Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nucleoside analog acyclovir is remarkably effective and selective in herpes simplex virus (HSF) infections. Acyclovir inhibits the viral enzyme DNA polymerase. Emergence of acyclovir-resistant HSV mutants occurs in immunocompromised patients, especially those with AIDS. Detection of HSV strains with resistance to antiviral drugs requires rapid in vitro tests to determine the IC50, i.e., the concentration of drug which inhibits viral replication by 50%. Studies of patterns of HSV resistance to the various antiviral agents used in medicine and characterization of mutant HSV strains have shown resistance to be due to loss or modification of the viral enzyme thymidine kinase or to changes in the viral DNA polymerase. The main clinically-significant acyclovir-resistant mutants are thymidine kinase-deficient and retain sensitivity to vidarabine and foscarnet. Development of resistance to both acyclovir and foscarnet due to changes in viral DNA polymerase is considerably less common but emphasizes the urgent need for new antiviral strategies for use in immunocompromised patients.
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PMID:[Resistance of herpes simplex viruses to antiviral drugs]. 839 60

Agents available to treat herpesvirus infections include idoxuridine, trifluridine, vidarabine and acyclovir for the topical treatment of herpetic eye infections; vidarabine and acyclovir for the systemic (intravenous) treatment of herpes encephalitis; acyclovir for the topical and systemic (oral) treatment of genital herpes; acyclovir for the systemic (intravenous, oral) treatment of HSV or varicella-zoster (VZV) infections in immunosuppressed patients; brivudin for the systemic (oral) treatment of HSV-1 or VZV infections in immunosuppressed patients; and ganciclovir and foscarnet for the systemic (intravenous) treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Brivudin is also effective in the treatment of herpetic eye infections that no longer respond to idoxuridine, trifluridine, vidarabine or acyclovir; and foscarnet is effective in the treatment of infections with acyclovir-resistant, thymidine kinase-deficient (TK-) HSV or VZV mutants. Other antiviral agents considered for use in herpesvirus infections include brovavir, penciclovir (and its prodrug famciclovir), desciclovir (a prodrug of acyclovir), bishydroxymethylcyclobutylguanine (BHCG) and, in particular, 1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). The latter is more active than either acyclovir or ganciclovir in the chemotherapy and prophylaxis of various HSV-1, HSV-2, TK- HSV, VZV or CMV infections in animal models.
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PMID:Antivirals for the treatment of herpesvirus infections. 840 94

Detection of novel DNA sequences in Kaposi's sarcoma (KS) and AIDS-related body cavity-based, non-Hodgkin's lymphomas suggests that these neoplasms are caused by a previously unidentified human herpesvirus. We have characterized this agent using a continuously infected B-lymphocyte cell line derived from an AIDS-related lymphoma and a genomic library made from a KS lesion. In this cell line, the agent has a large episomal genome with an electrophoretic mobility similar to that of 270-kb linear DNA markers during clamped homogeneous electric field gel electrophoresis. A 20.7-kb region of the genome has been completely sequenced, and within this region, 17 partial and complete open reading frames are present; all except one have sequence and positional homology to known gammaherpesvirus genes, including the major capsid protein and thymidine kinase genes. Phylogenetic analyses using both single genes and combined gene sets demonstrated that the agent is a gamma-2 herpesvirus (genus Rhadinovirus) and is the first member of this genus known to infect humans. Evidence for transient viral transmission from infected to uninfected cells is presented, but replication-competent virions have not been identified in infected cell lines. Sera from patients with KS have specific antibodies directed against antigens of infected cell lines, and these antibodies are generally absent in sera from patients with AIDS without KS. These studies define the agent as a new human herpesvirus provisionally assigned the descriptive name KS-associated herpesvirus; its formal designation is likely to be human herpesvirus 8.
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PMID:Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. 852 68

Herpes simplex virus (HSV) infections are very common in the general population and can be treated with the nucleoside analogue acyclovir. Acyclovir is initially phosphorylated intracellularly in HSV-infected cells by a viral-specific thymidine kinase to acyclovir-monophosphate. The monophosphate is subsequently di- and triphosphorylated by host cellular kinases to the active form of the drug, which inhibits HSV DNA polymerase and incorporates into the elongating viral DNA and causes chain termination. Acyclovir resistance has been increasingly described and is caused by mutations in either the thymidine kinase or the DNA polymerase genes. These mutations result in decreased or absent HSV thymidine kinase production, altered affinity of the thymidine kinase for acyclovir-triphosphate, or altered affinity of the HSV DNA polymerase for acyclovir-triphosphate. Thymidine kinase deficiency accounts for approximately 95% of acyclovir-resistant isolates. Clinical disease due to acyclovir-resistant HSV occurs primarily in immunocompromised patients and is usually characterized by a chronic, progressive ulcerative mucocutaneous disease with prolonged shedding of virus. Several large surveys have been done in an effort to determine the incidence of in vitro and clinical acyclovir resistance. Among immunocompetent hosts, even those who have received > or = 6 years of continuous acyclovir, the prevalence of acyclovir-resistant isolates has remained stable at approximately 3%. Only three cases of clinical resistance of HSV to acyclovir have been reported. However, the incidence in immunocompromised patients, particularly those with AIDS and those who have had bone marrow transplants, is increasing. Transmission of acyclovir-resistant isolates from person to person has not been documented, but due to the increased use of acyclovir and newer drugs, such as famciclovir, there is great concern that this transmission might occur in the future. Continued surveillance in both immunocompetent and immunocompromised hosts for the development of clinical acyclovir-resistant HSV disease is necessary.
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PMID:Herpes simplex virus resistance to acyclovir: clinical relevance. 854 89

Acyclovir is an effective drug for the treatment of HSV and VZV infections, which after phosphorylation to the triphosphate, inhibits viral DNA polymerase. Acyclovir has low oral bioavailability, therefore prodrugs have been developed, and the L-valyl ester, valaciclovir, recently has been licensed for the treatment of shingles. Ganciclovir is used against CMV, and famciclovir, a lipophilic prodrug of penciclovir, is marketed for shingles. The acyclic nucleoside phosphonates are active against thymidine kinase-resistant viral strains. Promising analogs are PMEA (in clinical trial for the treatment of AIDS) and (S)-HPMPC (good in vivo activity against HSV, VZV, CMV, and EBV). Oligonucleotides incorporating acyclic nucleosides at the 3'-and 5'-ends, or constituted of amino acyclic nucleosides, are resistant to cleavage by nucleases and may be useful in antisense and/or antigene therapy. HEPT is active against HIV-1: It binds in a hydrophic pocket on reverse transcriptase, rather than in the polymerase active site. Some acyclic nucleosides are potent inhibitors of purine and pyrimidine nucleoside phosphorylase. These compounds may have a therapeutic niche in combination therapy with antiviral and anticancer nucleosides, and in the treatment of diseases involving the T-cell.
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PMID:Acyclic nucleosides as antiviral compounds. 873 25

The development of an effective vaccine for human immunodeficiency virus type 1 (HIV-1) would be a major advance toward controlling the AIDS pandemic. Several disparate strategies for a safe and effective HIV vaccine have been proposed. Recent data suggest that loss-of-function live-attenuated virus could be a safe lentivirus vaccine. Here, we propose a gain-of-function approach that can complement loss-of-function in enhancing the safety profile of a live-attenuated virus. We describe an example in which ganciclovir (GCV) was used to treat effectively nef(-)HIV-1 engineered to express herpes simplex virus (HSV-1) thymidine kinase (TK). This treatment was found to be highly efficient in controlling HIV-1 spread in tissue culture and in a small animal (hu-PBL-SCID) model. We demonstrate that one distinct advantage of GCV-HSV-TK treatment is the elimination of integrated proviruses, a goal not easily achieved with other antiretrovirals.
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PMID:Conditional reduction of human immunodeficiency virus type 1 replication by a gain-of-herpes simplex virus 1 thymidine kinase function. 875 84

Herpes simplex virus (HSV) strain 1737, acyclovir-resistant and uniformly thymidine kinase-deficient (tkD) by all conventional assays, clinically reactivated in an AIDS patient in the absence of antiviral drug pressure. Investigation of its neurovirulence and latency characteristics in a mouse model using a tkD plaque isolate (1737-14), however, yielded a neurovirulent, homogeneous, acyclovir-sensitive, tk wild type (tkWT) strain (1737-14ME), while trigeminal ganglia from a surviving animal yielded a heterogeneous tkD/tkWT population (1737-14/10(5)B). Heterogeneity may have arisen due to selection of a preexisting tkWT subpopulation or to genetic reversion. "Ultralow" levels of tk, undetectable by conventional means, may be sufficient for reactivation while retaining the acyclovir-resistant phenotype. A possible mechanism for spontaneous reactivation of 1737 is in vivo complementation between heterogeneous tk populations. Eradication of acyclovir-resistant, tkD virus does not ensure subsequent reactivations to be acyclovir-sensitive, and alternating antivirals may be required for effective therapy.
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PMID:Spontaneous reactivation of thymidine kinase-deficient, acyclovir-resistant type-2 herpes simplex virus: masked heterogeneity or reversion? 876 3

The recent discovery of long term AIDS nonprogressors who harbor nef-attenuated HIV suggests that a naturally occurring live vaccine for AIDS may already exist. Animal models have shown that a live vaccine for AIDS, attenuated in nef, is the best candidate vaccine. There are considerable risks, real and perceived, with the use of live HIV vaccines. We have introduced a conditional lethal genetic element into HIV-1 and simian immunodeficiency virus (SIV) molecular clones deleted in nef. The antiviral strategy we employed targets both virus replication and the survival of the infected cell. The suicide gene, herpes simplex virus thymidine kinase (tk), was expressed and maintained in HIV over long periods of time. Herpes simplex virus tk confers sensitivity to the antiviral activity of acyclic nucleosides such as ganciclovir (GCV). HIV-tk and SIV-tk replication were sensitive to GCV at subtoxic concentrations, and virus-infected cells were eliminated from tumor cell lines as well as primary cell cultures. We found the HIV-tk virus to be remarkably stable even after being cultured in media containing a low concentration of GCV and then challenged with the higher dose and that while GCV resistant escape mutants did arise, a significant fraction of the virus remained sensitive to GCV.
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PMID:A candidate live inactivatable attenuated vaccine for AIDS. 879 Apr 13

The purpose of this study was to investigate the mechanism of acquired cellular resistance to AZT, a mechanism that has been described as a potential source of drug resistance in addition to viral mutations. To study this phenomenon the kinetics parameters of thymidine kinase (TK) activity have been defined in CEMazt, a cell line previously selected for resistance to AZT, in comparison with the parental AZT-sensitive CEM cells. The results revealed that the value of the maximum velocity (Vmax) of TK activity for deoxythymidine (dThd) phosphorylation is decreased in CEMazt as compared to the wild-type cell line (Vmax: CEM = 105.3 +/- 17.6 nmol/hr/mg of protein; CEMazt = 0.3 +/- 0.02 nmol/hr/mg of protein; p < 0.001). Furthermore, the enzyme affinity versus dThd is lower in CEMazt as compared to CEM (Km: CEM = 0.9 +/- 0.2 microM; CEMazt = 1.6 +/- 0.2 microM; p < 0.01). Consequently phosphorylation efficiency, expressed as the ratio between Vmax and Km, is also reduced in CEMazt (p < 0.001). To evaluate whether such a phenomenon may also occur in patients, ex vivo experiments were carried out by using PBMCs from HIV-infected patients, treated or not treated with AZT. The results (mean values from 10 patients for each group) indicate that a prolonged treatment (> 6 months) with AZT may modify the enzymatic kinetics of TK, leading to a significant reduction in the phosphorylation efficiency of the enzyme (4.07 +/- 1.7 in treated patients versus 13.5 +/- 1.7 in untreated patients; p < 0.001). These results indicate that AZT treatment can also induce a defect in TK activity in patients.
AIDS Res Hum Retroviruses 1996 Feb 10
PMID:Long-term exposure to zidovudine affects in vitro and in vivo the efficiency of phosphorylation of thymidine kinase. 883

Genetic alterations in malignant tissues are potential targets for gene-based cancer therapies. Alternatively, aberrant expression of certain specific genes associated with malignant transformation may be envisioned to enhance the expression of chemosensitizing drugs. Epstein-Barr virus (EBV)-related B-cell lymphomas are fatal complications of immunosuppression due to AIDS, organ transplantation or congenital immune abnormalities. The malignant cells latently infected with EBV typically express the transcription factor EBNA2 as one of nine latent viral genes. We tested whether an EBNA2-responsive EBV promoter may selectively target EBV-related lymphoma cells by virus-regulated expression of a suicide gene. Using the BamC promoter driving a hygromycin-thymidine kinase fusion gene or controls, we demonstrated that sensitivity to ganciclovir was selectively enhanced in cells expressing EBNA2. Further, there was complete macroscopic regression of established B-cell lymphomas in mice with severe combined immunodeficiency disease (SCID mice) treated with a single course of ganciclovir. These data provide in vitro and in vivo support for a model of exploiting the molecular basis of tumor development to enhance the specificity of gene therapy.
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PMID:Epstein-Barr virus-driven gene therapy for EBV-related lymphomas. 894 40


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