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)

Primer-template-based double-stranded nucleic acids capable of binding human immunodeficiency virus reverse transcriptase (HIV-RT) with high affinity were used as starting material to develop small single-stranded loop-back DNA aptamers. The original primer-templates were selected using a SELEX (Systematic Evolution of Ligands by EXponential enrichment) approach and consisted of 46- and 50-nt primer and template strands, respectively. The major determinant of the approximately 10-fold tighter binding in selected sequences relative to control primer-templates was a run of 6.8 G residues at the 3' primer end. Sixty, thirty-seven, twenty-seven, and twenty-two nucleotide loop-back single-stranded versions that retained the base pairs near the 3' primer terminus were constructed. Both the 60- and 37-nt versions retained high affinity for RT with K(d) values of approximately 0.44 nM and 0.66 nM, respectively. Random sequence primer-templates of the same length had K(d)s of approximately 20 nM and approximately 161 nM. The shorter 27- and 22-nt aptamers bound with reduced affinity. Several modifications of the 37-nt aptamer were also tested including changes to the terminal 3' G nucleotide and internal bases in the G run, replacement of specific nucleotides with phosphothioates, and alterations to the 5' overhang. Optimal binding required a 4- to 5-nt overhang, and internal changes within the G run had a pronounced negative effect on binding. Phosphothioate nucleotides or the presence of a 3' dideoxy G residue did not alter affinity. The 37-nt aptamer was a potent inhibitor of HIV-RT in vitro and functioned by blocking binding of other primer-templates.
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PMID:Novel aptamer inhibitors of human immunodeficiency virus reverse transcriptase. 1863 31

The metalloid Se is ubiquitous in soils, but exists mainly in insoluble forms in high-Fe, low-pH and certain leached soils, and hence is often of limited availability to plants. Consequently, it is often supplied by plants to animals and human consumers at levels too low for optimum health. Se deficiency and suboptimality are manifested in populations as increased rates of thyroid dysfunction, cancer, severe viral diseases, cardiovascular disease and various inflammatory conditions. Se deficiency probably affects at least a billion individuals. Optimal cancer protection appears to require a supra-nutritional Se intake, and involves several mechanisms, which include promotion of apoptosis and inhibition of neo-angiogenesis. Evidence suggests that in some regions Se is declining in the food chain, and new strategies to increase its intake are required. These could include education to increase consumption of higher-Se foods, individual supplementation, food fortification, supplementation of livestock, Se fertilisation of crops and plant breeding for enhanced Se accumulation. Se levels in Australian residents and wheat appear to be above the global estimated mean. Wheat is estimated to supply nearly half the Se utilised by most Australians. Increasing the Se content of wheat represents a food systems approach that would increase population intake, with consequent probable improvement in public health and large health cost savings. The strategies that show most promise to achieve this are biofortification by Se fertilisation and breeding wheat varieties that are more efficient at increasing grain Se density. Research is needed in Australia to determine the most cost-effective fertilisation methods, and to determine the extent of genetic variability for grain Se accumulation. Before recommending large-scale fortification of the food supply with Se, it will be necessary to await the results of current intervention studies with Se on cancer, HIV and AIDS, and asthma.
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PMID:High-selenium wheat: biofortification for better health. 1907 36

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes.
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PMID:Timing the emergence of resistance to anti-HIV drugs with large genetic barriers. 1928 58

Induction of an antigenically broad and vigorous primary T-cell immune response by myeloid dendritic cells (DC) in blood and tissues could be important for an effective prophylactic or therapeutic vaccine to human immunodeficiency virus type 1 (HIV-1). Here we show that a primary CD8(+) T-cell response can be induced by HIV-1 peptide-loaded DC derived from blood monocytes of HIV-1-negative adults and neonates (moDC) and by Langerhans cells (LC) and interstitial, dermal-intestinal DC (idDC) derived from CD34(+) stem cells of neonatal cord blood. Optimal priming of single-cell gamma interferon (IFN-gamma) production by CD8(+) T cells required CD4(+) T cells and was broadly directed to multiple regions of Gag, Env, and Nef that corresponded to known and predicted major histocompatibility complex class I epitopes. Polyfunctional CD8(+) T-cell responses, defined as single-cell production of more than one cytokine (IFN-gamma, interleukin 2, or tumor necrosis factor alpha), chemokine (macrophage inhibitory factor 1beta), or cytotoxic degranulation marker CD107a, were primed by moDC, LC, and idDC to HIV-1 Gag and reverse transcriptase epitopes, as well as to Epstein-Barr virus and influenza A virus epitopes. Thus, three major types of blood and tissue myeloid DC targeted by HIV-1, i.e., moDC, LC, and idDC, can prime multispecific, polyfunctional CD8(+) T-cell responses to HIV-1 and other viral antigens.
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PMID:Primary human immunodeficiency virus type 1-specific CD8+ T-cell responses induced by myeloid dendritic cells. 1935 76

The interferon-induced transmembrane protein BST-2/CD317 (tetherin) restricts the release of diverse enveloped viruses from infected cells. The HIV-1 accessory protein Vpu antagonizes this restriction by an unknown mechanism that likely involves the down-regulation of BST-2 from the cell surface. Here, we show that the optimal removal of BST-2 from the plasma membrane by Vpu requires the cellular protein beta-TrCP, a substrate adaptor for a multi-subunit SCF E3 ubiquitin ligase complex and a known Vpu-interacting protein. beta-TrCP is also required for the optimal enhancement of virion-release by Vpu. Mutations in the DSGxxS beta-TrCP binding-motif of Vpu impair both the down-regulation of BST-2 and the enhancement of virion-release. Such mutations also confer dominant-negative activity, consistent with a model in which Vpu links BST-2 to beta-TrCP. Optimal down-regulation of BST-2 from the cell surface by Vpu also requires the endocytic clathrin adaptor AP-2, although the rate of endocytosis is not increased; these data suggest that Vpu induces post-endocytic membrane trafficking events whose net effect is the removal of BST-2 from the cell surface. In addition to its marked effect on cell-surface levels, Vpu modestly decreases the total cellular levels of BST-2. The decreases in cell-surface and intracellular BST-2 are inhibited by bafilomycin A1, an inhibitor of endosomal acidification; these data suggest that Vpu induces late endosomal targeting and partial degradation of BST-2 in lysosomes. The Vpu-mediated decrease in surface expression is associated with reduced co-localization of BST-2 and the virion protein Gag along the plasma membrane. Together, the data support a model in which Vpu co-opts the beta-TrCP/SCF E3 ubiquitin ligase complex to induce endosomal trafficking events that remove BST-2 from its site of action as a virion-tethering factor.
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PMID:Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. 1947 68

Aqueous two-phase partition systems (ATPS) have been widely used for the separation of a large variety of biomolecules. In the present report, the application of a polyethylene glycol/phosphate (PEG/phosphate) ATPS for the separation of anti-HIV monoclonal antibodies 2G12 (mAb 2G12) and 4E10 (mAb 4E10) from unclarified transgenic tobacco crude extract was investigated. Optimal conditions that favor opposite phase partitioning of plant debris/mAb as well as high recovery and purification were found to be 13.1% w/w (PEG 1500), 12.5% w/w (phosphate) at pH 5 with a phase ratio of 1.3 and 8.25% w/w unclarified tobacco extract load. Under these conditions, mAb 2G12 and mAb 4E10 were partitioned at the bottom phosphate phase with 85 and 84% yield and 2.4- and 2.1-fold purification, respectively. The proposed ATPS was successfully integrated in an affinity-based purification protocol, using Protein A, yielding antibodies of high purity and yield. In this study, ATPS was shown to be suitable for initial protein recovery and partial purification of mAb from unclarified transgenic tobacco crude extract.
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PMID:Application of a PEG/salt aqueous two-phase partition system for the recovery of monoclonal antibodies from unclarified transgenic tobacco extract. 1955 96

Human immunodeficiency virus type 1 (HIV-1)-specific T-cell reactivity has been related to protection from disease progression. Optimal T-cell reactivity to HIV-1 presumably requires antigen processing and presentation by professional antigen-presenting cells, particularly dendritic cells (DC). Here we examined whether multiple HIV-1-specific T-cell functions are enhanced by stimulation with HIV-1 peptide-loaded DC derived from HIV-1-infected subjects on antiretroviral therapy. We first found that mature DC increased the number of gamma interferon (IFN-gamma)-producing T cells detected by enzyme-linked immunospot assay to overlapping 15-mer peptides of HIV-1 Gag and Nef, compared to stimulation with peptide-loaded, immature DC or to peptides without DC. IFN-gamma production was lower in response to large pools of the Gag and Nef peptides, regardless of presentation by DC. We further observed that HIV-1 peptide-loaded, mature DC stimulated greater CD8(+) and CD4(+) T-cell proliferation than did the peptides without DC and that T-cell proliferation was lower in response to larger pools of the peptides. The lower T-cell IFN-gamma and proliferation responses to the larger peptide pools were related to lower T-cell viability. Finally, the number of polyfunctional CD8(+) and CD4(+) T cells stimulated by HIV-1 peptide-loaded, mature DC, defined as positive by intracellular staining for more than one immune mediator (IFN-gamma, interleukin 2, tumor necrosis factor alpha, macrophage inhibitory protein 1beta, or CD107a), was greater than that stimulated by the peptides alone. These results indicate that DC can enhance multiple types of HIV-1-specific T-cell functions.
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PMID:Multiple T-cell responses to human immunodeficiency virus type 1 are enhanced by dendritic cells. 1969 26

Non-typhoidal salmonella (NTS) bacteremia is a significant cause of morbidity and mortality in HIV-infected individuals worldwide. Recent reports have noted increasing resistance of NTS isolates to fluoroquinolones, the recommended first-line therapy for NTS bacteremia. The outcomes and risk factors for NTS bacteremia in HIV-infected patients in an urban US setting were evaluated. From January 2002 to December 2006, 26 episodes of NTS bacteremia were identified in 16 patients. The risk factors for NTS bacteremia were low CD4 count, high viral load, and lack of antiretroviral therapy (ART). Recurrences appeared related to lack of immune reconstitution in patients not on ART. Unlike reports from Asia, no fluoroquinolone resistance was identified in any of the Salmonella strains isolated in this setting. Optimal treatment of NTS in the HIV-infected patient in the United States should include therapy with fluoroquinolones as well as attaining complete viral suppression and immune reconstitution with ART.
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PMID:Lack of fluoroquinolone resistance in non-typhoidal salmonella bacteremia in HIV-infected patients in an urban US setting. 1995 86

Infant to post-pubertal adolescent pediatric HIV/AIDS cases in Japan nowadays are almost exclusively originated via mother-to-child transmission of HIV-1(MTCT). According to the National Cooperative Study Group on HIV Infected Pregnant Women and MTCT in Japan, most recent MTCT rate in Japan is 0.45 %, so the cumulative number of MTCT cases is only 46. In this paper the guidelines to control pediatric HIV/AIDS are introduced to Japanese doctors who are unfamiliar to this disease and just considering or starting initial antiretrovirals (ARV). ARV for children should be palatable, unrelated to foods, CNS-penetrating and should have least short and long acting side effects. Optimal adherence to treatment is best kept through the awareness of its importance by the patients and their guardians.
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PMID:[Guidelines for treating and managing pediatric HIV/AIDS in Japan]. 2022 88

Optimal infectivity of HIV-1 virions requires synthesis of the HIV-1 regulatory protein Nef in some producer cells but not others. A survey of 18 lymphoid cell lines found that Nef was dispensable in three, each of which harbored gammaretroviruses. Nef-dependent cell lines were rendered Nef-independent by a cell-free supernatant from the independent lines or by transfection of cloned murine leukemia virus (MLV). Analysis of MLV deletion mutations identified glycosylated gag (glycogag) as the factor that rescues Nef-defective HIV-1 virions. Glycogag was also demonstrated to be required for the infectivity of MLV virions produced in lymphoid cells. Direct comparison of Nef and glycogag revealed identical dependence for activity on Env-pseudotype and producer cell type. The two proteins colocalize within cells, and both increase the yield of viral cDNA in target cells. The functional similarity of Nef and glycogag is a compelling example of convergent evolution in which two structurally unrelated proteins provide a function necessary for virion infectivity in lymphoid cells.
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PMID:MLV glycosylated-Gag is an infectivity factor that rescues Nef-deficient HIV-1. 2043 30


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