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)

The chemokine receptor CXCR6 is highly expressed on lung-derived T cells compared to blood T cells, especially in inflammatory diseases characterised by T-cell migration to the lung. This suggests that CXCR6 is a candidate lung homing receptor. The sole ligand of CXCR6, CXCL16, has previously been shown to be expressed by alveolar macrophages. The authors hypothesized that also structural lung cells express CXCL16. CXCL16 expression was detected using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and flow cytometry. Chemotaxis assays were used to test functionality of the secreted protein. Human bronchial epithelial cells secreted relatively high basal levels of CXCL16 (> 1000 pg/mL). Interferon (IFN)-gamma, but not tumor necrosis factor (TNF)-alpha or interleukin (IL)-4, caused a modest but significant up-regulation in secretion. Airway smooth muscle and fibroblasts also expressed CXCL16, but at lower levels. Western blotting detected expression of the full-length (60-kDa) form of the chemokine in cell lysates, and the cleaved (35-kDa) form in culture supernatants. Concentrated supernatants from a bronchial epithelial cell line (BEAS-2B) were chemotactic for CXCR6 expressing T cells from blood. In conclusion, these results suggest that the bronchial epithelium is an important source of constitutively expressed CXCL16, which may be involved in T-cell recruitment to the lung in health and disease.
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PMID:The chemokine CXCL16 is highly and constitutively expressed by human bronchial epithelial cells. 1941 45

More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to the ongoing limitations of drug resistance and adverse effects, new treatment options are still required. A number of promising new agents in existing or new drug classes are in development or have recently been approved by the US FDA. Since these agents will be used in combination with other new and existing antiretrovirals, understanding the potential for drug interactions between these compounds is critical to their appropriate use. This article summarizes the drug interaction potential of new and investigational protease inhibitors (darunavir), non-nucleoside reverse transcriptase inhibitors (etravirine and rilpivirine), chemokine receptor antagonists (maraviroc, vicriviroc and INCB 9471), integrase inhibitors (raltegravir and elvitegravir) and maturation inhibitors (bevirimat).
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PMID:Drug interactions with new and investigational antiretrovirals. 2002 May 64

UV wavebands in sunlight are immunomodulatory. About half the amount of UVA within a minimum erythemal dose of sunlight is systemically immunosuppressive, whereas higher doses protect from UVB immunosuppression in mice. We have earlier shown that these responses to UVA are genetically restricted, as they occur in C57BL/6 but not in Balb/c mice. We used gene set enrichment analysis of microarray data and real-time reverse transcriptase (RT)-PCR confirmation to determine the molecular mechanisms associated with UVA immunomodulation. We found upregulation of mRNA for the alternative complement pathway. The core-enriched genes complement component 3, properdin, and complement factor B were all activated by the immunosuppressive dose of UVA only in UVA-responsive C57BL/6 but not in unresponsive BALB/c mice. This therefore matched the genetic restriction and dose responsiveness of UVA immunosuppression. The immune-protective higher UVA dose prevented UVB from downregulating chemokine receptor 7 and IL-12B, and decreased IL-10, supporting the earlier identification of IL-12 and IL-10 in high-dose UVA protection from UVB immunosuppression. Our study has identified activation of the alternative complement pathway as a trigger of UVA-induced systemic immunosuppression and suggests that this pathway is likely to be an important sensor of UVA-induced damage to the skin.
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PMID:The alternative complement pathway seems to be a UVA sensor that leads to systemic immunosuppression. 1951 63

Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14-48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.
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PMID:Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. 1967 50

Novel antiretroviral drugs offer different degrees of improvement in activity against drug-resistant HIV, short- and long-term tolerability, and dosing convenience compared with earlier drugs. Those drugs approved more recently and commonly used in treatment-experienced patients include the entry inhibitor enfuvirtide, protease inhibitors (PIs) [darunavir and tipranavir], a C-C chemokine receptor (CCR) type 5 antagonist (maraviroc), an integrase inhibitor (raltegravir) and etravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI). Novel agents in earlier stages of development include a CCR5 monoclonal antibody (PRO 140) administered subcutaneously once weekly, once-daily integrase inhibitors (elvitegravir and S/GSK1349572), and several nucleoside (nucleotide) reverse transcriptase inhibitors and NNRTIs. Bevirimat, a maturation inhibitor, has compromised activity in the presence of relatively common Gag polymorphisms. Viral suppression is necessary to control the evolution of drug resistance, reduce chronic immune activation that probably underlies the excess morbidity and mortality in HIV-infected patients, and reduce viral transmission, including transmitted drug resistance. In general, the proportion of viraemic patients who achieve suppression increases with the number of active pharmacokinetically compatible antiretroviral drugs in the regimen. In the ANRS139-TRIO trial, 86% of highly treatment-experienced patients treated with darunavir-ritonavir, etravirine and raltegravir had HIV RNA <50 copies/mL at 48 weeks. In patients who had received at least 12 weeks of a stable regimen and had no darunavir resistance-associated mutations, once-daily darunavir boosted with ritonavir 100 mg was virologically noninferior with better lipid effects than with the twice-daily dosing, which requires a 200 mg total daily dose of ritonavir. Raltegravir plus a boosted PI is being investigated for second-line therapy in patients not responding to NNRTI-based first-line treatment in resource-limited settings (RLS). However, concerns about this potential strategy include the low barrier against resistance of raltegravir, limited penetration of some PIs into the CNS and the unknown impact of integrase polymorphisms seen more commonly in non-B subtype HIV-1. In patients who have already achieved viral suppression, novel agents may be used to simplify the dosing schedule, lower costs (such as by switching to boosted PI monotherapy), reduce adverse events or preserve antiretroviral drug options, especially since the absence of an HIV eradication strategy implies the need for life-long combination antiretroviral therapy. Switching enfuvirtide to raltegravir eliminated painful injection-site reactions without compromising virological suppression. Two studies found different virological outcomes when patients were switched from lopinavir/ritonavir to raltegravir, but there was an improvement in the lipid profile. Simplifying to darunavir-ritonavir monotherapy after suppression of plasma HIV RNA to <50 copies/mL has been found to be safe with no emergence of resistance in cases of viral rebound, but longer-term data are needed. The initial suggestion that maraviroc may possess unique CD4+ T-cell boosting effects was not confirmed in several clinical trials. Improved understanding of HIV pathogenesis has opened new frontiers for research such as identifying the sources, consequences and optimal management of residual viraemia in those with plasma HIV RNA <50 copies/mL. Globally, however, one of the most urgent priorities is providing the increasing number of treatment-experienced virologically failing patients in RLS with access to optimal treatment, including those treatments based on novel antiretroviral agents.
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PMID:Novel antiretroviral combinations in treatment-experienced patients with HIV infection: rationale and results. 2073 72

Etravirine is an effective and well-tolerated recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV type-1-infected patients with previous antiretroviral treatment experience. Considering the importance of combining antiretrovirals for their optimal use in treating HIV, a number of drug-drug interactions with etravirine and other antiretrovirals have been evaluated. Etravirine is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C9/CYP2C19 and P-glycoprotein, and although etravirine is metabolized by the CYP enzyme system, the extent of clinically relevant interactions with other antiretrovirals is limited. Etravirine can be combined with all currently available nucleoside/nucleotide reverse transcriptase inhibitors without dose adjustments, but not with other NNRTIs. Available data indicate that etravirine can be coadministered with most of the currently available ritonavir-boosted HIV protease inhibitors. Coadministration with tipranavir/ritonavir or unboosted HIV protease inhibitors is not recommended because of clinically relevant changes in exposure to etravirine or the coadministered HIV protease inhibitor, respectively. Etravirine can be coadministered with the integrase inhibitors elvitegravir/ritonavir or raltegravir, and with the fusion inhibitor enfuvirtide, without dose adjustments. Dose adjustment of the C-C chemokine receptor type-5 antagonist maraviroc is required, with the type of adjustment depending on whether a boosted HIV protease inhibitor is included in the regimen. In conclusion, etravirine can be combined with most antiretrovirals, with no clinically meaningful effect on drug exposure or safety/tolerability profiles.
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PMID:Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. 2083 94

A total of 29 cases of diffuse large B-cell lymphoma initially manifesting in the bone marrow (BM-DLBCL) were analyzed for V(H) gene sequence, and expression microarray of chemokines and chemokine receptors and immunohistochemical analysis were done. Seminested polymerase chain reaction (PCR) and sequencing analyses of 18 cases revealed that the V(H) gene usage in 6 cases was restricted to V(H)3-7, in 3 cases to V(H)4-34, and in 2 cases to V(H)4-39, which were all previously reported to be autoreactive. In total, 14 of 18 V(H) genes were those associated with autoimmune diseases, including V(H)3-21, V(H)3-23, and V(H)3-48. Furthermore, cDNA microarray analysis specific for chemokine and chemokine receptors revealed that chemokine receptor XCR1 expression was significantly elevated in the BM-DLBCL cases (P < .05), which was confirmed by quantitative reverse transcriptase-PCR and immunohistochemical analysis. Expression of the chemokine receptor XCR1 and frequent usage of autoreactive V(H) genes seem to be distinct characteristics of BM-DLBCL.
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PMID:XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. 2141 77

As the world enters the fourth decade of the HIV/AIDS epidemic a number of new drugs have been developed that address current challenges with antiretroviral therapy (ART), such as pill burden, toxicity and drug-resistance. These new agents have not only been developed from established drug-classes, namely nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), but also include innovative ways of suppressing viral replication. Intergrase inhibitors and chemokine receptor blockers have been developed which, combined with NRTIs, NNRTIs and PIs, comprise highly active antiretroviral therapy regimens able to tackle all aspects of the HIV life cycle with minimal toxicity. Furthermore, the ability of pharmaceutical companies to formulate these powerful drugs into fixed-dose combinations provides exciting new strategies for reducing pill burden, thus ensuring adherence and limiting the emergence of drug-resistance. The enthusiasm with which these new drugs have been received has, however, been tempered by the reality of limited access in the developing world, further highlighting the disparity between rich and poor countries in the fight against HIV/ AIDS. Access to these treatments in low- and middle-income countries will require the necessary political will, regulatory approval, affordability of drugs, as well as efficient procurement and supply management strategies. The priority of developing countries remains increased scale up of ART, but there is also a need to acquire new drugs in order to tackle toxicity and drug-resistance, both of which threaten the sustainability of such programmes. Thankfully, the vast majority of patients receiving ART in the developing world are still on first-line regimens, thus allowing time for newer agents to be made available as part of third-line treatment option. However, there is no room for complacency - the developing world needs access to new HIV treatments, an AIDS-free generation depends upon it.
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PMID:Recent developments in hiv treatment and their dissemination in poor countries. 2447 Sep 66

We report novel anti-HIV-1 agents with combined dual host-pathogen pharmacology. Lead compound 3, composed of a pyrazole-piperidine core, exhibits three concurrent mechanisms of action: (1) non-nucleoside reverse transcriptase inhibition, (2) CCR5-mediated M-tropic viral entry inhibition, and (3) CXCR4-based T-tropic viral entry inhibition that maintains native chemokine ligand binding. This discovery identifies important tool compounds for studying viral infectivity and prototype agents that block HIV-1 entry through dual chemokine receptor ligation.
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PMID:Pyrazolo-Piperidines Exhibit Dual Inhibition of CCR5/CXCR4 HIV Entry and Reverse Transcriptase. 2619 61


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