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)

Several recent studies have indicated the involvement of host cell factors in human immunodeficiency virus type 1 (HIV-1) assembly. To ascertain whether ATP-dependent factors play a role in this process, we quantified virus-like particle (VLP) production by ATP-depleted cells. Pharmacological ATP depletion abrogated VLP production without affecting cell viability or inducing degradation of HIV-1 Gag protein. This effect occurred even when the ATP-depleting agents were added 1 h into the assembly process, and it was reversed by removal of these agents. ATP depletion did not affect Gag membrane binding or multimerization. Density gradient analysis indicated that HIV-1 assembly intermediates were stalled late in the assembly process. This conclusion was further supported by electron microscopy analysis, which revealed a preponderance of plasma membrane-associated stalk-like structures in the ATP-depleted cells. Since no HIV-1 proteins bind or hydrolyze ATP, these findings indicate that an ATP-requiring cellular factor is an obligatory participant late in the HIV-1 assembly process.
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PMID:The late stage of human immunodeficiency virus type 1 assembly is an energy-dependent process. 1135 54

Successful restoration of the immune system and eradication of any chronic infection, possibly including cancer, requires the ability of healthy cells to process and present foreign antigens on the cell's surface. Areas addressed include: (1) defining a foreign antigen; (2) discussing how certain viruses, such as HIV, can evade an effective immune response; and (3) describing factors that depress antigen presentation, i.e., low ATP and L-glutathione levels. Excerpts from a report on the use of glutathione and ATP injections for improving immune function in patients with Chronic Fatigue Immune Dysfunction Syndrome (CFID) are presented. Results indicate that 226 out of 276 patients receiving injections reported less fatigue, 196 experienced improvement in memory and concentration, and 171 experienced lower levels of pain. Comments from CFID patients who used injectable glutathione are included. The link between high viral load, loss of DTH, and low glutathione levels is discussed. Using selenium to increase glutathione levels, lower beta 2 microglobulin levels, fight cancer, and improve survival in AIDS is also discussed. The reasons that cell metabolism needs healthy liver function and coenzymated B vitamins are given. Products and protocols that can improve ATP production, cell metabolism, and increased levels of glutathione and the treatments and factors that improve, and suppress, antigen presentation are summarized.
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PMID:Restoring antigen presentation: the first step on the road to complete immune restoration. 1136 19

Human immunodeficiency virus-1 (HIV-1) infection is associated with numerous effects on the nervous system, including pain and peripheral neuropathies. We now demonstrate that cultured rat dorsal root ganglion (DRG) neurons express a wide variety of chemokine receptors, including those that are thought to act as receptors for the HIV-1 coat protein glycoprotein120 (gp120). Chemokines that activate all of the known chemokine receptors increased [Ca(2+)](i) in subsets of cultured DRG cells. Many neurons responded to multiple chemokines and also to bradykinin, ATP, and capsaicin. Immunohistochemical studies demonstrated the expression of the CXCR4 and CCR4 chemokine receptors on populations of DRG neurons that also expressed substance P and the VR1 vanilloid receptor. RT-PCR analysis confirmed the expression of CXCR4, CX3CR1, CCR4, and CCR5 mRNAs in DRG neurons. Chemokines and gp120 produced excitatory effects on DRG neurons and also stimulated the release of substance P. Chemokines and gp120 also produced allodynia after injection into the rat paw. Thus these results provide evidence that chemokines and gp120 may produce painful effects via direct actions on chemokine receptors expressed by nociceptive neurons. Chemokine receptor antagonists may be important therapeutic interventions in the pain that is associated with HIV-1 infection and inflammation.
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PMID:Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. 1143 78

Cyclin-dependent kinases (cdk's) have recently been suggested to regulate human immunodeficiency virus type 1 (HIV-1) transcription. Previously, we have shown that expression of one cdk inhibitor, p21/Waf1, is abrogated in HIV-1 latently infected cells. Based on this result, we investigated the transcription of HIV-1 in the presence of chemical drugs that specifically inhibited cdk activity and functionally mimicked p21/Waf1 activity. HIV-1 production in virally integrated lymphocytic and monocytic cell lines, such as ACH(2), 8E5, and U1, as well as activated peripheral blood mononuclear cells infected with syncytium-inducing (SI) or non-syncytium-inducing (NSI) HIV-1 strains, were all inhibited by Roscovitine, a purine derivative that reversibly competes for the ATP binding site present in cdk's. The decrease in viral progeny in the HIV-1-infected cells was correlated with a decrease in the transcription of HIV-1 RNAs in cells treated with Roscovitine and not with the non-cdk general cell cycle inhibitors, such as hydroxyurea (G(1)/S blocker) or nocodazole (M-phase blocker). Cyclin A- and E-associated histone H1 kinases, as well as cdk 7 and 9 activities, were all inhibited in the presence of Roscovitine. The 50% inhibitory concentration of Roscovitine on cdk's 9 and 7 was determined to be approximately 0.6 microM. Roscovitine could selectively sensitize HIV-1-infected cells to apoptosis at concentrations that did not impede the growth and proliferation of uninfected cells. Apoptosis induced by Roscovitine was found in both latent and activated infected cells, as evident by Annexin V staining and the cleavage of the PARP protein by caspase-3. More importantly, contrary to many apoptosis-inducing agents, where the apoptosis of HIV-1-infected cells accompanies production and release of infectious HIV-1 viral particles, Roscovitine treatment selectively killed HIV-1-infected cells without virion release. Collectively, our data suggest that cdk's are required for efficient HIV-1 transcription and, therefore, we propose specific cdk inhibitors as potential antiviral agents in the treatment of AIDS.
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PMID:Inhibition of human immunodeficiency virus type 1 transcription by chemical cyclin-dependent kinase inhibitors. 1146 99

Several reverse transcriptases were studied for their ability to accept anhydrohexitol triphosphates, having a conformationally restricted six-membered ring, as substrate for template-directed synthesis of HNA. It was found that AMV, M-MLV, M-MLV (H(-)), RAV2 and HIV-1 reverse transcriptases were able to recognise the anhydrohexitol triphosphate as substrate and to efficiently catalyse the incorporation of one non-natural anhydrohexitol nucleotide opposite a natural complementary nucleotide. However, only the dimeric enzymes, the RAV2 and HIV-1 reverse transcriptases, seemed to be able to further extend the primer with another anhydrohexitol building block. Subsequently, several HIV-1 mutants (4xAZT, 4xAZT/L100I, L74V, M184V and K65A) were likewise analysed, resulting in selection of K65A and, in particular, M184V as the most succesful mutant HIV-1 reverse transcriptases capable of elongating a DNA primer with several 1,5-anhydrohexitol adenines in an efficient way. Results of kinetic experiments in the presence of this enzyme revealed that incorporation of one anhydrohexitol nucleotide of adenine or thymine gave an increased (for 1,5-anhydrohexitol-ATP) and a slightly decreased (for 1,5-anhydrohexitol-TTP) K(m) value in comparison to that of their natural counterparts. However, no more than four analogues could be inserted under the experimental conditions required for selective incorporation. Investigation of incorporation of the altritol anhydrohexitol nucleotide of adenine in the presence of M184V and Vent (exo(-)) DNA polymerase proved that an adjacent hydroxyl group on C3 of 1,5-anhydrohexitol-ATP has a detrimental effect on the substrate activity of the six-ring analogue. These results could be rationalised based on the X-ray structure of HIV-1 reverse transcriptase.
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PMID:Reverse transcriptase incorporation of 1,5-anhydrohexitol nucleotides. 1147 Aug 72

The presence of the HIV reverse transcriptase (RT) resistance mutation, M184V, induced by lamivudine and abacavir treatment results in increased tenofovir, adefovir and zidovudine susceptibility for HIV-1 with zidovudine-associated RT mutations in vitro. Treatment with oral prodrugs of tenofovir and adefovir has resulted in substantial HIV-1 RNA reductions in antiretroviral-experienced patient populations who have lamivudine- and zidovudine-resistant HIV-1. An enzymatic analysis was undertaken to elucidate the mechanisms of altered drug susceptibilities of HIV-1 containing zidovudine-associated mutations in the presence or absence of M184V. The inhibition constants (Ki) for the active metabolites of tenofovir, adefovir and zidovudine did not vary significantly between recombinant mutant and wild-type RT enzymes. Although increased removal of chain-terminating inhibitors by pyrophosphorolysis and ATP-dependent unblocking correlated with reduced susceptibility of viruses with zidovudine-associated mutations, a reduction in the removal of chain-terminators was not observed, which would explain the increased drug susceptibility of mutants containing M184V plus zidovudine-associated mutations. However, analyses of single-cycle processivity of the mutant RT enzymes on heteropolymeric RNA templates showed that all M184V-containing mutant RT enzymes were less processive than wild-type RT, most notably for mutants expressing both zidovudine-associated mutations and M184V. Similarly, the in vitro replication capacity of a mutant virus expressing a zidovudine-associated mutation and M184V was significantly reduced compared with wild-type virus. The observed decrease in enzymatic processivity of the M184V-expressing RT enzymes might result in decreased viral replication, which then might contribute to the increased drug susceptibility of HIV-1 expressing these RT mutations.
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PMID:Increased drug susceptibility of HIV-1 reverse transcriptase mutants containing M184V and zidovudine-associated mutations: analysis of enzyme processivity, chain-terminator removal and viral replication. 1149 16

Cyclin-dependent kinases (CDKs) play a key role in the cell division cycle, in neuronal functions, in transcription and in apoptosis. Intensive screening with these kinases as targets has lead to the identification of highly selective and potent small - molecule inhibitors. Co-crystallization with CDK2 shows that these flat heterocyclic hydrophobic compounds bind through two or three hydrogen bonds with the side chains of two amino acids located in the ATP-binding pocket of the kinase. These inhibitors are anti-proliferative; they arrest cells in G1 and in G2/M phase. Furthermore they facilitate or even trigger apoptosis in proliferating cells while they protect neuronal cells and thymocytes from apoptosis. The potential use of these inhibitors is being extensively evaluated for cancer chemotherapy and also in other therapeutic areas: neurology (Alzheimer's disease), cardiovascular (restenosis, angiogenesis), nephrology (glomerulonephritis), parasitology (Plasmodium, Trypanosoma, Toxoplasma, etc.) and virology (cytomegalovirus, HIV, herpes virus). Copyright 2000 Harcourt Publishers Ltd.
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PMID:Cyclin-dependent kinases inhibitors as potential anticancer, antineurodegenerative, antiviral and antiparasitic agents. 1149 72

In the central nervous system, the primary targets of the human immunodeficiency virus-1 (HIV-1) are microglia, resulting in a disorder called HIV-1 dementia. P-glycoprotein (P-gp), a membrane-associated ATP-dependent efflux transporter, limits entry into the brain of numerous xenobiotics, including anti-HIV drugs (i.e., protease inhibitors). This project investigates the functional expression of P-gp in the endogenous immune cells of the brain, a parenchymal compartment not previously studied. We used a cell line (MLS-9) derived from rat microglia to study the transport of digoxin, a known P-gp substrate. Reverse transcriptase-polymerase chain reaction analysis detected mRNA for only mdr1b in MLS-9 cells, whereas both mdr1a and mdr1b mRNA were expressed in primary cultured microglia from which they were derived. Western blot analysis with the C219 antibody detected a single band at ~170 to 180 kDa in MLS-9 cells, which is the size previously reported for P-gp. Immunocytochemical analysis with the monoclonal antibodies C219, MRK16, and MAB-448 labeled P-gp protein along the plasma membrane and nuclear envelope of MLS-9 cells. [3H]Digoxin accumulation by monolayers of MLS-9 cells was significantly enhanced in the presence of any of several P-gp inhibitors (verapamil, cyclosporin A, quinidine, PSC 833), protease inhibitors (i.e., saquinavir, indinavir, and ritonavir), and sodium azide, an ATPase inhibitor. These results provide the first evidence for the functional expression of P-gp in microglia and imply that entry of pharmacological agents, including protease inhibitors, may be prevented within the brain parenchyma, as well as at the blood-brain barrier.
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PMID:Functional expression of P-glycoprotein in rat brain microglia. 1156 Oct 81

Pyrophosphorolysis, the removal of nucleoside chain-terminators by a pyrophosphate (PPi) acceptor molecule, and a similar mechanism (nucleotide-dependent chain-terminator removal) which uses ATP as an acceptor molecule have been proposed as mechanisms of zidovudine (AZT) resistance. Recombinant HIV-1 wild-type reverse transcriptase (RT) and a mutant RT enzyme containing the AZT/thymidine analog resistance mutations D67N/K70R/T215Y were analyzed for pyrophosphorolysis and nucleotide-dependent chain-terminator removal activities. Our results confirm that pyrophosphorolysis and nucleotide-dependent chain-terminator removal are potential mechanisms of AZT and d4T resistance. However, tenofovir is less efficiently removed by pyrophosphorolysis and by nucleotide-dependent mechanisms. These results are consistent with the minor changes in susceptibility to tenofovir of the AZT/thymidine analog-resistant HIV RT mutants and the corresponding resistance of these mutants to AZT. The inability to remove tenofovir efficiently by these mechanisms may contribute to the durability of the HIV RNA response observed in patients treated with the oral prodrug, tenofovir disoproxil fumarate.
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PMID:Tenofovir (PMPA) is less susceptible to pyrophosphorolysis and nucleotide-dependent chain-terminator removal than zidovudine or stavudine. 1156 81

A variety of key mutations in HIV reverse transcriptase (RT) have been associated with nucleoside reverse transcriptase inhibitor (NRTI) exposure, which give rise to a diverse range of effects in terms of altered drug susceptibilities, viral replicative capacity and RT biochemistry. There are three basic mechanisms of resistance conferred by specific mutations in the coding region of RT. The first is drug discrimination, whereby a particular drug or drugs are either selectively excluded from uptake or from the RT-primer-template catalytic complex. Drug discrimination is, for the most part, relatively specific for individual drugs. Repositioning of the template-primer to prevent a catalytically competent complex in the presence of a bound drug molecule has also been observed in some instances, and forms a second mechanism. The third, and potentially most significant for long-term efficacy of the NRTIs, is pyrophosphorolysis, the primary mode of resistance to zidovudine. Mutations selected by this drug or stavudine serve to elevate the natural rate of the reverse reaction for RT. Pyrophosphorolysis uncouples the last nucleoside monophosphate added to the proviral transcript, and attaches it to either a free pyrophosphate (regenerating a deoxynucleoside triphosphate) or to a nucleoside di- or triphosphate (usually ATP). Uncoupling a chain-terminating NRTI residue therefore rescues reverse transcription and reduces drug susceptibility across the class, since the process is not specific for the selecting drug. Of all the nucleoside-associated mutations, the best known and most studied are the six associated with thymidine analogue exposure. These six mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q) enhance RT pyrophosphorolysis to confer high-level viral resistance to zidovudine, and clinically significant loss of response to stavudine and didanosine. They have also been found to confer reduced susceptibility to lamivudine and abacavir, particularly when present alongside other NRTI-induced changes. Other key mutations generally confer more limited resistance to specific agents, although the primary lamivudine- and abacavir-associated M184V substitution generates a broad spectrum of drug-dependent phenotypes, and uncommon mutational complexes conferring resistance across the entire class are well known. In addition to 'classical' multi-nucleoside-resistant genotypes, database-driven 'virtual phenotyping' for accumulations of NRTI-associated mutations around a core of thymidine analogue-induced changes predicts drug susceptibilities below wild-type across the entire NRTI class, even in the absence of key mutations associated with individual agents. When the natural range of drug susceptibilities for treatment-naive isolates is used as the basis for defining resistance, retrospective analysis of clinical isolates in the Virco database shows a significantly increased incidence of reduced susceptibility for the dideoxy NRTIs (didanosine, stavudine and zalcitabine) that was undetected in previous assays. These data imply a cumulative degradation of response to
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PMID:Mutational patterns in the HIV genome and cross-resistance following nucleoside and nucleotide analogue drug exposure. 1167 71


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