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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cytomegalovirus (HCMV, a betaherpes virus) is the cause of serious disease in immunologically compromised individuals, including those with acquired immunodeficiency syndrome. One of the compounds used in the chemotherapy of HCMV infections is the nucleoside analogue 9-(1,3-dihydroxy-2-propoxymethyl)-guanine (ganciclovir). The mechanism of action of this drug is dependent on the formation of the nucleoside triphosphate, which is a strong inhibitor of the viral DNA polymerase. Thymidine kinase, which is encoded by many of the herpesviruses, catalyses the initial phosphorylation of ganciclovir. But there is no evidence for the coding of this enzyme by HCMV, and DNA sequence analysis of the HCMV genome has shown that there is no open reading frame characteristic of a herpesvirus thymidine kinase. Here we present biochemical and immunological evidence that the HCMV UL97 open reading frame codes for a protein capable of phosphorylating ganciclovir. This protein seems to be responsible for the selectivity of ganciclovir and will be useful tool in the understanding and refinement of the antiviral activity of new selective anti-HCMV compounds.
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PMID:Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. 131 59

A number of HSV-2 isolates, sequentially recovered from ulcerative ano-genital lesions of an AIDS patient during a prolonged treatment with acyclovir (ACV), have been studied at the molecular level. All of them were highly resistant to ACV (ACV-r) and shown to be virtually deficient in thymidine kinase (TK) activity. The ACV-r phenotype was demonstrated to be due to the production of truncated TK polypeptide. Structural alteration of this gene, as shown in one isolate, was caused by a chain-terminating mutation that originated from a cytidine deletion at position 520 of the TK open reading frame. This mutation generated a TGA stop codon 27 nucleotides downstream. An additional isolate was also recovered following ACV discontinuation and after a cycle of treatment with foscarnet. This isolate had lost the ACV-r trait and was characterized by a wild type TK sequence and by the production of a functional enzyme. Data presented confirm that a prolonged treatment with acyclovir can easily select ACV-r HSV-2 isolates carrying a TK- phenotype caused by a frameshift mutation. Although recovered from lesions tributary of different myelomers, these isolates may belong to the same strain that has undergone multiple cycles of reactivation and has possibly mutated during its axonal route to the skin.
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PMID:A point mutation in the thymidine kinase gene is responsible for acyclovir-resistance in herpes simplex virus type 2 sequential isolates. 132 74

Herpes simplex virus (HSV) resistant to acyclovir can produce persistent mucocutaneous ulcerative disease in patients with the acquired immunodeficiency syndrome (AIDS). The incidence of clinically significant acyclovir-resistant HSV disease has dramatically increased since the advent of the AIDS epidemic. The primary mechanism of acyclovir resistance is induction of viral mutants defective or deficient in thymidine kinase, the viral-encoded enzyme, which catalyzes the rate-limiting step in the triphosphorylation of acyclovir to its active form (acyclovir triphosphate). Foscarnet, a potent inhibitor of HSV DNA polymerase, does not require phosphorylation for its antiviral activity. This compound has been found to be effective in the treatment of acyclovir-resistant HSV infection by several investigators. A recently completed dose-comparative trial of foscarnet in AIDS patients with acyclovir-resistant HSV has confirmed the safety and efficacy of two doses of foscarnet (40 mg/kg every 8 or 12 hours) in the treatment of this disease, as well as providing preliminary evidence supporting the utility of foscarnet maintenance therapy in delaying recurrence of HSV lesions. Analysis of data from this trial has been complicated by the tremendous variability in lesion size at initiation of therapy, making any statistically valid comparison of treatment regimens almost impossible. A further trial in AIDS patients with acyclovir-resistant HSV infection has been designed to define better the role of foscarnet maintenance and, in light of evidence that a significant proportion of initial recurrences are due to acyclovir-sensitive HSV, to examine the potential utility of acyclovir maintenance following foscarnet induction therapy.
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PMID:Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: preliminary results of a controlled, randomized, regimen-comparative trial. 153 Dec 85

Resistance to acyclovir in vitro in herpes simplex virus (HSV) isolates has been associated with failure of acyclovir therapy in immunosuppressed patients, and the frequency of reports of clinical resistance in patients with human immunodeficiency virus (HIV) infection is increasing. The primary mechanism of clinical resistance is mutation, producing deficiency in the virus-specified thymidine kinase. A number of case reports and patient series have suggested the efficacy of foscarnet in the treatment of acyclovir-resistant HSV infection in HIV-infected patients. In a recent AIDS Clinical Trials Group study comparing the efficacy of vidarabine and foscarnet in this indication, foscarnet therapy was found to be associated with statistically significant reductions in time to complete healing of lesions, cessation of viral shedding, and 50% reduction in pain, and all patients randomized to receive foscarnet had complete re-epithelialization of lesions. The majority of initial recurrences of herpetic lesions in patients in this study were susceptible to acyclovir; however, all patients ultimately experienced a recurrence due to acyclovir-resistant HSV. A trial comparing acyclovir suppression, foscarnet maintenance therapy, and no chronic antiviral therapy after successful initial treatment of acyclovir-resistant HSV infection would be useful in defining the optimal management of recurrent disease.
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PMID:Treatment of acyclovir-resistant herpes simplex virus infections in patients with AIDS. 160 61

A total of 100 herpes simplex viruses isolated from lesions not responding to acyclovir (ACV) therapy were recovered from 51 patients infected with human immunodeficiency virus. In vitro analysis of these isolates included testing their susceptibility to ACV and determining their thymidine kinase (TK) phenotypes. Of the 100 isolates evaluated, 23 were ACV sensitive and 77 were ACV resistant. Seventy-four of these ACV-resistant isolates were of the TK-deficient or low-TK-producer phenotype and three were of the TK-altered phenotype. The TKs isolates that represented each of the different autoradiographic phenotypes were further characterized by enzyme kinetics. The ability of selected isolates to cause disease in vivo was evaluated by using several mouse virulence models. Cutaneous virulence in normal and immunocompromised mice was evaluated, and neurovirulence in normal mice was determined. Latent infections were assayed by the cocultivation of trigeminal ganglia recovered from mice that had survived acute infection. These reactivated viruses were evaluated in vitro and compared with the original infecting isolate. The mechanisms of resistance and pathogenicity of these herpes simplex virus isolates recovered from patients positive for human immunodeficiency virus are similar to those reported for isolates recovered from normal and immunocompromised patients without AIDS.
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PMID:In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodeficiency virus. 166 96

The biological characterization of a number of sequential herpes simplex virus type 2 (HSV-2) isolates obtained from an AIDS patient undergoing sequential courses of antiviral treatment due to an extended mucocutaneous genital lesion is reported. Resistance to acyclovir (ACV) and related compounds was linked to a thymidine kinase-deficient (TK-) phenotype. After ACV discontinuation and a course of treatment with foscarnet, a new isolate was recovered, characterized by loss of the ACV-resistant trait and production of a functional TK enzyme. Data presented stress the need for monitoring chemosensitivity of HSV isolates in AIDS patients while suggesting that for better control of the infection, these patients should benefit from alternative treatments with drugs aimed at different viral targets.
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PMID:Acyclovir resistance/susceptibility in herpes simplex virus type 2 sequential isolates from an AIDS patient. 183 60

The isolation and description of acyclovir-resistant (ACVR) herpes simplex-2 viruses from patients with AIDS has recently been reported. These ACVR viruses were all markedly decreased in their thymidine kinase (TK) activity, and 6 of 10 of these TK viruses were able to establish latency. In addition, one of these isolates, ACVR-86012 was neuropathogenic in a murine encephalitis model. In this paper, the characteristics of these isolates with respect to TK polypeptide synthesis are examined. All but one isolate synthesized a detectable TK protein by immunoprecipitation, and 9/10 of the TK proteins had an altered electrophoretic mobility as compared to wild-type. The TK polypeptide from the neuropathogenic isolate ACVR-86012 was full-length and the gene was sequenced. An amino acid change from a glutamine to a proline at amino acid residue 105 was detected compared to the wild-type HSV-333 strain. These results indicate that an amino acid change in the NH2 portion of the TK protein is associated with a full-length peptide with decreased enzyme activity but the virus retains neuropathic virulence.
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PMID:Analysis of the thymidine kinase gene from clinically isolated acyclovir-resistant herpes simplex viruses. 184 99

Chronic exposure of H9 cells to 25 microM zidovudine (H9-AZT cells) causes a 2- to 3-fold increase in thymidine kinase (TK) activity (Agarwal RP, Int J Purines Pyrimidine Res, in press). The present study compared thymidine (TdR) and AZT anabolism in H9 and H9-AZT cells. After a 3.5-hr incubation with 10 microM TdR or AZT, the total intracellular accumulations of AZT (48.7 microM in H9 cells and 32.8 microM in H9-AZT cells) were 46.4% of TdR accumulation. Other major differences between TdR and AZT anabolism were: (i) the majority of TdR (84-87%) was incorporated into DNA compared to less than 1% of AZT; and (ii) whereas distribution of TdR in the nucleotides was TTP greater than TMP greater than TDP, zidovudine distributed was AZT-MP much greater than AZT-TP much greater than AZT-DP. Because of the poor substrate activity of AZT-MP for thymidylate kinase (TMP-kinase), most of the AZT (95-98%) remained as AZT-MP. TMP-kinase activities with TMP as substrate were 47.6 +/- 20.3 and 91.4 +/- 28.8 pmol/mg protein/min in H9 and H9-AZT cells, respectively. 5'-Nucleotidase activities with TMP as substrate were 428.9 +/- 37.8 and 255.9 +/- 28.7 pmol/mg protein/min in H9 and H9-AZT cells, respectively. Activities of these enzymes with AZT-MP as a substrate were very low. Despite an increase in TK and TMP-kinase, and a decrease in 5'-nucleotidase activities, the total intracellular accumulations of TdR and AZT were reduced significantly (P less than 0.05) to 67.5% in H9-AZT cells. Thymidine transport (0.66 to 0.68 pmol/sec/10(6) cells) was similar in both the cell lines. The severe reductions of TdR salvage caused by chronic exposure of cells to AZT, if it occurs in AIDS patients on AZT chemotherapy, may explain some of the long-term clinical toxicities of the drug.
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PMID:Thymidine and zidovudine metabolism in chronically zidovudine-exposed cells in vitro. 186 45

Toward gene therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in AIDS, Moloney murine leukemia virus-derived retroviral vectors were engineered to allow constitutive and tat-inducible expression of an HIV-1 5' leader sequence-specific ribozyme (Rz1). These vectors were used to infect the human CD4+ lymphocyte-derived MT4 cell line. The stable MT4 transformants expressing an HIV-1 RNA-specific ribozyme, under the control of the herpes simplex virus thymidine kinase (tk) promoter, were found to be somewhat resistant to HIV-1 infection as virus production was delayed. In cells allowing ribozyme expression under control of the simian virus 40 or cytomegalovirus promoter, the rate of HIV-1 multiplication was slightly decreased, and virus production was delayed by about 14 days. The highest level of resistance to HIV-1 infection was observed in MT4 cells transformed with a vector containing a fusion tk-TAR (trans activation-responsive) promoter to allow ribozyme expression in a constitutive and tat-inducible manner; no HIV-1 production was observed 22 days after infection of these cells. These results indicate that retroviral vectors expressing HIV-1 RNA-specific ribozymes can be used to confer resistance to HIV-1 infection.
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PMID:Resistance to human immunodeficiency virus type 1 (HIV-1) infection in human CD4+ lymphocyte-derived cell lines conferred by using retroviral vectors expressing an HIV-1 RNA-specific ribozyme. 189 2

A case is reported of relapsing fatal meningoencephalitis caused by a neurovirulent thymidine kinase-positive (TK+) type 2 herpes simplex virus (HSV) that developed thymidine kinase deficiency (TK-) during intravenous acyclovir therapy. A patient with AIDS was admitted for acyclovir treatment of a persistent perirectal herpetic ulcer. He subsequently developed meningoencephalitis. A TK+ type 2 HSV was isolated from a brain biopsy specimen. A progressive and fatal relapse occurred, and a TK- type 2 HSV was isolated from his cerebrospinal fluid. Restriction endonuclease analysis of viral DNA from perianal, brain, and cerebrospinal fluid isolates were similar, suggesting that they were the same viral strain. Animal virulence studies indicated significant cutaneous virulence in immunocompromised mice models for the TK- isolates. This case is notable because TK- HSV have, in the past, lacked neurovirulence and because acyclovir resistance developed during therapy and caused the patient's death.
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PMID:Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. 215 46


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