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)

Zoster is the clinical manifestation of the endogenous reactivation of the varicella-zoster virus. Current observations of viral reactivation emphasize the role of cellular immunity and show an inverse correlation between the specific cellular immune response of the host and the incidence of zoster. Thus, immunocompromised persons like patients with immune deficiency syndrome, lymphoproliferative cancer, or immunosuppressive therapy are at a high risk for the development of disseminated zoster, which may either involve the skin only, or affect more than one organ. During the last few years zoster has been proved a prognostic marker for HIV-positive persons. The incidence of zoster and post-zoster neuralgia increases with advancing age. In young children, immunosuppressive therapy and varicella in utero or during the first year of life are the only risk factors for zoster infection. Prevention of dissemination has been one of the major goals in antiviral chemotherapy of zoster in immunocompromised patients. Among the antiviral drugs available at present, aciclovir has proved especially useful, acting as an inhibitor of viral DNA polymerase. It is well-tolerated and can be applied together with corticoids, analgetics, and retrovir. It is most effective in reducing complications of zoster.
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PMID:[New knowledge regarding herpes zoster]. 266 Apr 44

9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), a potent inhibitor of human immunodeficiency virus (HIV) replication, was evaluated for its activity against human cytomegalovirus (HCMV) in vitro, and murine cytomegalovirus (MCMV) and rat CMV (RCMV) in vivo. PMEDAP strongly inhibited HCMV-induced cytopathicity in human embryonic lung (HEL) cell cultures (EC50 11 microM) and caused a concentration-dependent suppression of viral DNA synthesis (IC50 20 microM) [corrected]. PMEDAP had no effect on the expression of HCMV-specific immediate early antigens (IEA) as measured on day 1 post-infection, but inhibited the expression of HCMV late antigens as measured on day 6 post-infection (EC50 20 microM) [corrected]. The diphosphate derivative of PMEDAP (PMEDAPpp) selectively inhibited HCMV-induced DNA polymerase (IC50 0.1 microM). PMEDAP proved markedly effective in reducing the mortality rate of NMRI mice that had been infected intraperitoneally or intracerebrally with a lethal dose of MCMV. PMEDAP exhibited greater anti-MCMV activity when administered as a single dose immediately after infection than when this dose was divided over repeated administrations. 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) also prevented MCMV-induced mortality, but only at a dose ten-fold higher than that of PMEDAP. PMEDAP also delayed death in severe combined immune deficiency (SCID) mice that had been infected with MCMV. The effect of PMEDAP on RCMV infections in rats was less pronounced.
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PMID:Activity of the anti-HIV agent 9-(2-phosphonyl-methoxyethyl)-2,6-diaminopurine against cytomegalovirus in vitro and in vivo. 839 82

BK virus (BKV), a human polyomavirus, infects most of the human population, but clinically relevant infections are usually limited to individuals who are immunosuppressed. After primary infection, BKV remains latent in the kidneys and can be reactivated in immune deficiency conditions, including transplantation. As primary infection occurs in childhood, BKV may be particularly important in the pediatric transplant population. BKV is associated with tubulointerstitial nephritis and ureteric stenosis in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant recipients. There are increasing reports of BKV causing nephropathy and cystitis in non-renal solid organ transplant recipients and other immunodeficiency diseases. This might be related to the use of more potent immunosuppressive regimens or increasing awareness of BKV as an important pathogen. Diagnosis of BKV disease is by biopsy. Histopathological changes in renal biopsy specimens may mimic rejection or drug toxicity, but BKV nuclear inclusions can be seen. Treatment is by reduction of immunosuppression. Antiviral agents such as cidofovir are showing promise. BKV DNA polymerase chain reaction in blood or biopsy may be helpful in monitoring therapy. The impact of BKV disease in children is not well understood and prospective studies are needed to elucidate this further. This article reviews the current understanding of BKV-associated renal problems.
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PMID:BK virus-associated renal problems--clinical implications. 1280 40

Varicella zoster virus (VZV) is usually associated with mild to moderate illness in immunocompetent patients. However, older age and immune deficiency are the most important risk factors linked with virus reactivation and severe complications. Treatment of VZV infections is based on nucleoside analogues, such as acyclovir (ACV) and its valyl prodrug valacyclovir, penciclovir (PCV) as its prodrug famciclovir, and bromovinyldeoxyuridine (BVDU; brivudin) in some areas. The use of the pyrophosphate analogue foscarnet (PFA) is restricted to ACV-resistant (ACV(r)) VZV infections. Since antiviral drug resistance is an emerging problem, we attempt to describe the contributions of specific mutations in the viral thymidine kinase (TK) gene identified following selection with ACV, BVDU and its derivative BVaraU (sorivudine), and the bicyclic pyrimidine nucleoside analogues (BCNAs), a new class of potent and specific anti-VZV agents. The string of 6 Cs at nucleotides 493 to 498 of the VZV TK gene appeared to function as a hot spot for nucleotide insertions or deletions. Novel amino acid substitutions (G24R and T86A) in VZV TK were also linked to drug resistance. Six mutations were identified in the "palm domain" of VZV DNA polymerase in viruses selected for resistance to PFA, PCV, and the 2-phophonylmethoxyethyl (PME) purine derivatives. The investigation of the contributions of specific mutations in VZV TK or DNA polymerase to antiviral drug resistance and their impacts on the structures of the viral proteins indicated specific patterns of cross-resistance and highlighted important differences, not only between distinct classes of antivirals, but also between ACV and PCV.
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PMID:In vitro-selected drug-resistant varicella-zoster virus mutants in the thymidine kinase and DNA polymerase genes yield novel phenotype-genotype associations and highlight differences between antiherpesvirus drugs. 2219 Jul 13

Parvovirus B19 infection in healthy hosts is self-limited, but persistent infection has been described in patients with cellular immune defects. A 6-year-old boy presented with a 6-month history of weight loss and malaise and a 1-month history of fever and polyarticular arthritis. Parvovirus DNA was detected in plasma at 10 300 copies/mL. Levels of immunoglobulin (Ig)G, IgA, IgM, IgG-1, and IgG-2 were low, and antibody responses to vaccine antigens were impaired. HIV antibody and DNA polymerase chain reaction were negative, and the patient had normal immunophenotype, mitogen stimulation response, CD40 ligand and inducible costimulator expression, transmembrane activator and CAML interactor sequencing, genomic analysis, and fluorescent in situ hybridization for deletions at 22q11.2. Common variable immunodeficiency was diagnosed and replacement therapy with immune globulin intravenous was initiated. The parvovirus DNA level declined by half over 3 months and was undetectable at 15 months. Constitutional symptoms improved but arthritis persisted and eosinophilic fasciitis eventually developed. This case demonstrates that persistent parvovirus infection may be a presenting feature of humoral immune deficiency and can mimic juvenile rheumatoid arthritis. The infection may respond to immune globulin intravenous therapy.
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PMID:Common variable immunodeficiency presenting with persistent parvovirus B19 infection. 2312 76

Neutrophils are fast-moving cells essential for host immune functions. Although they primarily rely on glycolysis for ATP, isolated primary human neutrophils depend on mitochondrial membrane potential for chemotaxis. However, it is not known whether mitochondria regulate neutrophil motility in vivo, and the underlying molecular mechanisms remain obscure. Here, we visualized mitochondria in an interconnected network that localizes to the front and rear of migrating neutrophils using a novel transgenic zebrafish line. To disrupt mitochondrial function genetically, we established a gateway system harboring the CRISPR/Cas9 elements for tissue-specific knockout. In a transgenic line, neutrophil-specific disruption of mitochondrial DNA polymerase, polg, significantly reduced the velocity of neutrophil interstitial migration. In addition, inhibiting the mitochondrial electron transport chain or the enzymes that reduce mitochondrial reactive oxygen species also inhibited neutrophil motility. The reduced cell motility that resulted from neutrophil-specific knockout of sod1 was rescued with sod1 mRNA overexpression, or by treating with scavengers of reactive oxygen species. Together, our work has provided the first in vivo evidence that mitochondria regulate neutrophil motility, as well as tools for the functional characterization of mitochondria-related genes in neutrophils and insights into immune deficiency seen in patients with primary mitochondrial disorders.This article has an associated First Person interview with the first author of the paper.
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PMID:Neutrophil-specific knockout demonstrates a role for mitochondria in regulating neutrophil motility in zebrafish. 2959 Jun 39