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:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Symptomatic human herpes simplex virus type 1 (HSV-1) infections are rather benign in immunocompetent individuals. The primary clinical manifestations of HSV-2 infection, which is mainly transmitted sexually, are anogenital lesions. Genital herpes affects one third of the world's population, and possibly 80% of those infected with HIV. HSV infections are especially severe and even life-threatening in people with AIDS. Only 20% of herpes seropositive persons have symptomatic infection, with the remainder asymptomatic but able to shed the virus. HSV infections are usually treated with nucleoside analogs such as acyclovir (ACV), but HSV eventually becomes resistant to ACV due to the loss or mutation of the viral thymidine kinase (TK) or changes in viral DNA polymerase. Gramicidin has recently been identified as a potent nontoxic anti-HIV agent 3-5 times more active than nonoxynol-9. Findings are reported from an assessment of the effect of gramicidin upon the replication of HSV-1 and HSV-2. Human WI-38 fibroblasts were inoculated with either HSV type in the presence of serial dilutions of gramicidin, while reduction in viral yield was measured by ELISA. The 50% inhibitory dose (IC50) of gramicidin against 3 HSV-1 and 4 HSV-2 isolates was equal to 0.3 mcg/ml and was comparable to the efficacy of ACV. The IC50 of gramicidin required to protect WI-38 from the cytolytic effect of HSV was 10 mcg/ml at day 5 postinfection, indicating that gramicidin was less active than ACV. Gramicidin nonetheless suppressed the replication of ACV-resistant thymidine kinase and DNA polymerase HSV mutants at doses effective against ACV-sensitive strains. These results suggest that gramicidin could be used against STDs and to prevent sexually transmitted HIV and HSV infections.
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PMID:The effect of gramicidin, a topical contraceptive and antimicrobial agent with anti-HIV activity, against herpes simplex viruses type 1 and 2 in vitro. 967 88

In recent years several assays have been developed for quantitation of human cytomegalovirus (HCMV) in blood of immunocompromised (transplanted and AIDS) patients. It is currently agreed that the only reliable indication of the degree of dissemination of HCMV infection/disease is the measurement of HCMV in blood. Diagnosis of HCMV end-organ disease (organ localizations) often does not benefit from quantitation of virus in blood, but requires detection and quantification of virus in samples taken locally. The most important and clinically useful diagnostic assays for HCMV quantitation in blood are: i) viremia, quantifying infectious HCMV carried by peripheral blood leukocytes (PBL); ii) pp65-antigenemia, quantifying the number of PBL positive for HCMV pp65 in the nucleus; iii) circulating cytomegalic endothelial cell (CEC) viremia (CEC-viremia) measuring the number of circulating CEC carrying infectious HCMV (during the antigenemia assay); iv) leuko- and plasma-DNAemia, quantifying the number of HCMV genome equivalents present in PBL or plasma, respectively, by quantitative polymerase chain reaction (Q-PCR). Other less widely used assays are: i) determination of immediate early and late gene transcripts (mRNA) to detect active viral infection; ii) in situ hybridization to detect viral nucleic acid (DNA or RNA) in tissue sections or cell smears; iii) in situ PCR to detect a low DNA copy number in single cells. Monitoring of HCMV infection/disease in transplant recipients and AIDS patients has established threshold values for different assays above which HCMV-related clinical symptoms are likely to appear. These values are approximately 10 for viremia, 100 for antigenemia and 1,000 GE for leukoDNAemia, and are valid for both solid organ and bone marrow transplant recipients as well as AIDS patients, whereas presence of even a single circulating CEC is sufficient to suggest the presence of a disseminated HCMV infection with potential organ involvement. Monitoring of antiviral treatment of HCMV infection/disease with either ganciclovir or foscarnet has aimed at keeping virologic parameters below the threshold values reported above. On the other hand, rising levels of the same virologic parameters during antiviral treatment have mostly revealed emergence of resistant HCMV strains to either ganciclovir (mutations in the UL97 or DNA polymerase gene) or foscarnet (mutations in the UL54 gene) or both drugs (double resistance with both types of mutations). Rapid assays for chemosensitivity testing of virus directly in clinical specimens have been developed to allow timely (4-6 days) detection of resistance to a drug and provide clinicians with the rationale for shifting to an alternative treatment.
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PMID:Diagnostic significance and clinical impact of quantitative assays for diagnosis of human cytomegalovirus infection/disease in immunocompromised patients. 969 13

(R)-9-(2-Phosphonylmethoxypropyl)adenine (PMPA) is an acyclic nucleoside phosphonate that has been shown to be effective in the treatment of AIDS although it has a shorter separation between the adenine and phosphorus than dideoxy-AMP and dAMP. By using pre-steady state kinetic methods, we examined the incorporation of the diphosphate of PMPA, 2',3'-dideoxyadenosine 5'-triphosphate (ddATP), and dATP catalyzed by wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, an exonuclease-deficient T7 DNA polymerase (T7 exo-), and wild-type rat DNA polymerase beta in order to evaluate the selectivity of PMPA as an antiviral inhibitor. With a DNA/DNA or DNA/RNA 22/43-mer duplex, the diphosphate of PMPA (PMPApp) is as effective as ddATP in reactions catalyzed by HIV-1 reverse transcriptase in that both analogs have similar substrate specificity constants (kp/Kd) which are only 5-fold lower than dATP. In contrast, PMPApp is a much weaker inhibitor of the reaction catalyzed by T7 exo- (with the DNA/DNA 22/43-mer duplex) in that PMPApp has a 5 x 10(-4)-fold lower kp/Kd than ddATP and dATP. The lower kp/Kd of PMPApp is due to a 1000-2000-fold lower incorporation rate (kp) and a 35-45-fold lower binding constant (Kd). Similarly, PMPApp is 800-fold less inhibitory toward polymerase beta with the DNA/DNA 22/43-mer duplex, whereas in studies with a single nucleotide gapped DNA (22-20/43-mer) PMPApp is 13-fold less inhibitory than ddATP. Although parallel studies will need to be performed using appropriate human polymerases, these results begin to define the mechanistic basis for the reported lower toxicity of PMPA in the treatment of AIDS.
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PMID:Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor, (R)-9-(2-Phosphonylmethoxypropyl)adenine. 976 48

1. The subject of this review is the interaction between AZT (zidovudine) and mitochondria as described in papers dealing with AZT therapy both in AIDS patients and in model systems--that is, in cultured cells and in isolated mitochondria. 2. The structure and function of mitochondria are briefly described with discussion of the theoretical frame for a detailed bioenergetic investigation. 3. Experimental work is reported showing that mitochondria are cell AZT targets: changes in the structure and function induced by long-term AZT therapy as investigated both in AIDS patients and in model systems. 4. The AZT inhibition of energy-supplying reactions is considered in detail in studies dealing with long-term treatment and studies in which AZT was added to isolated mitochondria. In particular, adenylate kinase, ADP/ATP translocase and DNA polymerase gamma are reported as molecular targets of AZT. 5. Some perspectives of AZT therapy from the study of the effect of AZT on mitochondrion biochemistry are briefly reported.
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PMID:Mitochondria as cell targets of AZT (zidovudine). 979 11

We describe a 46-year-old man in whom retinitis was diagnosed as his initial HIV and AIDS defining illness. A diagnosis of CMV infection was made based on the clinical appearance of the fundus and confirmed by DNA polymerase chain reaction (PCR) on his vitreous biopsy. His CD4+ T lymphocyte count at the time was 580 x 10(6)/l (16%) with a CD4:CD8 ration of 0.28. He had a splenectomy following trauma more than 20 years earlier. He responded very well to intravenous and oral ganciclovir and remains recurrence-free almost 2 years later. This case and others highlight two issues: (i) CMV retinitis in HIV positive is not confined to those with very low CD4+ T lymphocyte counts; (ii) previous splenectomy may have an impact on CD4+ cell numbers and function.
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PMID:Cytomegalovirus retinitis, human immunodeficiency virus antibody positivity and normal T helper cell numbers. 982 Oct 96

Recently, a new herpesvirus-like DNA sequence named Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) has been isolated from almost all cases of Kaposi's sarcoma (KS). It has not been found in most benign and malignant cutaneous hemangioproliferative disorders other than KS. To further verify the specificity of the association of this new viral DNA with KS, we examined in total 42 cases of vascular neoplasms of endothelial derivation using nested polymerase chain reaction (PCR) for the presence of a 233-bp segment of this KSHV/HHV8 on paraffin-embedded specimens. In our investigation, we added an additional step to conventional PCR protocol that uses UV light to pretreat all the PCR regeants except Taq DNA polymerase and the target DNA to eliminate the false positives caused by trace contamination. All 15 cases of typical KS, both AIDS and non-AIDS related, as well as 4 cases of atypical vascular tumors suspicious of KS, were positive for this KSHV/HHV8 DNA sequence. The remaining 23 cases of hemangioproliferative disorders other than KS, including angiosarcoma, capillary hemangioma, angiolymphoid hyperplasia with eosinophilia, epithelioid hemangioma, histiocytoid hemangioma, hemangioendothelioma, and microvenous hemangioma, were negative for HHV8. These results confirm the previous observation that KSHV/HHV8 is specific for KS within hemangioproliferative cutaneous disorders, and PCR for detection of KSHV/HHV8 might be used as an additional diagnostic tool in distinguishing KS.
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PMID:Further confirmation of the association of human herpesvirus 8 with Kaposi's sarcoma. 982 66

The genetic characterization of a foscarnet-resistant strain of varicella-zoster virus (VZV) that was isolated from a patient with AIDS is reported. Compared with the sequence of the Dumas reference strain, this strain, which was isolated from a patient in whom foscarnet treatment failed, had two point mutations. The emergence of one of the mutations, which includes a change from a glutamic acid to a lysine at position 512 in the DNA polymerase, suggests that this mutation is implicated in the VZV foscarnet resistance. The other mutation, which replaces serine 863 by a glycine, is also present in 2 susceptible strains--Oka and a wild-type isolate.
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PMID:Single amino acid change in DNA polymerase is associated with foscarnet resistance in a varicella-zoster virus strain recovered from a patient with AIDS. 985 75

Cidofovir is the first nucleoside monophosphate analogue currently being used for the treatment of human cytomegalovirus (HCMV) retinitis in individuals with AIDS. Unfortunately, the period of therapy with the use of this compound may be limited due to the possible emergence of serious irreversible nephrotoxic effects. New drugs with improved toxicity profiles are needed. The goal of this study was to investigate the anticytomegaloviral properties and drug-induced toxicity of a novel phosphonate analogue, namely, (-)-2-(R)-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran (compound 1), in comparison with those of cidofovir. The inhibitory activities of both compounds on HCMV propagation in vitro were similar against the AD 169 and Towne strains, with 50% inhibitory concentrations ranging from 0.02 to 0.17 microgram/ml for cidofovir and < 0.05 to 0.09 microgram/ml for compound 1. A clinical HCMV isolate that was resistant to ganciclovir and that had a known mutation within the UL54 DNA polymerase gene and a cidofovir-resistant laboratory strain derived from strain AD 169 remained sensitive to compound 1, whereas their susceptibilities to ganciclovir and cidofovir were reduced by 33- and 10-fold, respectively. Both compound 1 and cidofovir exhibited equal potencies in an experimentally induced murine cytomegalovirus (MCMV) infection in mice, with a prevention or prolongation of mean day to death at dosages of 1.0, 3.2, and 10.0 mg/kg of body weight/day. In cytotoxicity experiments, compound 1 was found to be generally more toxic than cidofovir in cell lines Hs68, HFF, and 3T3-L1 (which are permissive for HCMV or MCMV replication) but less toxic than cidofovir in MRC-5 cells (which are permissive for HCMV replication). Drug-induced toxic side effects were noticed for both compounds in rats and guinea pigs in a 5-day repeated-dose study. In guinea pigs, a greater weight loss was noticed with cidofovir than with compound 1 at dosages of 3.0 and 10.0 mg/kg/day. An opposite effect was detected in rats, which were treated with the compounds at relatively high dosages (up to 100 mg/kg/day). Compound 1 and cidofovir were nephrotoxic in both rats and guinea pigs, with the epithelium lining the proximal convoluted tubules in the renal cortex being the primary target site. The incidence and the severity of the lesions were found to be dose dependent. The lesions observed were characterized by cytoplasm degeneration and nuclear modifications such as karyomegaly, the presence of pseudoinclusions, apoptosis, and degenerative changes. In the guinea pig model, a greater incidence and severity of lesions were observed for cidofovir than for compound 1 (P < 0.001) with a drug regimen of 10 mg/kg/day.
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PMID:Comparative study of the anti-human cytomegalovirus activities and toxicities of a tetrahydrofuran phosphonate analogue of guanosine and cidofovir. 1004 67

Varicella zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella, chickenpox) as well as reactivation (zoster, shingles) infections. In immunocompetent patients, the course of varicella is generally benign. For varicella zoster, post-herpetic neuralgia is the most common complication. In immunocompromised patients (particularly those with AIDS), transplant recipients and cancer patients, VZV infections can be life-threatening. For these patients and also for immunocompetent patients at risk such as pregnant women or premature infants, the current treatment of choice is based on either intravenous or oral aciclovir (acyclovir). The low oral bioavailability of aciclovir, as well as the emergence of drug-resistant virus strains, have stimulated efforts towards the development of new compounds for the treatment of individuals with VZV infections. Among these new compounds, penciclovir, its oral prodrug form famciclovir and the oral pro-drug form of aciclovir (valaciclovir), rank among the most promising. As with aciclovir itself, all of these drugs are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation (phosphorylation), and, upon conversion to their triphosphate form, they act as inhibitors/alternative substrate of the viral DNA polymerase. Therefore, cross-resistance to these drugs may be expected for those virus mutants that are TK-deficient and thus resistant to aciclovir. Other classes of nucleoside analogues dependent for their phosphorylation on the viral TK that have been pursued for the treatment of VZV infections include sorivudine, brivudine, fialuridine, fiacitabine and netivudine. Among oxetanocins, which are partially dependent on viral TK, lobucavir is now under clinical evaluation. Foscarnet, which does not require any previous metabolism to interact with the viral DNA polymerase, is used in the clinic when TK-deficient VZV mutants emerge during aciclovir treatment. TK-deficient mutants are also sensitive to the acyclic nucleoside phosphonates (i.e. [s]-1-[3-hydroxy-2-phosphonylmethoxypropyl]cytosine; HPMPC); these agents do not depend on the virus-encoded TK for their phosphorylation but depend on cellular enzymes for conversion to their diphosphoryl derivatives which then inhibit viral DNA synthesis. Vaccination for VZV has now come of age. It is recommended for healthy children, patients with leukaemia, and patients receiving immunosuppressive therapy or those with chronic diseases. The protection induced by the vaccine seems, to some extent, to include zoster and associated neuralgia. Passive immuniatin based on specific immunoglobulins does not effectively prevent VZV infection and is therefore restricted to high risk individuals (i.e. immunocompromised children and pregnant women).
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PMID:Current pharmacological approaches to the therapy of varicella zoster virus infections: a guide to treatment. 1018 60

Resistance of cytomegalovirus (CMV) to antiviral agents is a well-recognized phenomenon that has been observed in the laboratory and in the clinical setting. Infections caused by antiviral-resistant CMV have been found exclusively among immunocompromised individuals, including patients with AIDS, bone marrow and solid-organ transplant recipients, and patients with hematologic malignancies, and in individuals with primary immunodeficiencies. The majority of these infections have been described to occur in patients with AIDS receiving prolonged antiviral therapy for CMV end-organ disease. Antiviral agents currently licensed for the treatment of CMV infections include ganciclovir, foscarnet, and cidofovir. Resistance of CMV to ganciclovir is related to mutations in the UL97 region of the viral genome and/or mutations in the viral DNA polymerase. Resistance to foscarnet and cidofovir is associated with mutations in the viral DNA polymerase. Antiviral susceptibility of CMV strains containing DNA polymerase mutations is dependent on the region of the DNA polymerase where the mutations are located. Some DNA polymerase mutant viruses are cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition that specific UL97 and UL54 mutations are associated with resistance to antiviral agents has led to the development of molecular methods for detection of mutant viruses. This article reviews the mechanisms of resistance of CMV to antiviral agents, the laboratory methods for detection of resistant CMV, and the clinical aspects of infections caused by antiviral-resistant CMV.
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PMID:Resistance of human cytomegalovirus to antiviral drugs. 1019 60


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