Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus-infected patients occasionally exhibit alveolar septal wall thickening and decreases in gas diffusion capacity, but the mechanism underlying these abnormalities is unknown. The present study evaluated septal wall thickness and gas exchange properties in a murine model of the acquired immunodeficiency syndrome and determined whether there were alterations in lung lymphocyte deposition and activation that could contribute to changes in respiratory structure and function. Although alveolar septal wall thickness did not differ from control at 1, 2, and 4 wk postimmunosuppressive virus infection, at 8 wk after infection, septal wall thickness was substantially increased. Immunohistochemical evaluation at this time revealed marked increases in the septal wall deposition of fibronectin and collagen type IV. Pulmonary function tests on anesthetized mice with virus-induced septal wall thickening demonstrated that, although total lung capacity, compliance, and functional residual capacity were unaltered, diffusion capacity for carbon monoxide was significantly impaired. A diffuse nonspecific interstitial pneumonitis was present in lungs of immunodeficient mice, and flow cytometry indicated that both lymphocytes and macrophages were activated. Reverse transcriptase-polymerase chain reaction analysis of lung lymphocytes demonstrated enhanced mRNA expression for several cytokines known to affect lung structure. These results show that impaired gas exchange occurs in a murine model of acquired immunodeficiency syndrome and suggest that such alterations may be mediated by elaboration of cytokines from activated lung lymphocytes and macrophages.
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PMID:Pulmonary mechanical and immunologic dysfunction in a murine model of AIDS. 914 44

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

Failure to detect infection with HIV-1 non-B subtypes in some antibody screening assays has been shown. To date, however, no studies have been published evaluating the capacity of standard tests to quantify replication of divergent HIV-1 in cell culture. Reverse transcriptase (RT) activity and p24 antigen assays are the two methods most commonly used for this purpose. A homogeneous panel of HIV-1 subtype B viruses from northern Italy and a heterogeneous panel of diverse genetic subtypes (A to F and O) from different regions of the world were cultured under identical conditions. A new nonradioactive RT assay was used as a basis for comparison to evaluate the capacity of two p24 assays to quantify viral growth in both panels. Comparison of the p24 amount/RT activity (p24/RT) ratios showed that ratios in the subtype B panel tended to be markedly higher than in the diverse subtype panel. Greatest variation was seen with one of the subtype O isolates, where up to a 400 times lower ratio was obtained compared with the average ratio for the subtype B panel. In addition, one Thai subtype B virus also gave a markedly reduced ratio. Furthermore, comparison between the two p24 assays showed different abilities to detect p24 from different HIV-1 isolates. We discuss limitations for the use of anti-HIV-1 p24 antibodies produced by immunization with subtype B p24 in p24 assays.
AIDS Res Hum Retroviruses 1998 Mar 01
PMID:Differences in reverse transcriptase activity versus p24 antigen detection in cell culture, when comparing a homogeneous group of HIV type 1 subtype B viruses with a heterogeneous group of divergent strains. 951 96

(+)-Calanolide A, a novel dipyranocoumarin from the Malesian tree Calophyllum lanigerum var. austrocoriaceum, and a closely related compound, (-)-calanolide B, isolated from Calophyllum teysmannii var. inophylloide, are representatives of a distinct class of nonnucleoside HIV-1 specific reverse-transcriptase inhibitor under development as an AIDS chemotherapeutic. NCI repository specimens totalling 315 organic extracts from 31 taxa of Calophyllum were analyzed for related pyranocoumarins using a simple TLC system. A total of 127 extracts was initially classified as "positive"; eight out of the 31 taxa examined, representing perhaps 28 species already described (1/7-1/8 of all the species in this genus), contained prenylated coumarins, suggesting that these compounds, while sometimes abundantly present, are not widespread in the genus. Representative members of the TLC-positive extracts were partitioned between CH2C12 and 25% aqueous MeOH; the CH2C12-soluble materials were then analyzed by TLC and 1H NMR to confirm the presence of pyranocoumarins. The anti-HIV activity of the partitioned extracts are also presented. This study suggested that there are several distinctive coumarin chemotaxonomic markers distinguishing species of this genus.
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PMID:Pyranocoumarins from tropical species of the genus Calophyllum: a chemotaxonomic study of extracts in the National Cancer Institute collection. 978 62

The existence of extrahepatic reservoirs of hepatitis C virus (HCV) replication remains highly controversial. We searched for the presence of HCV-RNA negative strand in various tissues from eight HCV-infected patients who died of acquired immunodeficiency syndrome (AIDS)-related complications. Negative-strand RNA was detected by a Tth-based reverse-transcriptase polymerase chain reaction (RT-PCR), which was optimized for sensitivity and strand specificity on synthetic RNA templates. This assay was capable of detecting about 10(2) genomic Eq molecules of the correct strand while unspecifically detecting >/=10(8) genomic Eq molecules of the incorrect strand. Negative-strand viral RNA was detected in all but one liver, in lymph nodes (5 cases), in pancreas (5 cases), in adrenal gland (2 cases), in thyroid (2 cases), in bone marrow (1 case), and in spleen (1 case). These data suggest a possible presence of HCV replication sites outside the liver, at least in AIDS patients. Whether these findings relate to various extrahepatic manifestations of HCV infection remains to be determined.
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PMID:Search for hepatitis C virus extrahepatic replication sites in patients with acquired immunodeficiency syndrome: specific detection of negative-strand viral RNA in various tissues. 979 27

Monocytes (MOs) and macrophages (MACs) are well-known targets for HIV-1 infection. Even though the virus load is contributed mainly to lymphocytes during the asymptomatic phase of infection, the expression of HIV-1 in MO/MACs seems to be important for the course of the disease. To establish a model for restricted HIV-1 expression in MACs in vitro, we cultured MO-derived MACs under different culture conditions and analyzed their susceptibility to HIV-1 infection as well as their capacity for virus replication in vitro. MACs cultured under serum-free conditions with M-CSF (M-MACs) remain viable and functionally active as assessed by the analysis of cytokine production. In addition, the levels of CD4, CD14, CCR5, and HLA-DR expression are comparable to those of serum-derived MACs (SER-MACs). However, serum-free MACs were less susceptible to HIV-1 infection, with only 9.5+/-4.5% (mean+/-SEM) of all cells being p24 antigen positive on day 22 as compared with 51+/-9% under serum conditions (p < 0.005). Reverse transcriptase (RT) activity in the culture supernatant of M-MACs was always about 100-fold lower than that of SER-MACs even when comparable amounts of cells were infected. The addition of serum to serum-free cultures increased the percentage of HIV-1 p24 antigen-positive cells (21+/-8% positive cells on day 22) and increased the RT activity, indicating that serum factors could be important for HIV-1 replication in MACs. Therefore we also switched SER-MACs to serum-free culture conditions and found a sharp decrease in RT activity. However, the RT level could always be rescued by the addition of serum, even after a long serum-free culture period. This effect was dependent on the serum concentration added, with as little as 0.1% serum being effective in reestablishing viral production as measured by RT activity. In conclusion, we show that serum has an important role in the replication of HIV-1 in MACs. Our results suggest that besides the role of CD4 and CCR5 other microenvironmental factors, e.g., growth factors, cytokines, or hormones, which are not provided by the target cell itself, are involved in the regulation of MAC infection and of replication by HIV-1.
AIDS Res Hum Retroviruses 1998 Nov 20
PMID:Restricted HIV type 1 replication under serum-free culture conditions in human monocyte-derived macrophages. 984 Feb 91

This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.
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PMID:Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers. 986 98

A high incidence of herpes zoster was noticed among patients with AIDS, shortly after addition of a protease inhibitor to their baseline treatment with nucleoside analogue reverse-transcriptase inhibitors. Within a median follow-up of 64 weeks (range, 34-103 weeks), 14 patients (7%) had a first episode or a recurrence of herpes zoster (6.2 episodes per 100 patient-years). No episodes of zoster were diagnosed before week 4. Twelve episodes (86%) occurred between weeks 4 and 16. The risk of zoster was independent of age, sex, type of protease inhibitor, and CD4+ lymphocyte count and viral load at baseline and month 1. A CD8+ lymphocyte proportion at baseline of > 66% (hazard ratio [HR], 10.6; 95% confidence interval [CI], 3.4-33.1) and an increase in CD8+ lymphocyte proportion at month 1 of > 5% (HR, 32; 95% CI, 8.1-126.4) were independently associated with the risk of herpes zoster. These data might be clinically useful for determining transient prophylaxis for those patients at high risk.
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PMID:High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors. 986 69

The kinetics of non treated and especially of treated HIV1 is compared to that of non treated and of treated cancer cells. Contrary to Skipper's scheme, based on constancy of cancer cell proliferation or post-chemotherapy decrease slope, the same chemotherapy successive cycles decrease in fact less and less the proportion of cell number reduction, and the hope of killing the "last cell" is a utopian concept. Hence, the very poor global benefit in cancer medicine registered in the last 50 years. The only cures are seen in child tumors and young adults testis cancer: the immunity reaction being stronger before 40 years of age than after 40 may explain this difference with age. The a priori systematic opposition to active immunotherapy of cancer from some authorities has been a grave fault. Such fault should not be committed for the treatment of HIV1-AIDS complex. The continuous HIV1 so called intensive virostatic chemotherapy is complicated by severe toxicities, and resistances of relapses and virus re-activation when it must be discontinued. The widely accepted triple therapy only affects two virus targets (retro-transcriptase and virus protease), which is insufficient, as we have shown. We have also observed that the constant and most rapid VL decrease to < 200 or < 20 RNA copies/mL is obtained when four virus targets are affected, including some concerning DNA provirus (which is the case of acriflavine and methylhydroxy-ellipticine). As in acute lymphoid leukemia, two treatment phases can be distinguished: a) the VL reduction to 20 copies; b) the maintenance of the residual < 20 copies of viruses. Excellent results as far as VL decrease and maintenance at < 20 copies have been obtained with a follow-up between 1 1/2 and 6 years, without any toxicity nor global resistance, with combinations of four drugs affecting four viral targets, applied in short (3 week) sequences, different from each others owing to drug rotation. This can be compared with the 65% remission rate obtained with alternative different cycles of cancer chemotherapy in tumors resistant to conventional modalities. The possibility of repeating for ten patients the evaluation of viral load and of immunologic parameters has allowed us to discover that some VL decrease curves are fractal. As well, maintenance 20 copies are not rarely interrupted by short and reversible HIV1 rebounds as those we had described in "cured" acute lymphoid leukemia patients. Of utmost importance, all HIV1 rebounds were associated with the presence of one cofactor: chimerism, chronic hepatitis, CMV, herpes 8, herpes 6, and influenza are those we observed. The problem today is not to "kill the last tumor cell in cancer" or "the last HIV1 particle" in HIV1-AIDS complex. It is to keep the residual cells or virus in latency. Active immunotherapy and other biologic interventions, such as hypermethylation, should be studied in this aim, as they are also able to do so.
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PMID:The kinetics of cancer cells and of HIV1: the problems of cell and virus rebounds and of latency. 992 9

The recent discovery of chemokine receptors as coreceptors for human immunodeficiency virus-type 1 (HIV-1) entry offers new avenues for investigating the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related cytopenias. To this end, we sought to (1) phenotype human hematopoietic cells for CD4 and the HIV-1 coreceptors CXCR4, CCR5, CCR3, and CCR2b; (2) correlate CD4 and chemokine receptor expression with their susceptibility to HIV-1 infection; and (3) examine any potential interplay between inflammatory cytokines released during HIV-1 infection and regulation of chemokine receptor expression. Fluorescence-activated cell sorting (FACS) analysis of bone marrow mononuclear cells (BMMNC), cells derived from serum-free expanded hematopoietic lineages (colony-forming unit-granulocyte-macrophage [CFU-GM], colony-forming unit-megakaryocyte [CFU-Meg], and burst-forming unit-erythroid [BFU-E]), and CD34(+) cells showed differential expression of chemokine receptors and CD4 with some lineage specificity. Significantly, FACS-sorted CXCR4(+)/CD34(+) cells had the same clonogeneic potential as CXCR4(-)/CD34(+) cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of FACS-sorted human candidate stem cells (HSC; CD34(+), c-kit+, Rho123(low)) showed the presence of CXCR4 mRNA but not CD4 mRNA. Infection studies with HIV-1 Env-pseudotyped luciferase reporter viruses indicated that X4 Env (CXCR4-using) pseudotypes infected megakaryocytic cells, whereas R5 Env (CCR5-using) pseudotypes did not. Similarly, R5 but not X4 Env-pseudotyped viruses infected granulocyte-macrophage cells in a CD4/CCR5-dependent manner. Erythroid cells were resistant to R5 or X4 viral infection. Finally, we found that gamma-interferon treatment upregulated CXCR4 expression on primary hematopoietic cells. In summary, the delineation of chemokine receptor expression on primary hematopoietic cells is a first step towards dissecting the chemokine-chemokine receptor axes that may play a role in hematopoietic cell proliferation and homing. Furthermore, susceptibility of hematopoietic cells to HIV-1 infection is likely to be more complicated than the mere physical presence of CD4 and the cognate chemokine receptor. Lastly, our results suggest a potential interplay between gamma-interferon secretion and CXCR4 expression.
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PMID:Coreceptor/chemokine receptor expression on human hematopoietic cells: biological implications for human immunodeficiency virus-type 1 infection. 994 56


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