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Biomedical subjects

A M Fillet

Publications and source records attributed to A M Fillet.

At least 37 records · Page 2Linked to original sources
PubMed1998

Single amino acid change in DNA polymerase is associated with foscarnet resistance in a varicella-zoster virus strain recovered from a patient with AIDS.

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.

AIDS-Related Opportunistic Infections↗
PubMed1998

Acyclovir-resistant herpes zoster in human immunodeficiency virus-infected patients: results of foscarnet therapy.

We retrospectively studied 18 consecutive cases of acyclovir-resistant zoster. All the patients had chronic skin lesions that failed to heal despite treatment with intravenous acyclovir (30 mg/[kg.d]) in 15 cases and oral acyclovir (4 g/d) in three cases for > 10 days. The mean CD4+ cell count was 20 x 10(6)/L. The mean number of previous zoster episodes was 1.53. Fifteen of the 16 patients evaluable for previous acyclovir treatment had received the drug. Thirteen patients were treated with intravenous foscarnet (200 mg/[kg.d]) for a mean of 17.8 days. Complete healing was observed in 10 (77%) of the 13 treated patients. Zoster relapsed after cessation of foscarnet therapy in five of the 10 responding patients. The median time to relapse was 110 days. Four patients died of varicella-zoster virus-associated visceral complications. These results show that acyclovir-resistant zoster has a poor prognosis but responds well to foscarnet therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Acyclovir-resistant varicella-zoster virus: phenotypic and genetic characterization.

A man with acquired immunodeficiency syndrome (AIDS) developed zoster of the right arm which was resistant clinically to acyclovir. Varicella-zoster virus (VZV) was cultured from a skin biopsy performed at the beginning of acyclovir therapy (isolate 1) and after its failure (isolate 2). The emergence of acyclovir resistance during treatment was investigated by developing a simple and rapid drug sensitivity assay based on the plaque reduction reference method. This late-antigen synthesis reduction assay involved serial dilutions of cell-associated virus. The 50% inhibitory concentration (IC50) of acyclovir was 16 +/- 7.5 microM for the susceptible reference strain OKA, in agreement with published data. The acyclovir IC50 increased from 6.5 microM for isolate 1 to 100 microM for isolate 2. In comparison with the sequence of isolate 1, isolate 2 had a single mutation consisting of a C to T change at position 907 of the thymidine kinase gene, which changed a glutamine codon into a stop codon at position 303 of the thymidine kinase protein. These results show the emergence of acyclovir resistance through a single previously undescribed mutation in the thymidine kinase gene, and confirm the heterogeneity of mutations inducing acyclovir resistance.

AIDS-Related Opportunistic Infections↗
PubMed1998

[Acyclovir-resistance zona in a immunocompromised HIV seronegative patient].

INTRODUCTION: Resistance to antiviral therapy is getting actually more frequent. Immunocompromised host are more concerned with this problem. OBSERVATION: We present a case of disseminated zoster resisting to acyclovir (ACV) therapy, but healing with foscarnet in a man treated with chemotherapy for lymphoma and seronegative for HIV. CI50 of VZV strain was 48 microM for ACV, which was 2.8 times higher than value of the reference OKA strain tested simultaneously, which confirmed the resistance for ACV. DISCUSSION: Immunocompromised patients often present varicella zoster virus (VZV) infection. They usually heal in response to ACV therapy, but some HIV infected patients have already presented with resistant strains of VZV. This case is the first described in a non-HIV infected patient. Foscarnet therapy resulted twice in complete healing because of its direct activity on viral DNA polymerase, so it is efficaceous therapy for patients with thymidine-kinase-deficient ACV-resistant VZV infection.

Acyclovir↗
PubMed1997

[What is a virus?].

Viruses are simple biological particles, consisting of a genome, a protein capsid and, in the case of enveloped viruses, an external lipidic envelope. Owing to the presence of envelope, most enveloped viruses are fragile although some exceptions may be observed. Viruses behave as complete intracellular parasites. Their multiplication results from the replication and self-assembly of viral components, this process being directed by the viral genome after it has been released within an infected cell. Virus classification is now essentially based on molecular properties, concerning both the structure and replication strategy of viruses. In virus taxonomy, serial hierarchical levels are family, subfamily, genus and species. Within species, lower hierarchical levels are type, subtype, variant and strain. Knowledge of virus structure and classification is essential for considering the physiopathology, diagnosis and therapy of viral infections.

Humans↗
PubMed1997

[Drugs active against herpesviruses].

Drugs active against herpesvirus are undergoing rapid development. Acyclovir is the antiviral drug of choice for treatment of herpes simplex virus (HSV) infections and the varicella and zona virus (VZV) because of its efficacy and lack of toxicity. Valaciclovir, precursor of acyclovir, allows reducing the daily intake to 2 doses for HSV infections and to 3 doses for VZV. For cytomegalovirus infections and HSV that are resistant to acyclovir in immunodepressed patients, ganciclovir and foscarnet are available and effective but can involve respectively haematologic and renal toxicity. Penciclovir, the active form of famciclovir, is a new antiviral drug indicated in the treatment of zona.

Antiviral Agents↗
PubMed1996

Detection of human herpes virus 6 in AIDS-associated retinitis by means of in situ hybridization, polymerase chain reaction and immunohistochemistry.

The ubiquitous nature of HHV-6 and its genomic relationship with cytomegalovirus led us to evaluate an etiological link between HHV-6 and AIDS-associated retinitis in a prospective study. HHV-6 infection was studied in patients with AIDS-associated retinitis and in two control populations. Eye pairs were obtained at necropsy from nine patients with AIDS-associated retinitis, four human immunodeficiency virus (HIV)-sero-positive patients with normal fundus examination and three HIV-seronegative patients. HHV-6 infection was detected by polymerase chain reaction (PCR), in situ hybridization and immunohistochemistry. Human cytomegalovirus (CMV) and HIV-1 infections were detected in parallel by the same methods. HHV-6 infection was detected in three cases of AIDS-associated retinitis. In two of these patients, HHV-6 infection was detected both by immunohistochemistry and PCR while in the third case it was detected by in situ hybridization and PCR. In the three patients, fundus examination showed bilateral retinitis in two of them and unilateral retinitis in one of them. HHV-6 infection was not detected in the retina of the two control groups. CMV was also detected in the three cases positive for HHV-6 by all three methods. HIV DNA was detected by PCR in two of three cases and was confirmed in one of these cases by in situ hybridization. These results confirm that HHV-6 infects the retina but suggests that HHV-6 does not have an exclusive causative role in AIDS-associated retinitis, since CMV coinfection of the retina was detected in all three of the patients positive for HHV-6.

AIDS-Related Opportunistic Infections↗
PubMed1996

[Resistance of cytomegalovirus to ganciclovir: rapid detection of the mutations 460 of the UL97 phosphotransferase].

The substitution of methionine by either isoleucine or valine at residue 460 in the UL97 phosphotransferase has been shown to be responsible for resistance to ganciclovir (GCV) in 30% of resistant cytomegalovirus (CMV) isolates [4]. These substitutions require one nucleotide change in the gene (G- > T 1 380 and A- > G 1378 respectively). The aim of this study was to develop a discriminative PCR assay for rapid detection of these DNA changes. A PCR assay was duplicated in parallel for each mutation; to detect G- > T 1380 each reaction mixture contained primer VSUL14 and either primer LNW to distinguish wild type residues or LNM to distinguish mutant residues, and for A- > G 1378 primers were VSUL8 and either MCMW to detect wild type sequences or MCMM to detect mutated residues. For optimal discrimination, primers MCMW and MCMM were designed with a mismatch at position 3'-1. The reference strains AD169, Davis and Towne, a laboratory GCV-resistant mutant RCL1.7, and 33 CMV isolates (10 resistant, 2 indetermined and 21 sensitive) were tested by PCR. AD169, Davis and Towne, and 30 isolates were amplified only with non modified primers, and the absence of 460 mutations was confirmed by sequencing. Two isolates P1 and P2, from a transplanted patient were amplified with both MCMM and MCMW: sequencing analysis shown the presence of a mixture of strain, one of them harbouring A- > G 1378 mutation. One resistant strain was amplified neither with MCMM nor with MCMW: a C- > T silent mutation at nt 1368 was present. As sequencing analysis confirmed PCR results, discriminative PCR enables isolates to be rapidly assessed for the presence or absence of 460 mutations. Moreover, it can distinguish Met to Val from Met to Ile mutations, and allows the analysis of mixtures of sensitive ad resistant strains.

AIDS-Related Opportunistic Infections↗
PubMed1995

Controlled study of human herpesvirus 6 detection in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma. The French Study Group for HIV-Associated Tumors.

Human herpesvirus 6 (HHV-6) is a recently identified lymphotropic herpesvirus, which has been isolated from patients with acquired immunodeficiency syndrome (AIDS) or lymphoproliferative diseases. Two variants A and B of HHV-6 have been described, variant B being more common in children with exanthema subitum. HHV-6 infection was studied in cases of AIDS-associated non-Hodgkin's lymphoma (NHL), and in three control populations in order to evaluate the possible etiological role of HHV-6 in this lymphoproliferative disease. Tumor specimens from various organs were obtained from 27 patients with AIDS-associated NHL and 20 human immunodeficiency virus (HIV)-seronegative patients with NHL. Lymph node specimens were obtained from four HIV-seropositive and nine HIV-seronegative patients with lymph node follicular hyperplasia. A specific polymerase chain reaction (PCR) was used to detect HHV-6 DNA. Subsequently HHV-6 variant was identified by using variant-specific PCR. Human cytomegalovirus (CMV) infection was detected in parallel by means of specific PCR. HHV-6 DNA was detected in 12 of 27 tumor tissues (44%), including 8 of 15 lymph node specimens (53%) from patients with AIDS-associated NHL. The corresponding values in HIV-seronegative patients with NHL were 35% (7/20) and 36% (5/14), respectively. Lymph node specimens were positive for HHV-6 in two of four (50%) HIV-seropositive and five of nine (55%) HIV-seronegative patients with follicular hyperplasia. Variant A was detected in two cases of AIDS-associated NHL, variant B in one case, and both variants in six cases. The distribution of HHV-6 variants exhibited a similar pattern in the three control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Opportunistic Infections↗
PubMed1994

Expression of inducible nitric oxide synthase in cytomegalovirus-infected glial cells of retinas from AIDS patients.

The inducible isoform of nitric oxide synthase has been detected in cytomegalovirus (CMV)-infected retinas from acquired immunodeficiency syndrome (AIDS) patients by immunohistochemistry and NADPH-diaphorase staining. Subsequent immunohistochemistry using antibodies against CMV antigens and glial fibrillary acidic protein (GFAP) demonstrated that inducible NOS was localized in CMV-infected glial cells, particularly Müller cells. These findings indicate that inducible NOS is expressed in vivo in the human retina as a result of viral infection, and suggest that high levels of NO production might be involved in CMV-induced retinitis.

Acquired Immunodeficiency Syndrome↗
PubMed1993

In situ hybridization of HIV-1 RNA in retinal vascular wall.

In situ hybridization of human immunodeficiency virus-1 (HIV-1) has been performed on eight eyes from eight distinct acquired immune deficiency syndrome patients (three cases had a normal fundus examination and five presented with cytomegalovirus retinitis). The eyes were removed at autopsy and frozen immediately. Contiguous 10-mu cryostat sections were obtained and tested with a HIV probe labeled by nick-translation with [35S]-ATP. HIV-1 RNA was detected in the retina of two acquired immune deficiency syndrome patients. The first positive case presented with typical ophthalmological and histopathological cytomegalovirus retinitis, the second one was not related to cytomegalovirus, according to clinical or histopathological classical criterias. HIV-1 was localized in retinal vascular walls. This shows that there is an active replication of HIV in retina of some acquired immune deficiency syndrome patients.

Acquired Immunodeficiency Syndrome↗
PubMed1993

[Antiviral chemotherapy: mechanisms of action, evaluation of activity, resistance and future developments].

Antiviral chemotherapy is based on the selective inhibition of intracellular virus multiplication. Inhibitors of viral DNA polymerases perfectly exemplifies this mode of action. In spite of their selectivity, some of these drugs are cytotoxic and all remain unefficient against latent viruses. Evaluation of antiviral activity requires in vitro sensitivity tests, in vivo studies on animals and virological analyses during clinical trials. This evaluation needs well standardized assays. The emergence of in vitro resistance reflects the occurrence of mutations regarding target enzymes. Clinical significance of antiviral drug resistance needs to be assessed in many circumstances, even if its association with immunodeficiency often leads to a clear therapeutic failure. Further developments will include the synthesis of novel inhibitors, study of drug associations and improvement of virological diagnosis techniques relevant to therapy.

Acyclovir↗