Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Packaging cell lines are important tools for transferring genes into eukaryotic cells. Human immunodeficiency virus type 1 (HIV-1)-based packaging cell lines are difficult to obtain, in part owing to the problem that some HIV-1 proteins are cytotoxic in a variety of cells. To overcome this, we have developed an HIV-1-based packaging cell line which has an inducible expression system. The tetracycline-inducible expression system was utilized to control the expression of the Rev regulatory protein, which in turn controls the expression of the late proteins including Gag, Pol, and Env. Western blotting (immunoblotting) demonstrated that the expression of p24gag and gp120env from the packaging cells peaked on days 6 and 7 postinduction. Reverse transcriptase activity could be detected by day 4 after induction and also peaked on days 6 and 7. Defective vector virus could be propagated, yielding titers as high as 7 x 10(3) CFU/ml, while replication-competent virus was not detectable at any time. Thus, the cell line should enable the transfer of specific genes into CD4+ cells and should be a useful tool for studying the biology of HIV-1. We have also established an inducible HIV-1 Env-expressing cell line which could be used to propagate HIV-1 vectors that require only Env in trans. The env-minus vector virus titer produced from the Env-expressing cells reached 2 x 10(4) CFU/ml. The inducible HIV-1 Env-expressing cell line should be a useful tool for the study of HIV-1 Env as well.
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PMID:Inducible human immunodeficiency virus type 1 packaging cell lines. 867 79

Reverse transcriptase (RT) is an appropriate target for anti-HIV chemotherapy. In recent years several entirely new leads for the design of different structural classes of HIV-1-specific RT inhibitors were provided (also called non-nucleoside RT inhibitors or NNRTI). We performed profound studies on (i) the structure-antiviral activity relationship of TSAO (a prototype NNRTI compound), (ii) the biochemical and molecular mechanism of anti-viral action of TSAO and other NNRTI's, (iii) metabolism and antimetabolic effects of TSAO's in cell culture, and (iv) the pharmacokinetic properties of TSAO in mice. In addition, the molecular basis of resistance development of HIV-1 RT against other NNRTI's have also been profoundly studied. A mapping of the resistance mutations in the binding pocket of the RT and the sensitivity/resistance spectrum of the most important NNRTI's that are subject of clinical trials have been determined. Based on the information that became evident from these studies, a molecular model of interaction of the NNRTI inhibitor TSAO with the binding pocket in the HIV-1 reverse transcriptase has been proposed, and now provide the rational basis for the development of second generation TSAO molecules that may become suppressive to mutant HIV-1 strains. Also, resistance development could be markedly delayed, modulated, attenuated, or even fully suppressed by at least two different original approaches: (i) the knock-out drug concentration principle that exploits the limited capacity of mutant HIV-1 reverse transcriptases to respond to high NNRTI drug concentrations and (ii) the rational paired drug combination therapy that exploits the mutually exclusive sensitivity/resistance properties of NNRTI drugs against the different NNRTI-specific resistance mutations in the RT. Our findings have provided us with several powerful tools to have a more efficient chemotherapeutic impact on the HIV-1 infection and to better control the emergence of viral resistance.
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PMID:Novel concepts in the treatment of human immunodeficiency virus type 1 (HIV-1) infections by HIV-1-specific reverse transcriptase inhibitors. 868 72

Treatment of HIV disease with antiretroviral agents has changed considerably. We now know that monotherapy is not the best strategy in most cases to combat rapid turnover of virus and development of resistance (the exception being mother-to-child transmission) and various combination drug regimens are being explored. Apart from the main drug groups, consisting of nucleoside analogues, proteinase inhibitors, and reverse-transcriptase inhibitors, many new compounds are under development. The timing of therapy may likewise be important, and the indications of benefit from early initiation of treatment need to be confirmed in randomised trials. Overall, there is far more optimism about the use of drugs in HIV infection than there was several years ago.
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PMID:Antiretroviral drugs for AIDS. 881 90

Mycobacterium avium complex (MAC) infection is the most common disseminated opportunistic infection encountered in patients with AIDS. We have studied the ability of specific Mycobacterium avium (MA) antigen to stimulate human monocyte-derived macrophages (MDM) to produce tumor necrosis factor-alpha (TNF-alpha). MDM stimulated with MA sonicate, MA 68 kDa and MA 48-52 kDa antigens were found to produce TNF-alpha in a dose-dependent manner. Reverse transcriptase-polymerase chain reaction analysis of mRNA extracts from antigen-stimulated MDM indicated that TNF-alpha mRNA expression was of brief duration and the time point of peak TNF-alpha mRNA levels was found to be antigen-specific. A significant difference in TNF-alpha production in response to MA 48-52 kDa antigen and M. bovis 65 kDa antigen was observed between MDM from normal and HIV positive individuals.
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PMID:Macrophage release of tumor necrosis factor-alpha by Mycobacterium avium antigens. 887 Nov 13

A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.
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PMID:A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team. 889 68

Reverse transcriptase-coupled polymerase chain reaction (Amplicor HIV-1 Monitor), the branched DNA (bDNA) method (Quantiplex HIV-1 RNA) and the nucleic acid sequence-based assay (NASBA HIV-1 RNA QT) were comparatively evaluated for the quantitation of human immunodeficiency virus type 1 (HIV-1) RNA in plasma. Among 60 plasma specimens from HIV-1 infected patients, HIV-1 RNA was detected in 56 by Amplicor (sensitivity, 93.3%), in 41 by bDNA (sensitivity, 68.3%), and in 60 by NASBA (sensitivity, 100%). HIV-1 RNA was not detected by any of these methods in 34/34 plasma specimens from HIV-1-seronegative blood donors (specificity, 100%). The HIV-1 RNA levels as determined by the different methods were correlated significantly. The frequency of concordant results (log difference < 0.50) was 80.4% between Amplicor and NASBA, 77.5% between Amplicor and bDNA, and 58.6% between bDNA and NASBA. After initiation of antiviral therapy, HIV-1 RNA level variations observed with the three methods were similar. HIV-1 RNA levels were inversely correlated with the CD4+ T cell counts, whereas no correlation was found with HIV-1 p24-antigen levels. When the methods were evaluated for reproducibility, coefficients of variation ranged from 11% to 40% for Amplicor, from 6% to 35% for bDNA, and from 13% to 62% for NASBA. Quantitation of HIV-1 RNA in culture supernatants from HIV-1 subtype A to H strains showed that bDNA can be used to quantitate RNA from all HIV-1 subtypes, whereas Amplicor failed to detect RNA from subtype A strains and NASBA subtype G strains.
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PMID:Comparative evaluation of three assays for the quantitation of human immunodeficiency virus type 1 RNA in plasma. 895 Jun 85

Dialysable Leucocyte Extract (DLE) is a low molecular weight dialysable material of disrupted peripheral human leucocytes with widespread effects on the immune system. We described the in vitro anti-HIV activity of DLE as well as its three chromatographic fractions (Fa, Fb and Fc). To determine the levels of inhibition on HIV replication by DLE we infected MT-4 cell cultures, using the Bru viral isolate at 0.05, 0.1, 0.5 and 1 m.o.i. Previously, MT-4 cells cultures were treated with DLE or fractions at non-toxic concentrations. Reverse transcriptase (RT) activity and p24 antigen were evaluated in culture supernatants at seven days postinfection. No effect was observed when MT-4 cells were incubated with DLE for 3 h. Whereas inhibition of HIV production was observed when MT-4 cells were pre-treated for a longer period of time. DLE inhibited p24 production and RT activity more than 50% at 0.1 m.o.i. More than 80% of inhibition was observed for all doses of DLE tested at 0.05 m.o.i. Higher viral doses (m.o.i. 0.5 and 1) were used to assess the antiviral activity of DLE fractions. Fraction Fb inhibits viral production more than 80%. Otherwise, fractions Fa and Fc did not show inhibitory effect for any viral dose used. These results indicate that DLE is able to modulate cell susceptibility to viral infection in vitro.
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PMID:Inhibition of in vitro HIV infection by dialysable leucocyte extracts. 899 55

Human immunodeficiency virus type 1 (HIV-1) drug susceptibility testing is often curtailed because such testing is expensive and time consuming. A colorimetric tetrazolium dye method previously used for high-throughput antiviral drug screening was adapted to assess the susceptibility of 16 HIV-1 isolates to zidovudine, didanosine, lamivudine, and nevirapine in MT-2 cells. Cell viability was assessed colorimetrically, and all measurements and calculations were automated. Each HIV-1 isolate was tested in > or = 5 assays to determine the reproducibility of the assay in HIV-1 isolates with known reverse-transcriptase mutations. The drug susceptibility of several mutant HIV-1 strains whose drug susceptibilities had not previously been well defined was also determined. Data on HIV-1 replication from the susceptibility assays indicated that some mutant HIV-1 isolates may have been less cytopathic in MT-2 cells than wild type HIV-1 isolates.
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PMID:A novel approach to assessing the drug susceptibility and replication of human immunodeficiency virus type 1 isolates. 904 26

Only incomplete data are available to guide decision on anti-HIV treatment. A British HIV Association consensus is that guidance must draw on other evidence besides the randomised trial. Marker studies, work on disease pathogenesis and viral dynamics, and expanding knowledge of resistance patterns mean that the approach to therapy is constantly evolving. There is a need for well-informed dialogue between HIV-infected patient and physician to achieve rational, individualized treatment. However, the following broad principles have a wide consensus amongst HIV-treating physicians in the UK: (1) treatment should be offered before substantial immunodeficiency ensues; (2) initial treatment should include combinations of at least two drugs; (3) switches in therapy should involve substitution or addition of at least two new agents; (4) viral load and CD4 measurements are essential; (5) reduction in viral load to below the detection level of a sensitive assay represents the optimal treatment response and failure to achieve or sustain this control should prompt consideration of therapy modification. This response seems to be achieved most reliably with combinations of two nucleoside analogues plus a third agent (a protease inhibitor, a non-nucleoside reverse-transcriptase inhibitor, or a third nucleoside analogue) or of two protease inhibitors.
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PMID:British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. BHIVA Guidelines Co-ordinating Committee. 926 33

Structures consistent in size, shape and character with various stages of a Lentivirus replicative cycle were observed by electron microscopy in 12-day peripheral-blood lymphocyte cultures from 10 of 17 Chronic Fatigue Syndrome patients and not in controls. Attempts to identify a lymphoid phenotype containing these structures by immunogold labelling failed and the results of reverse-transcriptase assay of culture supernatants were equivocal. The study was blind and case-controlled, patients being paired with age, sex and ethnically matched healthy volunteers. Prescreening of subjects included the common metabolic and immunological disorders, functional conditions and a virus-screen against hepatitis B and C, Epstein-Barr Virus, Cytomegalovirus and Human Immunodeficiency Virus.
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PMID:Electron microscopic immunocytological profiles in chronic fatigue syndrome. 920 53


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