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Dan Turner

Publications and source records attributed to Dan Turner.

30 records · Page 2Linked to original sources
PubMed2004

Variability in the PR and RT genes of HIV-1 isolated from recently infected subjects.

To study variability in reverse transcriptase (RT) and protease (PR) genes of HIV-1 isolated from recently infected patients identified between 1997 and 2003, sequences were obtained on the RT and PR genes of viruses harvested from plasma of 121 non-treated subjects who had undergone primary HIV infection. The degree of dissimilarity between the viruses studied and a reference HIV-1 subtype B strain (LAV-1) was calculated for each of RT and PR by counting all of the nucleotide substitutions that could be identified. Mutations associated with drug resistance were excluded from analysis. We observed a mean percentage of variation in the RT and PR genes of the viruses analysed of 0.42% between the years 1997--2003 (P<0.01). In PR, the mean variation was 0.71% (P<0.05), while that in RT was 0.3% (P<0.05). Increased diversity was also observed among nucleotides conferring amino-acid changes, although no significant differences in patterns of nucleotide substitutions were apparent over the period of analysis. In conclusion, variability in the RT and PR genes of viruses from recently infected patients has increased over time in a manner that is independent of variability attributable to HIV drug resistance.

Anti-HIV Agents↗
PubMed2004

The influence of protease inhibitor resistance profiles on selection of HIV therapy in treatment-naive patients.

Although protease inhibitors (PIs) have dramatically improved outcomes in HIV-infected patients, half still fail treatment with PI-based combination therapy. Genetic pressure from incomplete viral suppression rapidly selects for HIV variants with protease gene mutations that confer reduced susceptibility to PI drugs. A number of specific amino acid substitutions have been associated with PI resistance. However, high-level resistance to individual PIs requires the accumulation of several primary and secondary mutations, developing along drug-specific, step-wise pathways. HIV variants resistant to saquinavir and ritonavir usually contain L90M and V82A substitutions, respectively. Indinavir resistance may be linked to substitutions at positions 46 or 82. Resistance to nelfinavir is primarily associated with D30N but may alternatively be found with L90M. Resistance during exposure to amprenavir can follow development of I50V, which also may confer resistance to lopinavir. Failure during treatment with atazanavir is closely linked to 150L. The overlapping of these pathways can lead to multiple-PI resistance, limiting therapeutic options in antiretroviral-experienced patients. Reduced susceptibility to more than one PI is most likely to be associated with amino acid substitutions at six positions: 10, 46, 54, 82, 84 and 90. Other mutations (D30N, G48V, I50V or I50L) are relatively specific for particular PIs and are less likely to produce cross resistance. Certain resistance mutations selected by exposure to one PI may actually increase susceptibility to others. Patients newly diagnosed with HIV infection are increasingly found to harbour virus that is resistant to the more commonly used drugs. Newer PIs may select for mutations that result in less cross resistance with older agents.

Amino Acid Substitution↗
PubMed2003

Relationships among various nucleoside resistance-conferring mutations in the reverse transcriptase of HIV-1.

Highly active antiretroviral therapy has significantly improved HIV-related morbidity and mortality, and nucleoside reverse transcriptase inhibitors remain an essential component of treatment. However, the emergence of HIV-1 mutated strains that are resistant to one or more antiretroviral drugs is a leading cause of treatment failure among patients living with HIV/AIDS. These resistant strains may often suffer from a replication disadvantage in comparison with wild-type viruses when grown in the absence of drug pressure and a potential benefit in this regard has been shown for lamivudine-resistant viruses that contain a M184V mutation in reverse transcriptase, as well as for several other drug-resistant viral variants. Interactions between different mutations may complicate the understanding of HIV drug resistance with regard to the likelihood of therapeutic success.

Drug Resistance, Viral↗
PubMed2003

A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors.

OBJECTIVE: We have shown that HIV-1 clade C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG<--ATG) after selection with efavirenz (EFV). This study evaluates the prevalence of V106 (GTG) and 106M (ATG) codons in clinical isolates as well as the effects of V106M on resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). METHODS: Genotypic analysis ascertained sequence diversity at codon 106, including both valine polymorphisms (GTA and GTG) and the V106A (GCA) and V106M (ATG) resistance-conferring mutations in B (n = 440) and non-B (n = 84) clinical isolates. Cell-based phenotypic assays were performed to determine the effects of V106M and V106A on levels of resistance to EFV, nevirapine and delavirdine. RESULTS: Most subtype B isolates harbored GTA (valine) at codon 106 (97% of cases) while the GTG (valine) polymorphism was generally present in clade C viruses (94% of cases). Under conditions of EFV but not nevirapine or delavirdine pressure (n = 8) in tissue culture, clade C isolates developed the V106M mutation (GTG<--ATG), conferring high-level (100-1000-fold) cross-resistance to all NNRTI. Generation of V106M recombinant viruses by site-directed mutagenesis confirmed the ability of V106M to confer NNRTI cross-resistance. This mutation also developed in three of six EFV-treated patients harboring clade C infections. In current genotypic interpretative reports (including 15 algorithmic databases), V106A is listed as an nevirapine-specific mutation while V106M is not recognized. CONCLUSIONS: V106M may be a signature mutation in clade C patients treated with EFV and may have the potential to confer high-level multi-NNRTI resistance.

Alkynes↗
PubMed2003

An intracellular antigen that reacts with MO2, a monoclonal antibody to CD14, is expressed by human lymphocytes.

CD14, a lipopolysaccharide (LPS) receptor, is present on the surface membrane of phagocytic leukocytes; it is also present in a soluble form in serum. Recently published results confer to this molecule novel functions that are linked to T-cell activation and to apoptosis. We report here that we have defined and characterized a novel lymphocyte population in human peripheral blood, a population that expresses an intracellular antigen detectable with MO2, a monoclonal antibody directed against the human CD14 molecule. This population is composed primarily of CD8-positive T-cells. We found surprisingly that this novel MO2-positive population of lymphocytes was greatly enhanced in asymptomatic, untreated HIV-positive individuals.

Antibodies, Monoclonal↗
PubMed2003

Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance.

HIV-1 infection is characterized by genetic diversity wherein distinct viral subtypes (clades A, B, C, D, E, F, G, K and O) are expanding in different geographical regions. This article deals with the topic of HIV-1 subtype diversity in the context of sensitivity to antiretroviral drugs, drug resistance and viral fitness. Increasing evidence suggests that all clades of HIV probably display similar sensitivity to antiviral drugs. However, viruses from some subtypes and/or geographical regions may have a greater propensity to develop resistance against certain drugs than do other viral variants. In addition, differences in regard to replication capacity or fitness may exist among various HIV subtypes and differences in this regard may potentially become magnified under conditions of drug resistance. Immunological pressures may also play an important role in the evolution of viral subtypes that may impact on ultimate drug resistance profiles.

Animals↗
PubMed2003

Occurrence and phenotypic characteristics of extended-spectrum beta-lactamases among members of the family Enterobacteriaceae at the Tel-Aviv Medical Center (Israel) and evaluation of diagnostic tests.

We assessed the prevalence and phenotypic characteristics of extended-spectrum beta-lactamase (ESBL) producers among cefuroxime-resistant (CXM-R) (MIC > or = 32 micro g/ml) members of the family Enterobacteriaceae in our institution. The 438 CXM-R clinical isolates obtained from nonurine sources among inpatients were screened. ESBL production was confirmed by disk diffusion assay using cefpodoxime (CPD), cefotaxime (CTX), and ceftazidime (CTZ) with and without clavulanate (CLAV). A difference of > or =5 mm in the size of the zone of inhibition in the presence of CLAV for at least one of the agents was considered representative of the ESBL phenotype: 186 isolates (42.5%) were confirmed as ESBL producers. The isolates tested and the rates of ESBL producers were as follows: Klebsiella spp. (n = 81), 79%; Proteus spp. (n = 58), 62%; Escherichia coli (n = 64), 53%; Enterobacter spp. (n = 69), 42%; Serratia spp. (n = 70), 14%; Citrobacter spp. (n = 25), 24%; Providencia spp. (n = 21), 24%; Morganella spp. (n = 41), 5%; and Kluyvera (n = 3), 0%. The overall sensitivity of isolated ESBL confirmatory tests was 79% for CPD-CLAV, 66% for CTZ-CLAV, and 91% for CTX-CLAV. Sensitivities of CTZ-CLAV confirmatory tests for Klebsiella spp., Proteus spp., E. coli, and Enterobacter spp. were 84, 22, 76, and 62%, respectively, and those for CTX-CLAV were 95, 97, 94, and 83%, respectively. They were 90% for CPD-CLAV and CTZ-CLAV, 95% for CPD-CLAV and CTX-CLAV, and 100% for CTZ-CLAV and CTX-CLAV. ESBL production was highly prevalent among Enterobacteriaceae. Using resistance to CXM as an ESBL screening criterion is a suitable option in high-incidence areas where Klebsiella spp. are not the dominant ESBL producers. This screening criterion may simplify the screening test and improve its sensitivity, although at the price of testing more isolates. The CTX-CLAV combination confirmed ESBL producers better than the CTZ-CLAV combination, with sensitivity varying between species. Combined CTZ-CLAV and CTX-CLAV testing detected all these strains; CPD-CLAV provided no additional benefit.

Anti-Bacterial Agents↗
PubMed2002

Acute otitis media in infants younger than two months of age: microbiology, clinical presentation and therapeutic approach.

BACKGROUND: Information on the causative agents of acute otitis media (AOM) in infants <2 months of age is limited. OBJECTIVES OF THE STUDY: To analyze the etiology, pathogen susceptibility patterns, clinical presentation and frequency of serious bacterial infections in infants <2 months of age with AOM and to determine the relationship between the organisms isolated systemically and those isolated from the middle ear fluid in the patients with serious bacterial infections in the presence of AOM. METHODS: The medical records of 137 infants <2 months of age with AOM who underwent tympanocentesis in the emergency room of Soroka University Medical Center between January 1, 1995, and May 30, 1999, were reviewed. The main variables analyzed included demography, frequency of serious bacterial infections, bacteriologic results, susceptibility patterns of the pathogens and clinical presentation. RESULTS: Median age was 38.7 +/- 13 days; 112 of 137 (82%) infants were hospitalized. Six (4%), 27 (20%), 46 (34%) and 58 (42%) episodes were recorded at age 0 to 2, 3 to 4, 5 to 6 and 7 to 8 weeks, respectively. Fever (temperature >38 degrees C) was present in 96 (70%) of the cases. Culture-negative (bacterial) meningitis was diagnosed in 3 cases. Blood and urine cultures were positive in 1 and 6 infants, respectively. None of the afebrile infants developed serious bacterial infection. One hundred twenty-two bacterial pathogens were isolated from the middle ear fluid of 109 of 137 (80%) patients: Streptococcus pneumoniae in 56 (46%), Haemophilus influenzae in 41 (34%), group A Streptococcus in 12 (10%), enteric gram-negative bacilli in 9 (7%), Moraxella catarrhalis in 3 (2%) and Streptococcus faecalis in 1 (1%). Eleven (20%) of the 56 S. pneumoniae isolates were nonsusceptible to penicillin. Serious bacterial infections were diagnosed in 6 of 137 (4%) patients. Whereas blood and urine grew pathogens typical for blood and urinary tract infections, the middle ear fluid isolates represented different pathogens usually isolated in AOM without any correlation between these 2 groups of pathogens. CONCLUSIONS: (1) Most cases of AOM in infants <2 months of age are caused by pathogens similar to those causing AOM in older children; (2) antibiotic resistance may already be present at early age and should be considered in the empiric treatment of AOM in infants <2 months of age; (3) the presence of AOM does not predict a higher risk for serious bacterial infections in afebrile and febrile infants <2 months of age.

Acute Disease↗
PubMed2002

HIV-1 drug resistance: can we overcome?

Highly active antiretroviral therapy (HAART) targeting the viral reverse transcriptase and protease enzymes has advanced the treatment of HIV/AIDS. Nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors used in combination can suppress viral replication thereby delaying disease progression. Emergence of HIV-1 mutated strains, resistant to one or more antiretroviral inhibitors or drug classes, remains one of the leading causes of treatment failure among patients living with HIV/AIDS. While advances in genotypic and phenotypic testing allow for drug resistance guided therapeutic management, the increasing prevalence of multi-drug resistance and an absence of new drug classes forewarn new problems in sustaining the effectiveness of HAART. One promising hope for continued benefit of antiretroviral therapy despite emergent resistance is the observed reduction in replicative ability or 'fitness' of multimutated viruses. This review discusses the development and influence of known drug mutations on drug susceptibility versus viral fitness.

Animals↗
PubMedDate not supplied

HIV transmission and primary drug resistance.

Transmission of HIV viruses harboring resistance mutations is already a major concern in developed countries, with the potential to impact on therapeutic strategies. Several factors influence the transmission of such viruses, including viral replication fitness and transmission fitness, although behavioral characteristics must also be considered. Rates of transmission of specific mutations are related to therapeutic strategies. Reports of the transmission of multidrug-resistant viruses should alarm the medical community. An additional concern is the use of monotherapy with nevirapine for the prevention of mother-to-child transmission of HIV in developing countries as this practice selects for resistance to nonnucleoside reverse transcription inhibitors and could limit future therapeutic options of both the mothers and infected children. HIV treatment guidelines have evolved, shifting from more aggressive to more conservative approaches. This change of strategy has had a direct impact on the prevalence of drug-resistant virus in the population and the transmission of resistant viral species.

Anti-Retroviral Agents↗