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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus type 1 (HIV-1) subtype C viruses have been found to almost exclusively use the chemokine receptor CCR5 as a coreceptor for entry, even in patients with advanced AIDS. We have characterized subtype C virus isolates from 28 patients from Harare, Zimbabwe, 20 of whom were receiving antiretroviral treatment. Virus from 10 of the treated patients induced syncytium formation (SI virus) when cultured with MT2 cells. Only non-syncytium-inducing (NSI) virus was cultured from the peripheral blood mononuclear cells of the eight patients who had not received treatment. The majority of these subtype C SI viruses were capable of using both CCR5 and CXCR4 as coreceptors for viral entry, and the consensus V3 loop sequences from the SI viruses displayed a high net charge compared to those of NSI viruses. While those on treatment had reverse transcriptase (RT) and protease mutations, there was no clear association between RT and protease drug resistance mutations and coreceptor tropism. These results suggest that CXCR4-tropic viruses are present within the quasispecies of patients infected with subtype C virus and that antiretroviral treatment may create an environment for the emergence of CXCR4 tropism.
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PMID:High frequency of syncytium-inducing and CXCR4-tropic viruses among human immunodeficiency virus type 1 subtype C-infected patients receiving antiretroviral treatment. 1280 70

The replicative cycle of the human immunodeficiency virus (HIV) can be interrupted at several stages. Until recently only the viral reverse transcriptase and protease were the only enzymes targeted by antiretroviral agents. However, the first HIV entry inhibitor (T-20, Enfuvirtide, Fuseon) to be used in humans has been approved by the Food and Drug Administration (FDA). The HIV entry process is considered as an attractive target for chemotherapeutic intervention, as blocking HIV entry into its target cell leads to suppression of viral infectivity, replication and the cytotoxicity induced by virus-cell contacts. HIV-1 entry into target cells is a multistep process: virus attachment is initiated by the binding of trimeric envelope glycoprotein gp120 complexes on the virions to glycosylated T-cell surface receptor (CD4) and HIV GPCR coreceptors (CCR5 or CXCR4) leading to envelope glycoprotein gp41-dependent fusion-pore formation and membrane fusion. A number of compounds are being developed to specifically target each of these steps leading to virus entry and some compounds have reached early clinical development. Conversely, agents such as the CCR5 antagonist Tak-779 and the CXCR4 antagonist AMD3100 are not longer being thought as relevant anti-HIV agents but have given way to new analogues with improved properties. This review summarizes the current state of HIV entry inhibitors, their mechanisms of action and their therapeutic value against HIV infection and AIDS.
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PMID:Virus entry as a target for anti-HIV intervention. 1287 Nov 11

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

CXCR3, predominately expressed on memory/activated T cells, is a receptor for both interferon-gamma inducible protein-10/CXC ligand 10 (CXCL10) and monokine induced by interferon-gamma/CXCL9. We reported here that CXCR3 was highly up-regulated on infiltrating eosinophils in Schistosoma japonicum egg-induced granuloma in the mouse liver. It was also highly and functionally up-regulated on peritoneal exudate eosinophils in mice infected with S. japonicum. The phenomena were demonstrated at protein and mRNA levels using immunohisto- and immunocytochemistry evaluation of biopsy, flow cytometry and real-time quantitative reverse transcriptase-polymerase chain reaction technique, and verified by Northern blotting and chemotaxis assay in vitro. We also found that CCR3 expression on the infiltrating and peritoneal exudate cells was significantly decreased, CXCR4 expression was unchanged during the 42-day period of infection. We screened mRNA expression levels of the all known chemokine receptors in purified peritoneal exudate eosinophils and liver granuloma dominated by eosinophils. CXCR3 was highly and functionally up-regulated on peritoneal exudate eosinophils in mice infected with S. japonicum, meanwhile CCR3 was significantly and functionally down-regulated in these cells. The findings could lead to a better understanding of the chemokine receptor expression pattern of eosinophils at inflamed tissue sites caused by parasites. These could be also crucial for establishing a therapeutic strategy for eosinophilic inflammation via intervention in chemokine actions.
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PMID:Highly up-regulated CXCR3 expression on eosinophils in mice infected with Schistosoma japonicum. 1467 5

CXCR4, a coreceptor for human immunodeficiency virus type 1 (HIV-1) X4 virus, plays an important role in virus entry into the target cells. Antiviral agents that bind to CXCR4 are expected to inhibit HIV-1 entry. A cell-based enzyme-linked immunosorbent assay (ELISA) was developed utilizing an anti-CXCR4 monoclonal antibody, 12G5, and cells expressing CD4 and CXCR4, U373-MAGI-CXCR4(CEM) cells. Using this assay, we demonstrated that 12G5 specifically binds to the CXCR4-expressing cells, but not to CCR5-expressing cells and cells without CXCR4 and CCR5, consistent with the results obtained by using flow cytometry. The well-characterized CXCR4 antagonists, T22, T14012 (a downsized analog of T-22), and AMD3100, effectively inhibited 12G5 binding to CXCR4-expressing cells, while HIV-1 entry inhibitors targeting CD4 and gp41 as well as HIV-1 reverse transcriptase and protease inhibitors did not block the binding of 12G5 to U373-MAGI-CXCR4(CEM) cells. The prepared plates containing the fixed cells could be stored at -80 degrees C for at least 5 months without affecting the cell reactivity with 12G5, which enhances the convenience of this method. This suggests that the cell-based ELISA is specific, sensitive, convenient, rapid, and economic. With a robotic sample processing system, this assay can be used for high-throughput screening of HIV-1 entry inhibitors targeted to the HIV-1 coreceptor CXCR4.
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PMID:Development of a cell-based enzyme-linked immunosorbent assay for high-throughput screening of HIV type 1 entry inhibitors targeting the coreceptor CXCR4. 1467 1

The novel immunosuppressant FTY720 activates sphingosine 1-phosphate receptors (S1PRs) that affect responsiveness of lymphocytes to chemokines such as stromal cell-derived factor 1 (SDF-1), resulting in increased lymphocyte homing to secondary lymphoid organs. Since SDF-1 and its receptor CXCR4 are also involved in bone marrow (BM) homing of hematopoietic stem and progenitor cells (HPCs), we analyzed expression of S1PRs and the influence of FTY720 on SDF-1/CXCR4-mediated effects in human HPCs. By reverse transcriptase-polymerase chain reaction (RT-PCR), S1PRs were expressed in mobilized CD34+ HPCs, particularly in primitive CD34+/CD38- cells. Incubation of HPCs with FTY720 resulted in prolonged SDF-1-induced calcium mobilization and actin polymerization, and substantially increased SDF-1-dependent in vitro transendothelial migration, without affecting VLA-4, VLA-5, and CXCR4 expression. In nonobese diabetic-severe combined immunodeficient (NOD/SCID) mice, the number of CD34+/CD38- cells that homed to the BM after 18 hours was significantly raised by pretreatment of animals and cells with FTY720, tending to result in improved engraftment. In addition, in vitro growth of HPCs (week-5 cobblestone area-forming cells [CAFCs]) was 2.4-fold increased. We conclude that activation of S1PRs by FTY720 increases CXCR4 function in HPCs both in vitro and in vivo, supporting homing and proliferation of HPCs. In the hematopoietic microenvironment, S1PRs are involved in migration and maintenance of HPCs by modulating the effects of SDF-1.
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PMID:The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells. 1498 50

Limited information is available on the activity of antiretroviral drugs against human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) strains to guide their use in treatment or prophylaxis. We evaluated the antiviral activity of 16 approved drugs and one experimental drug, AMD3100, against two wild-type HIV-2 (ROD and EHO) isolates, two strains of SIV (mac251 and B670), and two strains of simian-human immunodeficiency virus (SHIV) that contain the reverse transcriptase (RTSHIV) or envelope glycoprotein (SHIV89.6) of human immunodeficiency virus type 1 (HIV-1) in a SIV(mac239) background. Drug susceptibility was measured conventionally by the MT-4/MTT assay, and results were analysed as fold changes in 50% effective concentration (EC50) relative to the EC50 for HIV-1 (IIIB). The nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, lamivudine, stavudine, didanosine, zalcitabine and abacavir as well as the nucleotide reverse transcriptase inhibitor tenofovir retained full activity against all six viruses except for SIV and SHIV89.6 that showed low-level resistance to didanosine. The protease inhibitors (PIs) ritonavir, indinavir, saquinavir and nelfinavir were found to be active against some HIV-2 or SIV strains. However, a significant reduction in susceptibility was seen with indinavir against SHIV89.6 (3.3-fold), and with amprenavir against HIV-2(ROD) (8.8-fold). All viruses except for RTSHIV showed a >200-fold decrease in susceptibility for the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and efavirenz, indicating high-level resistance. AMD3100, a CXCR4 antagonist, was active against HIV-2 and SHIV89.6, a finding consistent with the use of the CXCR4 co-receptor by these isolates, but was inactive against SIV strains. In contrast, enfuvirtide (T-20) was active against SHIV89.6 but had reduced inhibitory activity against both HIV-2 and SIV strains predicting little therapeutic value against these viruses. These findings support the use of NRTIs, tenofovir, but not NNRTIs, for treating HIV-2-infected persons or for prophylaxis against HIV-2 and SIV. The clinical significance of the low-level resistance of HIV-2 and SIV to some PIs is unclear. Co-receptor antagonists such as AMD3100 show promising anti-HIV-2 therapeutic modalities. Both AMD3100 and enfuvirtide could be used for prophylaxis against SHIV89.6.
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PMID:Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. 1504 May 30

The chemokine receptors CXCR4 and CCR5 are used as the main co-receptors by the T-cell-tropic (CXCR4-dependent, X4) and macrophage-tropic (CCR5-dependent, R5) HIV-1 strains, respectively, for entering their target cells. The natural ligands for CXCR4, the CXC-chemokine SDF-1 and CCR5, the CC-chemokines RANTES, MIP-1alpha and MIP-1beta are described to inhibit viral entry. In this review we focus on chemokine receptor/HIV co-receptor inhibitors. Modified chemokines such as Met-RANTES and AOP-RANTES showed antiviral activity against R5 viruses. Several low-molecular weight CCR5 antagonists have been described (such as TAK-779 and SCH-C) with potent antiviral activity. The latter compound is also orally available and is able to decrease R5 viral load levels in HIV-infected subjects. Several peptidic compounds, such as T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer) and CGP 64222 (also a 9-mer) have anti-HIV activity and have been identified as CXCR4 antagonists. Also, the HIV-1 Tat protein has been described as a "natural" CXCR4 antagonist with anti-HIV-1 activity. The most potent and specific CXCR4 antagonists are the bicyclam derivatives, which also potently inhibit X4 HIV replication. AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks X4 viral replication in any target cell-type evaluated so far. AMD3100 was selected as the clinical drug candidate, which, after initial phase I (safety) studies, had proceeded to phase II (efficacy) trials. The compound dose-dependently inhibited X4 viruses after 10 days of continuous infusion of the drug. Recently, the orally bioavailable CXCR4 antagonist, AMD070, is presented as a candidate HIV drug. We believe that chemokine receptor antagonists will become important new antiviral drugs to combat AIDS. Both (CXCR4 and CCR5) chemokine receptor inhibitors will be needed in combination to inhibit viral replication and even in combinations of antiviral drugs that also target other aspects of the HIV replication cycle, such as reverse transcriptase and protease, to obtain optimum therapeutic effects.
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PMID:HIV co-receptors as targets for antiviral therapy. 1513 47

Hypoxia is a characteristic feature of many human pathologies, including cancer. The sustained proliferation rate of tumor cells leads to alterations of the tumor microenvironment, that progressively becomes more acidic, nutrient-deprived, and hypoxic. The reduced partial pressure of oxygen triggers the onset of an adaptive response, aimed at increasing the local oxygen concentration by several complementary actions. Although directly exposed to the blood stream, endothelial cells lining the vascular lumen in tumors also can be exposed to hypoxia and therefore can contribute to the onset of the adaptive response that leads to tumor angiogenesis. Aiming at getting a detailed insight into the oxygen-dependent regulation of the transcriptional program of vascular endothelial cells and at identifying new relevant markers that may be used as targets for therapeutic intervention in tumor angiogenesis, we have performed a broad-range transcriptomic analysis, using the Affymetrix HG-U133A Gene Chips, of mRNA expression levels in human umbilical cord vein endothelial cells (HUVEC), exposed in vitro to hypoxia for different time periods. The transcriptomic analysis was complemented by a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of mRNA levels and alternative splicing for some selected extracellular matrix protein genes, and by a proteomic analysis, using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and tandem mass spectrometry for protein separation and identification, of hypoxic and normoxic HUVEC whole-cell lysates and subcellular fractions. Our analysis confirmed previous findings on genes whose expression is regulated by oxygen concentration but also identified new genes (e.g., CXCR4, claudin 3, CD24, tetranectin, Del-1, procollagen lysyl hydroxylase 1 and 2) which are transcriptionally upregulated in hypoxic conditions.
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PMID:Modulation of gene expression by hypoxia in human umbilical cord vein endothelial cells: A transcriptomic and proteomic study. 1517 42

The development of novel drugs active against multi-drug resistant (MDR) HIV-1 strains is urgently required. HIV protease inhibitors and reverse transcriptase inhibitors constitute two categories of important drugs, which have greatly improved the clinical treatment of HIV-infected patients by their cocktail use designated as highly active anti-retroviral therapy (HAART). By combinatorial chemistry involving substructure units contained in known HIV protease inhibitors, we found effective protease inhibitors, TYA5 and TYB5, which showed potent anti-HIV activity even against MDR strains. Selection of drug-resistant viruses is also decreased when these new agents are tested in vitro. Subsequently, introduction of an (E)-alkene dipeptide isostere into TYB5 led to the development of a pure non-peptide protease inhibitor, TYB1. We have also studied the development of effective inhibitors for blocking HIV-entry into host cells based on recent discovery of an HIV entry mechanism involving the viral usage of chemokine receptors as coreceptors, CXCR4 and CCR5. We developed highly selective CXCR4 antagonists, T22 and T140 (18-mer and 14-mer peptides, respectively), which strongly suppress T-cell line-tropic HIV-1 (X4-HIV-1) entry through their specific binding to CXCR4. Recently, molecular-size reduction of T140 yielded low molecular weight CXCR4 antagonists, which might be more useful leads to drug-like structures. In this review, we discuss the development of two types of anti-HIV agents, protease inhibitors and CXCR4 antagonists, which would improve clinical AIDS chemotherapy.
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PMID:Two orthogonal approaches to overcome multi-drug resistant HIV-1s: development of protease inhibitors and entry inhibitors based on CXCR4 antagonists. 1518 Apr 58


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