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)

The effect of a concurrent herpes simplex virus (HSV) infection on human immunodeficiency virus type 1 (HIV-1) load was evaluated. Sixteen subjects were identified with an active HSV infection and had pre-outbreak, acute-phase, and post-outbreak plasma (n = 16) and peripheral blood mononuclear cell (PBMC) (n = 8) samples for evaluation. All subjects were treated for an acute HSV outbreak with acyclovir for 10 days, followed by chronic prophylaxis. HIV-1 plasma RNA levels were determined by branched DNA, and intracellular HIV gag mRNA copy numbers were determined by quantitative reverse transcriptase-polymerase chain reaction ELISA. Plasma virus load increased a median of 3.4-fold during the acute outbreak (range, 0- to 10-fold; P = .002), while post-outbreak levels (30-45 days after the appearance of lesions) remained above pre-outbreak, baseline levels in some subjects. Intracellular HIV gag mRNA increased during the outbreak as well. Thus, an acute HSV episode can result in increased HIV transcription and plasma virus load.
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PMID:The impact of active herpes simplex virus infection on human immunodeficiency virus load. 929 29

The primary herpes simplex virus type 2 (HSV-2) latency-associated transcript (LAT) promoter influences LAT expression and rates of virus reactivation. We explored the biological importance of particular neuronally responsive regions within the promoter by creating new recombinant viruses bearing a targeted deletion (246 bp [strain 524]) or a point mutation (2 bp [strain 167]) in this region. These recombinant viruses grew efficiently in vitro and in vivo, caused acute genital disease in guinea pigs, and, as measured by quantitative-competitive (QC) DNA PCR, established latency, all as well as did the wild-type parental HSV-2 strain 333, the rescuant strain 524R, and the previously described 624-bp LAT- promoter deletion mutant. By QC-reverse transcriptase PCR of RNA from latently infected ganglia, mutant 167 expressed wild-type levels of LAT and the deletion mutant 524 expressed 9- to 15-fold less LAT than normal, while the LAT expression of the LAT- mutant was undetectable or at least 5 log units less than that of the wild type. The rates of recurrence of genital lesions were normal for recombinant viruses 524 and 167 but reduced (as expected) for the LAT- mutant. Alteration of a subset of LAT promoter elements reduced LAT expression by 1 log unit but did not influence the rate of spontaneous disease reactivation in vivo. Far greater reductions in LAT expression are necessary before reactivation rates are noticeably changed.
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PMID:Mutations in the 5' end of the herpes simplex virus type 2 latency-associated transcript (LAT) promoter affect LAT expression in vivo but not the rate of spontaneous reactivation of genital herpes. 931 80

Skin from acute and healed herpes simplex virus or herpes simplex virus-associated erythema multiforme (HAEM) lesions was examined by polymerase chain reaction with primers for DNA polymerase, ICP8, thymidine kinase (5' end of herpes simplex virus genome), and ICP27 (3' end of herpes simplex virus genome). The primers were herpes simplex virus specific and equally sensitive. The four herpes simplex virus genes were seen in acute herpes simplex virus lesions, but except for one patient, only polymerase (or polymerase and ICP8) were seen in 7-d healed lesional skin. Herpes simplex virus DNA was not seen 1-1.5 mo after healing. HAEM skins from 18 of 24 patients (75%) were positive for polymerase DNA and four of 24 (17%) were also positive for ICP8 or thymidine kinase DNA. Only one tissue (4%) was positive for polymerase, ICP8, and ICP27 DNA. Skin from healed HAEM lesions was still polymerase DNA positive 1-3 mo after lesion resolution. The polymerase DNA signal was in the basal and spinous cell layers of the epidermis and in the outer root sheath of the hair follicle. Polymerase RNA was identified by reverse transcriptase polymerase chain reaction in skin from acute, but not healed polymerase DNA positive HAEM lesions, suggesting that polymerase expression is associated with HAEM lesion development.
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PMID:Expression of herpes simplex virus DNA fragments located in epidermal keratinocytes and germinative cells is associated with the development of erythema multiforme lesions. 932 89

This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes simplex virus type 1 and varicella-zoster virus infections: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC [cidofovir]) for the therapy of various DNA virus (i.e., herpesvirus, adenovirus, papillomavirus, polyomavirus, and poxvirus) infections; 9-(2-phosphonylmethoxyethyl)adenine (PMEA [adefovir]) for the therapy of retrovirus, hepadnavirus, and herpesvirus infections; (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for the therapy and prophylaxis of retrovirus and hepadnavirus infections; and nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(IH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), alpha-anilinophenylacetamide (alpha-APA), and 2',5'bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxat hiole- 2",2"-dioxide)pyrimidine (TSAO) derivatives, and thiocarboxanilides for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. For the clinical use of NNRTIs, some guidelines have been elaborated, such as starting treatment with combinations of different compounds at sufficiently high concentrations to effect a pronounced and sustained suppression of the virus. Despite the diversity of the compounds described here and the different viruses at which they are targeted, they have a number of characteristics in common. As they interact with specific viral proteins, the compounds achieve a selective inhibition of the replication of the virus, which, in turn, should be able to develop resistance to the compounds. However, as has been established for the NNRTIs, the problem of viral resistance may be overcome if the compounds are used from the start at sufficiently high doses, which could be reduced if different compounds are combined. For HIV infections, drug treatment regimens should be aimed at reducing the viral load to such an extent that the risk for progression to AIDS will be minimized, if not avoided entirely. This may result in a real "cure" of the disease but not necessarily of the virus infection, and in this sense, HIV disease may be reduced to a dormant infection, reminiscent of the latent herpesvirus infections. Should virus replication resume after a certain time, the armamentarium of effective anti-HIV and anti-herpesvirus compounds now available, if applied at the appropriate dosage regimens, should make the virus return to its dormant state before it has any chance to damage the host. It is unlikely that this strategy would eradicate the virus and thus "cure" the viral infection, but it definitely qualifies as a cure of the disease.
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PMID:In search of a selective antiviral chemotherapy. 933 68

Interferon gamma (IFN-gamma) production as a measure of cellular sensitization was studied by detection of the cytokine in culture supernatant by enzyme immunoassay (EIA) and by measuring cellular mRNA using the reverse transcriptase polymerase chain reaction (RT-PCR) method. These assays were compared to the standard lymphocyte proliferation assay as a marker of T cell responsiveness to foreign antigens. When blood donors seropositive for herpes simplex virus (HSV) were compared to seronegative donors, all measurements of cellular sensitization separated the groups without overlap. There were significant correlations between the IFN-gamma mRNA titre and the secreted IFN-gamma (r = 0.57, P = 0.03), and the proliferative response and the secreted IFN-gamma (r = 0.78, P = 0.001), as well as between the IFN-gamma mRNA titre and the proliferative response (r = 0.78, P < 0.001). When tetanus toxoid (TT) responses were studied in immunized subjects, a wide range of responsiveness could be seen and correlation between various measurements was poor. However, constant individual levels of the cytokine production were demonstrated. Six people who had received their last TT booster vaccination more than 5 years ago were revaccinated and repeatedly studied. An increase in the levels of produced IFN-gamma could be seen in all subjects and two who lacked a lymphocyte proliferation response developed it after revaccination.
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PMID:Interferon-gamma production in antigen specific T cell response: quantitation of specific mRNA and secreted protein. 935 Feb 90

The inhibitory effects of polyanionic substances on the replication of herpes simplex virus (HSV) and other viruses were reported almost four decades ago. However, these observations did not generate much interest, because the antiviral action of the compounds was considered to be largely nonspecific. Shortly after the identification of human immunodeficiency virus (HIV) as the causative agent of the acquired immune deficiency syndrome (AIDS) in 1984, heparin and other sulfated polysaccharides were found to be potent and selective inhibitors of HIV-1 replication in cell culture. Since 1988, the activity spectrum of the sulfated polysaccharides has been shown to extend to various enveloped viruses, including viruses that emerge as opportunistic pathogens (e.g., herpes simplex virus [HSV] and cytomegalovirus [CMV]) in immunosuppressed (e.g., AIDS) patients. As potential anti-HIV drug candidates, sulfated polysaccharides offer a number of promising features. They are able to block HIV replication in cell culture at concentrations as low as 0.1 to 0.01 microgram ml-1 without toxicity to the host cells at concentrations up to 2.5 mg ml-1. We noted that some polysulfates show a differential inhibitory activity against different HIV strains, suggesting that marked differences exist in the target molecules with which polysulfates interact. They not only inhibit the cytopathic effect of HIV, but also prevent HIV-induced syncytium (giant cell) formation. Furthermore, experiments carried out with dextran sulfate samples of increasing molecular weight and with sulfated cyclodextrins of different degrees of sulfation have shown that antiviral activity increases with increasing molecular weight and degree of sulfation. A sugar backbone is not strictly needed for the anti-HIV activity of polysulfates because sulfated polymers composed of a carbon-carbon backbone have also proved to be highly efficient anti-HIV agents in vitro. Other, yet to be defined, structural features may also play an important role. Sulfated polysaccharides may act synergistically with other anti-HIV drugs (e.g., azidothymidine [AZT]). They are known to lead very slowly to virus-drug resistance development and they show activity against HIV mutants that have become resistant to reverse transcriptase inhibitors, such as AZT, tetrahydro-imidazo [4,5,l-jk] [1,4]-benzodiazepin-2(1H)-thione (TIBO) and others. From studies on their mechanism of action we concluded that polysulfates exert their anti-HIV activity by shielding off the positively charged sites in the V3 loop of the viral envelope glycoprotein (gp120). The V3 loop is necessary for virus attachment to cell surface heparan sulfate, a primary binding site, before more specific binding occurs to the CD4 receptor of CD4+ cells. This general mechanism also explains the broad antiviral activity of polysulfates against enveloped viruses. Variations in the viral envelope glycoprotein region may result in differences in the susceptibility of different enveloped viruses to compounds that interact with their envelope glycoproteins. The efficacy of polysulfates in the therapy and/or prophylaxis of retroviral infections and opportunistic infections remains to be demonstrated both in animal models and humans. It is important to consider not only treatment of patients who are already infected with HIV, but also prophylaxis and protection from HIV and/or other virus infections. Because (i) sexual transmission is responsible for the large majority of HIV infections worldwide; (ii) this transmission is mostly mediated via mononuclear cells that infect epithelial cells of the genital tract; and because (iii) polysulfates effectively inhibit cell-cell adhesion, polysulfates may be considered as potentially effective in a vaginal formulation to protect against HIV infection.
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PMID:Sulfated polysaccharides extracted from sea algae as potential antiviral drugs. 935 94

We have recently reported that certain ribosylated polyhalogenated benzimidazoles are potent and selective inhibitors of HCMV replication at noncytotoxic concentrations. To extend the structure-activity relationship beyond these first-generation compounds, we alkylated 5,6-dichloro-2-substituted-benzimidazoles with either a series of substituted benzyl halides or (2-bromoethyl)benzene to obtain five series of nonnucleoside analogues. Evaluation of these compounds for activity against herpes viruses revealed that the new compounds were less active than the benzimidazole ribonucleosides against human cytomegalovirus (HCMV) and inactive against herpes simplex virus type 1 (HSV-1). However, as part of our broader antiviral testing, we found that some of these compounds were active against HIV. Comparisons of the biological data revealed that a chloro or bromo group was required at the 2-position for the best separation of activity against HIV and cytotoxicity. Evaluation of the most active compounds against drug-resistant HIV suggested that they act by a mechanism other than inhibition of reverse transcriptase.
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PMID:Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)-2-substituted-5,6-dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole. 954 15

Laboratory techniques for the diagnosis of central nervous system (CNS) infections are rapidly improving but at present have limitations that necessitate our guarded enthusiasm. Enteroviruses are the most common infectious agents of viral meningitis for which an etiology can be determined, and it is anticipated that the use of the reverse transcriptase polymerase chain reaction (RT-PCR) technique should significantly improve the identification of the etiologic agent of aseptic meningitis. The combination of the polymerase chain reaction technique with laboratory methods for the determination of intrathecal antibody production to herpes simplex virus and varicella-zoster virus have improved the rapidity with which these viral infections can be diagnosed. The pearls and pitfalls of the use of these laboratory techniques in the diagnosis of viral meningitis, recurrent meningitis, and focal encephalitis are included. Recommendations for the empiric therapy of bacterial meningitis in children and adults have changed because of the emergence of penicillin and cephalosporin-resistant pneumococcal organisms. The currently recommended antibiotics and their dosages are included. The evidence for the efficacy of dexamethasone therapy in bacterial meningitis is provided. Meningitis due to Mycobacterium tuberculosis is increasingly recognized, and the initiation of empiric antituberculous chemotherapy should not await the results of CSF cultures. Toxoplasma encephalitis and primary CNS lymphoma are the most common cause of mass lesions in patients with HIV, and the diagnostic techniques to distinguish between these two infections is reviewed. A short discussion of the best test for the diagnosis of neurosyphilis is provided.
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PMID:Pearls and pitfalls in the diagnosis and management of central nervous system infectious diseases. 960 16

Hepatitis G virus (HGV) is a recently discovered RNA virus, which belongs to the Flaviviridae family. Although HGV infection is usually not associated with elevated serum transaminases, some recent studies have reported that HGV infection is found in a significant number of patients with fulminant hepatitis and may play a role in its etiopathogenesis. In this study the prevalence of HGV infection was determined in 500 healthy blood donors and in 24 patients admitted to hospital because of acute liver failure caused by fulminant hepatitis. The presence of HGV RNA was tested in sera, obtained at admission and before any transfusion was given, by a sensitive seminested reverse transcriptase-polymerase chain reaction (RT-PCR) assay specific for detection of the non-structural (NS)5 region. Nine of the 500 blood donors (1.8%) and two of the 24 patients (8.3%) were found to be HGV RNA positive. One patient was co-infected with HCV and was known to be an intravenous (i.v.) drug user. After intensive supporting treatment, this patient recovered completely. The second patient had no serological markers of known viral hepatitis infection, including hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV). This patient was successfully transplanted. From both patients, from HGV RNA-positive healthy blood donors and from other patients coinfected with HCV, a part of the HGV NS3 region (nucleotides 4191-4345, EMBL entry U45966) was cloned and sequenced. Sequence comparison revealed that the NS3 region of HGV in patients with fulminant hepatitis contained three nucleotide substitutions as part of the six substitutions described in previous work. These nucleotide substitutions were not found in the tested blood donors or in patients with HCV co-infection. Our findings therefore support the concept of the association of fulminant hepatitis with infection of a specific HGV strain.
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PMID:Hepatitis G virus infection in acute fulminant hepatitis: prevalence of HGV infection and sequence analysis of a specific viral strain. 979 13

Mice exercised to fatigue and exposed to herpes simplex virus type 1 (HSV-1) exhibit greater mortality than control mice. In this study, we examined lung macrophage resistance to HSV-1 after exercise in terms of both viral replication and interferon (IFN)-beta production. We utilized the reverse transcriptase-rapid polymerase chain reaction to measure the IFN-beta mRNA content in alveolar macrophages. IFN release was measured with a bioassay, and viral replication within the macrophage was assessed by plaque titration. Exercised (Ex) mice ran on a treadmill until fatigue while control (Con) mice remained in lanes above the treadmill. After exercise, alveolar macrophages were removed and incubated with HSV-1. Alveolar macrophage IFN-beta mRNA was greater in Ex than in Con mice. Culture supernatant from infected macrophages showed a higher degree of IFN release and a higher number of infectious viral particles in Ex vs. Con mice. It is likely that the increase in IFN-beta mRNA occurs in response to a higher degree of viral replication. These results suggest that macrophages from Ex mice are less resistant to infection with HSV-1.
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PMID:Exercise effects on IFN-beta expression and viral replication in lung macrophages after HSV-1 infection. 984 45


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