneous disorders. The most frequent diagnoses are oral candidiasis, mollusca contagiosa, oral hairy leuokoplakia, herpes zoster and herpes simplex, seborrheic dermatitis, and Kaposi's sarcoma. Incompatibility reactions to drugs are observed on a strikingly frequent basis in HIV infection. Such severe incompatibility reactions are much more frequent in HIV patients than in the normal population. Inducers often include sulfonamides, cotrimoxazole, tuberculostatics as well as nucleoside-type reverse transcriptase inhibitors.
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PMID:Dermatological diseases and signs of HIV infection. 1189 Nov 45

Latent infections by herpes simplex virus are characterized by repression of productive-cycle gene expression. Several hypotheses to explain this repression involve inhibition of expression of the immediate-early gene activator ICP0 during latency. To address these hypotheses, we developed quantitative reverse transcriptase-PCR assays that detected spliced and intron-containing ICP0 transcripts in mouse ganglia latently infected with wild-type virus. In these ganglia, the numbers of spliced ICP0 transcripts correlated better with the numbers of transcripts from the immediate-early gene encoding ICP4 than with those from the early gene encoding thymidine kinase. There were fewer spliced than intron-containing ICP0 transcripts on average, with considerable ganglion-to-ganglion variation. We then investigated whether ICP0 expression in latently infected ganglia is reduced by the latency-associated transcripts (LATs) and whether splicing of ICP0 transcripts is inhibited by the product of open reading frame (ORF) P. A LAT deletion mutation which essentially eliminates expression of the major LATs did not appreciably increase levels of ICP0 transcripts. LAT deletion mutants did, however, appear to express reduced levels of intron-containing ICP0 transcripts. ORF P mutations did not alter levels of ICP0 transcripts in a manner consistent with inhibition of ICP0 splicing by ORF P. Although these results argue against antisense inhibition of ICP0 expression by LATs or inhibition of ICP0 splicing by ORF P, they are consistent with the possibilities of a block between immediate-early and early gene expression and regulation of spliced versus intron-containing ICP0 transcripts in latently infected ganglia.
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PMID:Neither LAT nor open reading frame P mutations increase expression of spliced or intron-containing ICP0 transcripts in mouse ganglia latently infected with herpes simplex virus. 1196 93

Nitric oxide (NO) is an important biologically active molecule that plays a key part in host defence against bacteria, protozoa, and tumour cells. NO has antiviral effects against several DNA viruses, such as murine poxvirus, herpes simplex virus, and Epstein-Barr virus, and some RNA viruses, such as coxsackievirus. In several studies, in vitro and in vivo, overproduction of NO has been noted in the presence of HIV-1 infection. Furthermore, increased NO production may contribute directly to the pathogenesis of HIV-1-associated dementia. The mechanisms of virus infection mediated by NO may be related to: direct antiviral effects of NO; impairment of antiviral defence mediated by T-helper-1 immune response by suppressing T-helper-1 functions; NO-induced cytotoxic effects by oxidative injury with cellular and organ dysfunctions; and NO-induced oxidative stress leading to rapid viral evolution with productions of drug-resistant and immunologically tolerant mutants. By contrast, there is some evidence of NO activity--directly, indirectly, or both--decreasing or blocking HIV-1 replication, through inhibition of viral enzymes, such as reverse transcriptase, protease, or cellular nuclear transcription factor (NF-kappa B) and long-terminal repeat-driven transcription. Therefore, although NO surely plays an important part in HIV-1 infection, that role is sometimes helpful and other times damaging to the host. Future challenges are to learn more about the beneficial and harmful effects of NO in HIV-1 infection, and how to selectively inhibit excessive NO production or to use NO-releasing drugs to decrease viral replication. This review discusses the role of NO in the pathogenesis of HIV-1 infection, inasmuch as its role against HIV-1 is unequivocal in inhibiting or increasing viral replication.
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PMID:Role of nitric oxide in HIV-1 infection: friend or foe? 1261 27

The US11 protein of herpes simplex virus type 1 (HSV-1) is a small, highly basic phosphoprotein expressed at late times during infection. US11 localizes to the nucleolus in infected cells, can associate with ribosomes, and has been shown to bind RNA. The RNA substrates of US11 identified thus far have no apparent role in the virus lytic cycle, so we set out to identify a novel, biologically relevant RNA substrate(s) for this protein in HSV-1-infected cells. We designed a reverse transcriptase PCR-based protocol that allowed specific selection of a 600-bp RNA binding partner for US11. This RNA sequence, designated 12/14, is present in the coterminal HSV-1 mRNAs UL12, UL13, and UL14. We show that the binding of US11 to 12/14 is sequence-specific and mediated by the C-terminal domain of the protein. To elucidate the role of US11 in the virus life cycle, we infected cells with wild-type virus, a cosmid-reconstructed US11 HSV-1 null mutant, and a cosmid-reconstructed wild-type virus and analyzed expression of UL12, -13, and -14 during a time course of infection. These experiments revealed that this interaction has biological activity; at early times of infection, US11 down-regulates UL13 protein kinase mRNA and protein.
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PMID:The herpes simplex virus type 1 US11 protein binds the coterminal UL12, UL13, and UL14 RNAs and regulates UL13 expression in vivo. 1213 14

Acute hemorrhagic leukoencephalitis (AHL) is a rare and usually fatal disorder characterized clinically by an acute onset of neurologic abnormalities. It may occur in association with a viral illness or vaccination. Radiology and brain biopsy are essential for the diagnosis. The etiology of AHL is unclear. We postulated that viral/bacterial infection might be responsible, directly or through an immune-mediated mechanism, for this acute inflammatory myelinopathy. Fifteen cases of AHL were studied. Infectious agents, including varicella zoster virus (VZV), herpes simplex virus (HSV), human herpes virus-6 (HHV-6), cytomegalovirus, Epstein-Barr virus, and Mycoplasma, were investigated in brain specimens using the polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, and immunohistochemistry. Using PCR, HSV DNA was found in four cases, VZV DNA in two, and HHV-6 DNA in one. Among the control cases, two were HSV DNA positive. Further investigation to detect HSV RNA and antigens in HSV DNA-positive cases revealed that two cases with AHL were both HSV RNA and antigen positive. AHL is a hyperacute disease, which is considered the most acute form of acute disseminated encephalomyelitis (ADEM). Our findings suggests that a viral infection may be implicated in its pathogenesis, most likely through an indirect mechanism; however, as only a few cases of this rare disease were examined, statistical significance was not achieved. As a number of patients with disorders of the ADEM group may progress to develop multiple sclerosis (MS), we argue that an organism that has produced the former may remain in the brain tissue and be subsequently involved in the production of a self-sustained disorder such as MS.
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PMID:Detection of infectious agents in brain of patients with acute hemorrhagic leukoencephalitis. 1240 70

The persistence of herpes simplex virus (HSV) and the diseases that it causes in the human population can be attributed to the maintenance of a latent infection within neurons in sensory ganglia. Little is known about the effects of latent infection on the host neuron. We have addressed the question of whether latent HSV infection affects neuronal gene expression by using microarray transcript profiling of host gene expression in ganglia from latently infected versus mock-infected mouse trigeminal ganglia. (33)P-labeled cDNA probes from pooled ganglia harvested at 30 days postinfection or post-mock infection were hybridized to nylon arrays printed with 2,556 mouse genes. Signal intensities were acquired by phosphorimager. Mean intensities (n = 4 replicates in each of three independent experiments) of signals from mock-infected versus latently infected ganglia were compared by using a variant of Student's t test. We identified significant changes in the expression of mouse neuronal genes, including several with roles in gene expression, such as the Clk2 gene, and neurotransmission, such as genes encoding potassium voltage-gated channels and a muscarinic acetylcholine receptor. We confirmed the neuronal localization of some of these transcripts by using in situ hybridization. To validate the microarray results, we performed real-time reverse transcriptase PCR analyses for a selection of the genes. These studies demonstrate that latent HSV infection can alter neuronal gene expression and might provide a new mechanism for how persistent viral infection can cause chronic disease.
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PMID:Latent herpes simplex virus infection of sensory neurons alters neuronal gene expression. 1291 67

The real-time principle of reverse transcriptase polymerase chain reaction (RT-PCR) provides a quantitative and reproducible method to detect low copy number transcripts. The quantitative detection of cytokines from tissue samples is complicated by the low expression rates and the short half-lives of the cytokine proteins. The methods have been insensitive and labor-intensive. The LightCycler technique provides a 30-min PCR system with continuous fluorescent detection, analysis of the melting points of the products and user-friendly software for the analysis of the unknown samples. External copy number standards enable the measurement of amounts of the desired targets. We demonstrate the dynamic range of the RT-PCR system from a 100 to 10(7) mRNA copies of the mouse Th1 cytokines interleukin- (IL-) 12p35, 12p40 and IL-23p19 as well as gamma interferon (IFN-gamma) and the housekeeping gene beta-actin, with the usage of fluorescent hybridization probes. The cytokine quantitation was exemplified in murine nervous system samples. A viral transcript, mRNA of alpha trans-inducing factor (alphaTIF), or VP16 gene, of herpes simplex virus (HSV) type 1 was used to quantitate the viral replication in infected cells and in murine nervous system samples. For this viral transcript the linear dynamic range spanned from ten copies to one million copies (highest tested). For all tested cytokine transcripts, the detection level with the dsDNA binding dye SYBR Green I was one log lower than with the hybridizing fluorescent probes. The viral transcript was detected even with the SYBR Green I system at the level of ten copies. The specificity of the PCR was reached with the use of TaqStart antibody, by careful design of primers and probes, by melting temperature analysis and comparison with the gel electrophoresis and Southern blot analysis.
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PMID:Low copy number detection of herpes simplex virus type 1 mRNA and mouse Th1 type cytokine mRNAs by Light Cycler quantitative real-time PCR. 1295 Dec 13


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