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

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Porcine enteric calicivirus (PEC/Cowden) causes diarrhea in pigs, grows in cell culture, and is morphologically and genetically similar to the Sapporo-like human caliciviruses. Genetic analysis revealed that the tissue culture-adapted (TC) Cowden PEC has one distant and three clustered amino acid substitutions in the capsid region and 2 amino acid changes in the RNA polymerase region compared to wild-type (WT) PEC (M. Guo, K.-O. Chang, M. E. Hardy, Q. Zhang, A. V. Parwani, and L. J. Saif, J. Virol. 73:9625-9631, 1999). In this study, the TC PEC, passaged in a porcine kidney cell line, and the WT PEC, passaged in gnotobiotic (Gn) pigs, were used to orally inoculate 13 4- to 6-day-old Gn pigs. No diarrhea developed in the TC-PEC-exposed pigs, whereas moderate diarrhea developed in the WT-PEC orally inoculated pigs, persisting for 2 to 5 days. Fecal virus shedding persisting for at least 7 days was detected by both reverse transcription (RT)-PCR and antigen-enzyme-linked immunosorbent assay (antigen-ELISA) in both TC-PEC and WT-PEC orally inoculated pigs but not in mock-inoculated pigs. The PEC particles were detected by immunoelectron microscopy (IEM) in intestinal contents from all the WT-PEC-inoculated pigs, but not from the TC-PEC-inoculated pigs. Mild (duodenum and jejunum) or no (ileum) villous atrophy was observed in histologic sections of the small intestines of TC-PEC-inoculated pigs, whereas WT PEC caused mild to severe (duodenum and jejunum) villous atrophy and fusion. Scanning electron microscopy confirmed mild shortening and blunting of villi in the duodenum and jejunum of the TC-PEC-inoculated pigs, in contrast to moderate to severe villous shortening and blunting in the duodenum and jejunum of WT-PEC-inoculated pigs. Higher numbers of PEC antigen-positive villous enterocytes were detected by immunofluorescent (IF) staining in the proximal small intestine of the WT-PEC-inoculated pigs, in contrast to low numbers of PEC antigen-positive enterocytes in only one of four TC-PEC-inoculated pigs. No PEC antigen-positive cells were observed in the colon or extraintestinal tissues of all inoculated pigs or in the small intestine of one mock-inoculated pig. Thus, the TC PEC was at least partially attenuated (no diarrhea, mild lesions) after serial passage in cell culture. In further experiments, three 4- to 6-day-old Gn pigs were intravenously (i.v.) inoculated with WT PEC, and all pigs developed diarrhea and villous atrophy in the small intestines resembling that observed in the orally inoculated pigs. Fecal viral shedding persisting for 8 days was detected by both RT-PCR and antigen-ELISA, and PEC was detected by IEM in feces or intestinal contents. The PEC RNA and antigens (at low titers) were detected in acute-phase sera from all the WT-PEC i.v.-inoculated pigs and also from seven of nine of the WT-PEC orally inoculated pigs. Oral or i.v. inoculation of four additional pigs with the PEC-positive acute-phase sera induced diarrhea, small intestinal lesions, PEC shedding in feces, and seroconversion to PEC, confirming the occurrence of viremia during PEC infection, with infectious PEC present in acute-phase sera. No diarrhea, histopathologic changes, or IF staining in the small intestine or fecal or serum detection of PEC was evident in two pigs i.v. mock-inoculated or a pig inoculated i.v. with inactivated WT PEC. To our knowledge, this is the first report of an attenuated enteric calicivirus, the induction of diarrhea, and intestinal lesions in Gn pigs caused by i.v. inoculation of WT PEC and the presence of viremia following PEC infection.
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PMID:Comparative pathogenesis of tissue culture-adapted and wild-type Cowden porcine enteric calicivirus (PEC) in gnotobiotic pigs and induction of diarrhea by intravenous inoculation of wild-type PEC. 1153 86

Mutations in human immunodeficiency virus type 1 reverse-transcriptase codons 89 and 184 confer inhibitor resistance and alter the mutation spectrum of the enzyme. Six macaques were inoculated with wild-type or mutated derivatives (E89G or E89G and M184V) of simian immunodeficiency virus macaque (SIVmac) 239. Five of the infected monkeys maintained high virus loads; the sixth, which was infected with the E89G mutant strain, maintained viremia at a level below the limit of detection. Sequence analysis demonstrated substantial reversion of the E89G mutation in the animals with progressive infection and preservation of this mutation in the animal with controlled infection. A P272S mutation occurred at high frequency in the viruses containing M184V, which did not revert. These results demonstrate that the E89G mutation has a significant negative impact on SIVmac fitness, whereas SIVmac bearing M184V achieved high, sustained virus loads, perhaps with a compensatory effect of the P272S mutation.
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PMID:Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys. 1167 14

Highly active antiretroviral therapies (HAARTs) that contain human immunodeficiency virus (HIV) protease inhibitors (PIs) or nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were compared for their effect on secretory aspartyl proteinase (Sap), a virulence trait for mucosal candidiasis. In therapy-naive HIV-positive subjects, oral Sap was detected in 11, 6, 3, 0, and 0 of 15 subjects treated with PI-HAART and in 7, 7, 9, 6, and 5 of 15 subjects treated with NNRTI-HAART, on days 0, 14, 30, 90, and 180 of treatment, respectively. In another 30 subjects, Sap was detected in 0 and 7 of 15 subjects after 1 year of treatment with PI-HAART or NNRTI-HAART, respectively. The anti-Sap effect of PI-HAART was associated with clinical resolution of oral candidiasis but not with late and inconstant recovery of anticandidal cellular immunity. In all subjects, the 2 therapeutic regimens compared well in increasing CD4(+) cell count and abating viremia. Thus, PIs exert an early, immune reconstitution-independent effect on Candida virulence in the oral cavities of HIV-positive subjects.
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PMID:Antiretroviral therapy with protease inhibitors has an early, immune reconstitution-independent beneficial effect on Candida virulence and oral candidiasis in human immunodeficiency virus-infected subjects. 1180 92

The relative potency and tolerability of multidrug regimens used to treat infants and children infected with human immunodeficiency virus type 1 (HIV-1) are largely unknown. In Pediatric AIDS Clinical Trials Group (PACTG) Protocol 377, 181 infants and children were assigned to receive stavudine (d4T) plus nevirapine (NVP) and ritonavir (RTV); d4T plus lamivudine (3TC) and nelfinavir (NFV); d4T plus NVP and NFV; or d4T plus 3TC, NVP, and NFV. Eleven additional children received d4T and NVP plus NFV given twice daily. All subjects had not previously received protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and all had been immunologically stable while receiving reverse-transcriptase inhibitor therapy. After 48 weeks of therapy, 17 (41%) of 41 subjects receiving d4T-NVP-RTV, 13 (30%) of 44 receiving d4T-NVP-NFV, 21 (42%) of 50 receiving d4T-3TC and NFV (3 times daily), and 22 (52%) of 42 receiving d4T-3TC-NVP-NFV were still receiving their assigned therapy and had HIV-1 RNA suppression to </= 400 copies/mL. These regimens were similar in their drug activity, but the 4-drug regimen offered slightly more durable suppression of viremia.
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PMID:Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. 1188 Sep 66

The complete genome of spring viremia of carp virus (SVCV) was cloned and the sequence of 11019 nucleotides was determined. It contains five open reading frames (ORF's) encoding for the nucleoprotein N; phosphoprotein P; matrix protein M; glycoprotein G; and the viral RNA dependent RNA polymerase L. Genes are organised in the order typical for rhabdoviruses: 3'-N-P-M-G-L-5'. The short leader and trailer regions of SVCV exhibit inverse complementarity and are similar to the respective 3' and 5' ends of the genome of vesicular stomatitis virus. To verify the predicted open reading frames proteins were expressed in bacteria and analysed with a polyclonal anti-SVCV serum. Furthermore, monospecific antisera against the distinct viral proteins were generated. Comparison of genome and protein confirm the assignment of SVCV to the genus Vesiculovirus.
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PMID:Determination of the complete genomic sequence and analysis of the gene products of the virus of Spring Viremia of Carp, a fish rhabdovirus. 1190 Aug 42

A model of vertical HIV transmission was developed using oral HIV-2(287) exposure of newborn Macaca nemestrina. The minimal Animal Infectious Dose for this oral route was found to be 10-fold higher than that for atraumatic viral transmission across other mucosal membranes (vaginal/rectal) of juvenile macaques. However, once infection was established, viral replication was rapid and plasma viremia could be detected by reverse-transcriptase polymerase chain reaction and viral co-culture within 1 week following exposure. No animal was resistant to infection and all macaques initially exposed to a subinfectious viral inoculum were subsequently infected by re-exposure of mucosal membranes. Higher viral load during primary infection correlated with a more rapid CD4 depletion; however, all HIV-2(287)-infected animals developed CD4 depletion during the observation period. This animal model can now be used to study early viral replication in the presence and absence of anti-retroviral agents to help identify conditions to reduce vertical HIV transmission in human newborns.
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PMID:Viral dynamics of early HIV infection in neonatal macaques after oral exposure to HIV-2287: an animal model with implications for maternal-neonatal HIV transmission. 1207 46

We evaluated the efficacy of a 5-drug salvage regimen, preceded by a 12-week, structured treatment interruption (STI), in 46 multidrug-treated, human immunodeficiency virus type 1-infected patients with detectable viremia. Patients were randomly assigned to receive a 5-drug salvage regimen immediately (noninterruption [NI] group; n=24 patients) or after 12 weeks of STI (interruption [I] group; n=22 patients). At week 48, 45% of patients in the I group and 46% of patients in the NI group had virus loads <50 HIV-1 RNA copies/mL (P=.619). No differences in CD4 cell counts were seen between groups at week 48 (P=.734). A complete reversion to wild-type genotype was detected in 35% of patients in the I group, but this phenomenon did not affect the virological response. The only overall baseline factor associated with ensuing virus suppression was a lower number of nucleoside reverse-transcriptase inhibitor-resistant mutations (relative risk, 0.66; 95% confidence interval, 0.47-0.93; P=.021). A prior STI seems to confer no additional benefit to subsequent virological or immunological outcomes of a salvage regimen.
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PMID:Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. 1451 17

Only some twenty years has passed since the first discovery of severe immunodeficiency among previously healthy homosexual men through the discovery of the causing virus and till the status today where the knowledge on the HIV virus and the pathogenic mechanisms induced by the virus are extensive, though still incomplete. Furthermore, steadily better treatments have been introduced at a paste that is probably without precedents. These processes have been fuelled by various molecular biological methods. The abilities to quantify viremia and to sequence virus and hence describe the evolution of the virus represent valuable tools for understanding the pathogenic processes. The current thesis describes some of the findings obtained. While it was initially thought that the virological profile mimicked the clinical with an acute infection followed for years by clinical latency and only after on average ten years signs of severe immunodeficiency, this understanding has been revised. There is no virological latency. The viral replication is on going throughout the infection. However, the virological profile does resemble the clinical. Viremia is high shortly after infection; hereafter declines, and stabilises around what has been termed the viral set point. This level of viremia is predictive of the clinical course of the infection. We have shown that the viremic levels, measured both as HIV RNA load and proviral DNA load, early in infection carry significant information about the course of the infection. It is; however, not only early viral loads that carry prognostic information, also viral load during late-stage infection is clinically informative. Viral load measurements have evolved as the major tool for monitoring the efficacy of antiretroviral therapy. HIV RNA has been shown to be a good surrogate marker for the clinical efficacy of antiretroviral treatment. How to use the measurements most optimally has however not been fully delineated. Various methods for describing virological response might yield different results, and it is recommended that the pros and cons of the various methods be investigated. In a cohort of patients who had obtained good virological suppression on antiretroviral therapy followed prospectively for two years we found that only few patients experienced high-grade viremia. Furthermore, baseline HIV DNA differed between the patients with various longitudinal HIV RNA profiles. The patients with the most pronounced HIV RNA suppression had lowest proviral load at baseline, with a clear gradient across the groups. The interplay between proviral load and treatment response deserves further investigations. Resistance can develop against all the available antiretrovirals. The high turnover rate of HIV along with the error-prone reverse transcriptase leads to the possibility of steady accumulation of resistance mutations if the viremic suppression is incomplete. While the interplay between viremia and resistance development is clear-cut for some antiretrovirals i.e. Lamivudine, the pattern is more complex for i.e. Zidovudine. With the availability of assays for resistances testing the knowledge on this issue has been ever evolving. How to use resistance testing in the clinical monitoring of patients remains to be clarified. Resistance testing can aid in the process of choosing salvage therapy for patients experiencing virological failure. Whether resistance testing will be of clinical benefit in other situations remains to be determined. Investigation of the viral sequences and evolution herein has not only been used for resistance analyses, but also for tracing the spread of the infection. HIV-1 exists in many subtypes, with various geographic distributions. Hence subtype analyses have been used to investigate the introduction and spread of the HIV infection into many countries. Phylogenetic analyses have also been used to investigate nosocomial transmission events. We used analyses of env and gag sequences to trace a case of nosocomial infection at the Department of Infectious Diseases, Rigshospitalet, Denmark. The study underlines the importance of steady awareness of the infection control precautions and possible breaks herein. The usefulness of this type of analyses was confirmed. In the early years of the AIDS epidemic various replicative patterns were described. Virus obtained from patients with late-stage infection often had virus that could induce syncytium formation (SI) when cultured, while virus obtained from patients in the early stages of infection did not have this ability. A correlation between the SI ability and the ability to yield high virus titres rapidly as well as the ability to establish infection in certain cell lines was found. Patients infected with SI virus experience more rapid clinical deterioration. We found that patients harbouring SI virus have HIV RNA loads no different from patients harbouring NSI virus. This is in line with the findings of other groups. Though patients harbouring SI virus had a more rapid development of resistance when treated with nucleoside reserve transcriptase inhibitor (NRTI's) monotherapy, this was not the case when treated with highly active antiretroviral therapy (HAART). HAART is today considered the treatment modality of choice; both for established HIV-infection and in cases where post exposure prophylaxis (PEP) is given in order to prevent establishment of infection after exposure. In a case of transfusion of HIV-contaminated though HIV antibody negative blood the recipient was treated with HAART. As the risk of infection is close to 100% under these circumstances the fact that the recipient remained uninfected is probably attributable to the prompt initiation and thorough maintenance of PEP. PEP is recommended to health care workers after percutaneous HIV exposure as well as after sexual exposure. Even with NRTI monotherapy PEP has been shown to be efficacious. While the explanation for the dichotomy (SI vs. NSI) was for many years unresolved, it is now known that this is due to the requirements of the virus for different co-receptors for cell entry. SI virus uses mainly CXCR4 while NSI virus uses CCR5. Being heterozygous for a 32 basepair deletion in the gene encoding CCR5 leads to slower disease progression. We have shown that heterozygotes have lower HIV RNA levels in the early years of the infection, possibly explaining the clinical advantage of having the deletion. HIV replicates in activated cells, and there is an intriguing interplay between HIV replication and immune activation. HIV-infected patients have elevated levels of immunoglobulins. HIV induces polygonal immunoglobulin production. We found that patients experiencing good virological suppression of HAART had lower IgA levels than patients with less complete viral suppression. Whether IgA can be used as a marker for imminent viral break-through remains to be determined. The full understanding of the interplay between immune activation and HIV replication awaits further studies. The finding of increased viremia in conjunction with acute bacterial or viral infection led to concerns about the safety of vaccinating HIV-infected patients against influenza and pneumococcal infection. We found no difference in HIV RNA levels measured before and median 42 days after anti-pneumococcal vaccination. This is in line with many other studies showing either no or only transient increases in viremia. In conclusion, the knowledge on HIV virology has expanded tremendously. This has led to significant improvements in treatments in the Western World leading to declines in HIV morbidity and mortality. The ability to quantify viral load and to perform sequence analyses represent valuable tools both for understanding the pathogenic actions of the virus and for the clinical monitoring of HIV-infected patients. The optimal usage of these tools in the clinical setting, however, still remains to be defined. The progresses obtained have unfortunately been restricted to the Western World and the calamities of HIV is spreading and worsening in the Developing World. The progress in the development of a vaccine has been disappointing and it is urgently necessary that the progresses obtained within the fields of prevention and treatment are translated into useful strategies in the parts of the world mostly affected by the HIV pandemic.
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PMID:Molecular biological assessment methods and understanding the course of the HIV infection. 1462 50

Resistance of HIV to antiretroviral drugs was studied in 210 samples taken in the last two years from patients at the Molecular Biology Unit of the Microbiology Department of the Hospital La Fe in Valencia, Spain. Once the viral load in plasma was determined, resistance was detected using complete gene sequencing for protease until position 3464 of the HIV-1 inverse transcriptase gene. The results were analyzed using the programs Omiga 1.2 (Oxford Molecular Group) and HR-ASAP 1.0 (Stanford University). The protease inhibitors the least affected by the presence of mutations leading to resistance were amprenavir (68.96% activity), and lopinavir (70.69% activity), and of the inverse transcriptase inhibitors, tenofovir (94.02% activity), D4T (74.62% activity) and 3TC (76.12% activity). The treatment combination with the greatest activity, based on the different mutations, was D4T + 3TC + NNRTI. To justify the persistence of viremia with relatively low genotypic resistance to antiretroviral drugs other variables must be considered, such as treatment compliance and the pharmacokinetics of the drugs.
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PMID:[Resistance of HIV-1 to antiretroviral drugs in Valencia (Spain): mutations and susceptibility]. 1470 23

Human immunodeficiency virus (HIV) production continues in patients receiving highly active antiretroviral therapy (HAART) with undetectable (<50 copies/mL) virus loads. Our initial cross-sectional study showed that this viremia is composed of viruses that lack new resistance mutations to the HAART regimen. Here we describe a longitudinal, clonal genotypic analysis of plasma virus loads in treated adults who had undetectable virus loads. We document a continuous production of virus in 8 HIV-1-infected adults who maintained suppression of viremia for up to 15 months. Using analytical approaches for distinguishing selected resistance mutations from nonselected mutations and polymerase chain reaction errors, we detected no evolution of resistance in the reverse-transcriptase and protease genes. Sporadic resistance mutations were detected in some viral clones that were not selected for subsequently. Thus, in some patients, HAART suppresses replication to a level that does not allow the evolution of drug resistance over a time frame of years.
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PMID:Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without evolution in treated adults with undetectable HIV loads. 1507 83


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