Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4+ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the effect of the activation status of CD4+ T cells on the predominance of R5 and X4 HIV-1 variants in different subsets of CD4+ T cells in ex vivo-infected human lymphoid tissues and peripheral blood mononuclear cells (PBMCs). In these cell systems, we examined the sensitivity of HIV replication to reverse transcriptase inhibitors. We demonstrate that R5 HIV-1 variants preferentially produced productive infection in HLA-DR- CD62L- CD4+ T cells. These cells were mostly in the G1b phase of the cell cycle, divided slowly, and expressed high levels of CCR5. In contrast, X4 HIV-1 variants preferentially produced productive infection in activated HLA-DR+ CD62L+ CD4+ T cells, which expressed high levels of CXCR4. The abilities of the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine and lamivudine to stop HIV-1 replication were 20 times greater in activated T cells than in slowly dividing HLA-DR- CD62L- CD4+ T cells. This result, demonstrated both in a highly physiologically relevant ex vivo lymphoid tissue model and in PBMCs, correlated with higher levels of thymidine kinase mRNA in activated than in slowly dividing HLA-DR- CD62L- CD4+ T cells. The non-NRTI nevirapine was equally efficient in both cell subsets. The lymphoid tissue and PBMC-derived cell systems represent well-defined models which could be used as new tools for the study of the mechanism of resistance to HIV-1 inhibitors in HLA-DR- CD62L- CD4+ T cells.
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PMID:R5 variants of human immunodeficiency virus type 1 preferentially infect CD62L- CD4+ T cells and are potentially resistant to nucleoside reverse transcriptase inhibitors. 1637 87

Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection. Several compounds which block the attachment of HIV gp120 to either the CD4 T cell receptor or the CCR5/CXCR4 co-receptors are currently in clinical development. Most of these compounds have different molecular structures and specific mechanisms of action. These agents are eagerly awaited by a growing number of patients carrying viruses resistant viruses to many of the current available reverse transcriptase and protease inhibitors. For enfuvirtide, the first and, so far, only entry inhibitor approved for clinical use, the main mechanism of resistance is the selection of changes within a 10 amino acid segment encompassing residues 36-45 within the HR1 region of gp41. For other entry inhibitors, multiple changes in different gp120 domains (V1, V2, V3, C2 and C4) have been associated with loss of susceptibility to these agents, although in most cases with limited cross-resistance.
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PMID:HIV entry inhibitors: mechanisms of action and resistance pathways. 1646 88

The new generation of antiviral drugs intended to counter HIV-1 entry into susceptible cells is emerging swiftly. The antiviral agents that inhibit HIV entry to the target cells (denoted as HIV entry inhibitors) are already in different phases of clinical trials. Operating early in the viral life cycle, they prevent viral entry, and have a novel, highly specific mechanism of action with a low toxicity profile. Entry inhibitors have different toxicity and resistance profiles than the existing reverse transcriptase and protease inhibitors. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, thus offering the rationale for their combination in therapies for HIV-infected individuals. It is worth focusing on recent developments in HIV entry inhibitors, as most of the current drug regimens suffer from the events of developing resistance against existing combination therapies. Recent advances in the understanding of the cellular and molecular mechanisms of HIV-1 entry provide the basis for novel therapeutic strategies that prevent viral penetration of the target cell-membrane, while reducing detrimental virus and treatment effects on cells and prolonging virion exposure to immune defenses. A number of potential sites for therapeutic intervention become accessible during the narrow window between virus attachment and the subsequent fusion of viral envelope with the cell membrane. The HIV-1 coreceptors are particularly attractive from the perspective of identifying new antiviral compounds, since they are seven-transmembrane motif G protein-coupled receptors (GPCRs), a family of proteins that is a well-validated target for drug development. Among the many chemokine receptors that can mediate HIV-1 entry in vitro, only CCR5 and CXCR4 are of frontline pharmacological importance. In particular, CCR5 is essential for viral transmission and replication during the early and clinically latent phase of disease. Several small-molecule antagonists of CCR5 and CXCR4 that block chemokine binding and HIV-1 entry have been identified in recent years. Considerable advances have been made in the last years in the design of derivatives acting as inhibitors of HIV entry. The molecular mechanism involved in viral entry, the structural and functional aspects of entry inhibitors are reviewed here. We have also summarized the recent insights into how small-molecule antagonists interact with CCR5 and CXCR4, focusing on drug development programs that are well documented in the scientific literature. An overview of the entry inhibitors that are in preclinical or early clinical development, and the Quantitative Structure-Activity Relationships (QSAR) studies reported for the coreceptor antagonists are also be presented.
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PMID:The HIV entry inhibitors revisited. 1661 Oct 75

In the absence of a vaccine which could stop the HIV/AIDS pandemic, the development of therapeutic options is of utmost interest. The combined use of inhibitors of reverse transcriptase and protease as highly active antiretroviral therapy (HAART) provided the first effective treatment of HIV/AIDS and significantly decreased the number of AIDS related deaths in industrialized countries. However, the emergence of resistant viruses and the toxic side effects of HAART highlights that novel therapies are urgently required. The inhibition of HIV-1 entry is a promising option. Entry of HIV-1 into target cells involves interactions of the viral envelope protein (Env) with CD4 and a coreceptor, usually CCR5 or CXCR4. Env binding to receptor triggers several conformational rearrangements in Env, which involve the creation and/or exposure of structural intermediates pivotal to fusion of the viral and cellular membranes. Both, cellular receptors and structures in Env associated with membrane fusion are targets for therapeutic intervention. Here, we will discuss how HIV-1 enters cells and introduce strategies how this process can be inhibited.
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PMID:Cellular entry of HIV: Evaluation of therapeutic targets. 1678 41

Although combinations of drugs that target the HIV reverse transcriptase and protease enzymes have clearly revolutionized the treatment of HIV/AIDS, problems with these agents, such as viral escape mutants, persistence of viral reservoirs, poor patient compliance due to complicated regimens, and toxic side effects, have emphasized the need for development of new drugs with novel mechanisms of action, as well as an HIV vaccine. Recently two new classes of drugs have been identified that interfere with the membrane fusion reaction required for HIV entry of target cells. Two such agents, T-20 (enfuvirtide) and T-1249, which have been approved by the Food and Drug Administration (FDA), block the action of the fusogenic envelope glycoprotein gp41. Others target the HIV coreceptors CCR5 and CXCR4, and are now in clinical trials. Also under development are novel agents that target the HIV integrase and HIV regulatory gene products as well as immunomodulators such as IL-12 and IL-2. This article will focus on these and other novel approaches to HIV therapeutics.
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PMID:Anti-HIV therapy: Current and future directions. 1678 46

There are many promising new agents in development for the treatment of HIV type 1 (HIV-1). The targets of antiretroviral drugs include the three major HIV-1 enzymes (reverse transcriptase, protease, and integrase), final packaging and export of mature virions, and entry mediated by the CD4 receptor and the CCR5 and CXCR4 coreceptors. Drugs in development in existing classes are primarily designed to provide new options for those with resistance to existing agents. Novel agents such as those targeting integrase, entry inhibitors, and those targeting viral processing likely will be useful the treatment of antiretroviral-experienced patients. Depending on safety, efficacy, tolerability, and convenience of dosing, new agents may also alter the current treatment paradigms for first-line therapy. This review summarizes data on several drugs that could move forward into the clinical arena and affect the lives of those infected with HIV-1.
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PMID:Novel antiretroviral agents in HIV therapy. 1706 43

The majority of HIV isolated from infected patients uses CCR5 as a coreceptor (R5-HIV). Although R5-HIV fails to replicate efficiently in human transformed T-cell lines, HIV using CXCR4 (X4-HIV) can replicate well in such cell lines. Therefore, most of screening systems using the T-cell lines detect only X4-HIV replication. Here we report a new assay to monitor the replication of R5- as well as X4-HIV. An MTT assay using CD4-, CXCR4-, and CCR5-transduced human glioma NP-2 cells (NCK45 cells) was established and then compared with the representative assays including multinuclear activation of a galactosidase indicator assay (MAGI assay). The antiviral activities of not only an adsorption inhibitor and reverse transcriptase inhibitors but also a Tat antagonist in the NCK45 cells, were comparable to those obtained from the MTT assay using MT-4 cells or the MAGI assay. However, the activity of protease inhibitors (PIs) was underestimated, even though expressions of major multidrug resistant genes involved in efflux of PIs were comparable in MT-2, NP-2, and NCK45 cells. After cultivation of more than 6 months, NCK45 cells remained susceptible to HIV infection since NCK45 cells consistently expressed CD4, CXCR4, and CCR5. On the other hand, MAGI cells lost the CD4 expression during culture. Thus, this assay system can stably detect the replication of both X4- and R5-HIV, indicating that it should be useful for the evaluation of HIV replication and drug susceptibility.
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PMID:A novel colorimetric assay for CXCR4 and CCR5 tropic human immunodeficiency viruses. 1706 99

Chemokines help to establish cerebral inflammation after ischemia, which comprises a major component of secondary brain injury. The CXCR4 chemokine receptor system induces neural stem cell migration, and hence has been implicated in brain repair. We show that CXCR1 and interleukin-8 also stimulate chemotaxis in murine neural stem cells from the MHP36 cell line. The presence of CXCR1 was confirmed by reverse transcriptase PCR and immunohistochemistry. Interleukin-8 evoked intracellular calcium currents, upregulated doublecortin (a protein expressed by migrating neuroblasts), and elicited positive chemotaxis in vitro. Therefore, effectors of the early innate immune response may also influence brain repair mechanisms.
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PMID:The MHP36 line of murine neural stem cells expresses functional CXCR1 chemokine receptors that initiate chemotaxis in vitro. 1728 63

Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection. It has also been observed that in some neuropathic pain models, chemokines and their receptors are upregulated, perhaps contributing to the pain state. In order to understand if chemokines are involved in NRTI-mediated sensory neuropathies, we treated rats with the anti-retroviral drug, 2',3'-dideoxycytidine (ddC), which is known to produce an extended period of hyperalgesia and allodynia. Using in situ hybridization, we observed that under normal conditions, CXCR4 chemokine receptors were widely expressed by satellite glia in the dorsal root ganglia (DRG) and Schwann cells in the sciatic nerve. A limited number of DRG neurons also expressed CXCR4 receptors. The chemokine SDF-1/CXCL12 was similarly expressed in glial cells in the DRG and peripheral nerve. Following a single administration of ddC, expression levels of CXCR4 mRNA in glia and neurons and SDF-1 mRNA in glia increased considerably. The functional nature of increased CXCR4 mRNA expression was confirmed by measuring SDF-1 induced [Ca2+]i increases in acutely isolated DRG neurons and glia. In contrast, the expression of the chemokine receptors CCR2 and CCR5 did not change following ddC treatment. Pain hypersensitivity produced by ddC could be inhibited by treatment with the CXCR4 antagonist, AMD3100. Hence, we postulate that NRTIs produce pain hypersensitivity through the upregulation of CXCR4 signaling in the DRG. Increased numbers of CXCR4 receptors would also explain the synergism observed between NRTI treatment and the proalgesic effects of HIV-1 infection.
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PMID:CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. 1729 84

The chemokine receptors CCR5 and CXCR4 were identified as HIV-1 co-receptors in 1996. Since then, a range of agents that bind these receptors and potently block HIV-1 infection have been described, including monoclonal antibodies, peptides and modified chemokines. However, small organic molecules that bind CCR5 are currently the most promising of the co-receptor antagonists for the potential treatment of HIV. These agents are now in advanced stages of clinical development and should soon augment current therapies, as well as being candidates for inclusion in microbicides. Unlike existing drugs that target HIV proteins (eg, reverse transcriptase and protease), co-receptor antagonists bind receptors encoded by the host. As a consequence, blockade of these receptors may result in immunosuppressive effects or other disorders. Furthermore, co-receptor inhibitors may also be more toxic than currently available HIV therapies, and it is not yet clear whether they will become candidates for first-line therapy. Nonetheless, safer, less toxic versions of such inhibitors may be achievable in the future. The use of CCR5 inhibitors as a second-line treatment increases the possibility that these reagents will select for more pathogenic CXCR4-using variants. The development of effective CXCR4 antagonists for dual treatment would be beneficial; however, whether long-term treatment with antagonists of the widely expressed CXCR4 receptor is feasible without toxicity is unknown. This review discusses the current status of CCR5 antagonists, their modes of action and their development for therapeutic use.
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PMID:The promise of CCR5 antagonists as new therapies for HIV-1. 1732 29


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