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

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

We report the first application of ultra-deep sequencing (UDS) to varicella-zoster virus (VZV) genotypic antiviral testing in a case of acyclovir-resistant VZV infection initially detected by Sanger sequencing within a deeply immunocompromised heart transplant recipient. As added-value compared to Sanger analysis, UDS revealed complex dynamics of viral population under antiviral pressure. Varicella-zoster virus (VZV) is a ubiquitous human herpesvirus affecting populations worldwide. VZV is commonly acquired in youth whose primary infection usually manifests as benign varicella (chickenpox). After the initial infection, the virus establishes lifelong latency in sensory ganglia leading to a risk of subsequent reactivation. Reactivation usually results in the development of localized herpes zoster (HZ) lesions, a painful skin rash commonly known as shingles (Cohen, 2013). The incidence and severity of HZ increase with impaired specific cell-mediated immunity mainly as a result of increasing age, malignancy, immunodeficiency, organ transplantation, or immunosuppressive drug therapy (Cohen, 2013; Koo et al., 2014; Pavlopoulou et al., 2015). In particular, HZ remains a significant cause of morbidity among solid organ transplant (SOT) recipients, especially in patients undergoing heart transplantation (HT) compared with liver, kidney, or lung transplant recipients (Carby et al., 2007; Koo et al., 2014; Pavlopoulou et al., 2015). These particular individuals are at increased risk of primary infection, reactivation followed by dissemination with visceral involvement and associated with bacterial superinfection, and chronic recurrences (Cohen, 2013). VZV infections may also engender debilitating neuralgia among highly immunocompromised patients (Sampathkumar et al., 2009). HT is also associated with the risk of reactivation of other latent viruses belonging to the Herpesviridae family as herpes simplex virus (HSV). Currently licensed drugs to prevent or to cure HSV- or VZV-associated diseases target the viral DNA polymerase (Pol). Acyclovir (ACV) and its prodrug valacyclovir (VACV) are considered as the first-line therapy, whereas foscarnet (FOS) or cidofovir (CDV) constitute alternative options. After primophosphorylation by the viral thymidine kinase (TK), ACV targets the viral DNA polymerase and inhibits the viral genome replication by a chain termination mechanism. According to this mechanism of action, viral mutations conferring resistance to ACV have been mapped both in TK and Pol encoding genes. Viral mutations conferring resistance to FOS and CDV are only detected in Pol gene. VZV ACV-resistance is mostly mediated by TK alterations, consisting in either translational frameshifts, sometimes associated with premature stop codon, or amino acid substitutions. In the remaining cases, amino acid substitutions are detected within Pol (De et al., 2015; Piret and Boivin, 2014). Classically, Sanger sequencing has been recognized as the gold standard for the detection of drug resistance mutations (DRMs) within VZV TK and Pol genes (Perrier et al., 2016; Piret and Boivin, 2014). However, this approach cannot detect minor variants present at a frequency below 20%. Ultra-deep sequencing (UDS) has an enhanced sensitivity compared to Sanger method and allows quantitative evaluation of the viral mutants (Chin et al., 2013). We report here a case of VZV resistant infection in an HT recipient. Our retrospective study aimed at showing the utility of UDS for DRM detection as a complement of Sanger method.
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PMID:Utility of ultra-deep sequencing for detection of varicella-zoster virus antiviral resistance mutations. 2933 63