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PubMed1993

Natural killer cells and the MHC class I pathway of peptide presentation.

Natural killer (NK) cells are TcR-Ig- lymphocytes that can mediate resistance to tumor growth, virus infections and bone marrow transplants. The receptors and specificity of NK cells are not clear, although it has been suggested that cytolytic triggering may be facilitated by lack of host matched MHC expression in the target or the graft. This article reviews and analyzes the role of the MHC class I pathway of peptide presentation in regulation of NK cells. This subject is introduced by brief overviews on NK cells, the 'missing self hypothesis' and studies establishing that MHC class I molecules of the target and the host can influence NK reactivity against certain normal and malignant cells. The main focus is then set on recent studies indicating that this influence occurs through interactions involving the antigen binding groove or its bound peptides. This includes discussion of modulation of NK sensitivity by peptides, beta 2 microglobulin, allelic differences or point mutations in MHC class I heavy chains, virus infection and peptide loading deficiency. While it is clear that alterations affecting the groove and its contents can change NK sensitivity, the evidence should be interpreted with caution, as the structural integrity of the whole class I molecule is dependent on the conformation and the stability of the antigen binding groove. Two models for recognition, 'target interference' and 'effector inhibition', are discussed. Each of these (mutually non-exclusive) models can accommodate a role for the groove and its peptide.

Alleles↗
PubMed2004

Tetrahydrobiopterin protects phenylalanine hydroxylase activity in vivo: implications for tetrahydrobiopterin-responsive hyperphenylalaninemia.

The natural cofactor of phenylalanine hydroxylase (PAH), tetrahydrobiopterin (BH4), regulates the enzyme activity as well as being essential in catalysis. BH4-responsive PAH deficiency is a variant of hyperphenylalaninemia or phenylketonuria (PKU) caused by mutations in the human PAH gene that respond to oral BH4 loading by stimulating enzyme activity and therefore lowering serum phenylalanine. Here, we showed in a coupled transcription-translation in vitro assay that upon expression in the presence of BH4, wild-type PAH enzyme activity was enhanced. We then investigated the effect of BH4 on PAH activity in transgenic mice that had a complete or partial deficiency in the endogenous cofactor biosynthesis. The rate of hepatic PAH enzyme activity increased significantly with BH4 content without affecting gene expression or Pah-mRNA stability. These results indicate that BH4 has a chaperon-like effect on PAH synthesis and/or is a protecting cofactor against enzyme auto-inactivation and degradation also in vivo. Our findings thus contribute to the understanding of the regulation of PAH by its cofactor BH4 on an additional level and provide a molecular explanation for cofactor-responsive PKU.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Disruption of RhoGDI and RhoA regulation by a Rac1 specificity switch mutant.

Rho family GTPases are important regulators of the actin cytoskeleton. Activation of these proteins can be promoted by guanine nucleotide exchange factors containing Dbl and Pleckstrin homology domains resulting in membrane insertion of a Rho family member, whereas the inactive GDP-bound form is sequestered primarily in the cytoplasm, bound to the guanosine dissociation inhibitor RhoGDI. Dominant interfering variants of Rac1, but not Cdc42, inhibit beta1 integrin-promoted uptake of Yersinia pseudotuberculosis. Unexpectedly, we found that the Rac1(W56F) guanine nucleotide exchange factors specificity switch mutant blocked invasin-promoted uptake as well as Cdc42-dependent uptake of enteropathogenic Escherichia coli. Fluorescence resonance energy transfer experiments demonstrated that Rac1(W56F) retained the ability to be loaded with GTP, bind a downstream effector, and interact with RhoGDI. Mutational analyses of intragenic suppressors and coexpression studies demonstrated that binding of the Rac1(W56F) mutant to RhoGDI appeared to play a role in the inhibition of uptake. As RhoGDI inhibits RhoA, overactivation of RhoA may account for the uptake interference caused by Rac1(W56F). Consistent with this model, a dominant interfering form of RhoA restored significant uptake in the presence of the Rac1(W56F) mutant but had no effect on another interfering Rac1 form. Furthermore, the cellular GTP-RhoA level was elevated by the presence of Rac1(W56F) mutant protein. These data are consistent with the proposition that Rac1(W56F) blocks invasin-promoted uptake by preventing RhoGDI from inactivating RhoA. We conclude that RhoGDI allows cross-talk between Rho family members that promote potentially antagonistic processes, and disruption of this cross-talk can interfere with invasin-promoted uptake.

Amino Acid Substitution↗
PubMed2005

Systemic regulation of intestinal iron absorption.

The intestinal absorption of the essential trace element iron and its mobilization from storage sites in the body are controlled by systemic signals that reflect tissue iron requirements. Recent advances have indicated that the liver-derived peptide hepcidin plays a central role in this process by repressing iron release from intestinal enterocytes, macrophages and other body cells. When iron requirements are increased, hepcidin levels decline and more iron enters the plasma. It has been proposed that the level of circulating diferric transferrin, which reflects tissue iron levels, acts as a signal to alter hepcidin expression. In the liver, the proteins HFE, transferrin receptor 2 and hemojuvelin may be involved in mediating this signal as disruption of each of these molecules decreases hepcidin expression. Patients carrying mutations in these molecules or in hepcidin itself develop systemic iron loading (or hemochromatosis) due to their inability to down regulate iron absorption. Hepcidin is also responsible for the decreased plasma iron or hypoferremia that accompanies inflammation and various chronic diseases as its expression is stimulated by pro-inflammatory cytokines such as interleukin 6. The mechanisms underlying the regulation of hepcidin expression and how it acts on cells to control iron release are key areas of ongoing research.

Animals↗
PubMed2005

Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection.

BACKGROUND: CXCR4-using virus is associated with higher viral load and accelerated human immunodeficiency virus (HIV) disease progression. Additionally, CCR5 antagonists may not reduce the HIV-1 RNA load when mixed/dual-tropic or CXCR4-using virus is present. The determination of coreceptor tropism may be required before CCR5 or CXCR4 antagonists are initiated, unless reliable predictive markers of coreceptor use are established. METHODS: Samples from treatment-naive and -experienced HIV-1-positive individuals with date-matched CD4 and CD8 cell counts and HIV-1 RNA, clade, and pol sequences were assessed for coreceptor usage, by use of the ViroLogic PhenoSense assay. RESULTS: Coreceptor use determination was successful in 563 of 861 samples. Non-clade B virus was present in 18.6% of samples. CXCR4 or mixed/dual-tropic CCR5/CXCR4 virus was present in 112 of samples (19.9%). Only 4 samples (0.7%) showed exclusive CXCR4 use. In a multivariate model, higher CD4 cell count, lower viral load, and higher natural killer cell counts were significantly associated with CCR5 usage. No associations with treatment experience, clade, or pol gene mutations were observed. CONCLUSION: The prevalence of CCR5-tropic HIV-1 phenotype declines with decreasing CD4 cell count and increasing viral load. Mixed/dual tropic virus is found in all CD4 cell count and viral load strata. Coreceptor usage is not influenced by viral clade.

Adult↗
PubMed2000

Population structure, parasitism, and survivorship of sexual and autodiploid parthenogenetic Campeloma limum.

Two theories for the maintenance of sexual reproduction, the Red Queen hypothesis and mutation accumulation, suggest that the dispersal rates of sexuals and asexuals may determine the elimination or persistence of asexuals. Under higher dispersal rates of asexuals, asexuals may temporarily escape virulent parasites and reduce the effects of deleterious mutations. In the present study, I examine the population structure, parasite loads, and juvenile survivorship of Campeloma limum sexuals and autodiploid parthenogens from the southeastern U.S. Atlantic coastal plain. Using mtDNA sequence variation, it is shown that parthenogenetic haplotypes with limited sequence divergence are geographically widespread throughout this region and there is no significant population differentiation over a broad geographical scale. Sexual C. limum populations show significant mtDNA differentiation among and within river drainages and there is significant isolation by distance. These patterns are consistent with a recent origin and range expansion of parthenogens. Prevalence of infection by digenetic trematodes is significantly higher in autodiploid parthenogens, and the variance of prevalence is also higher in autodiploid parthenogens. I argue that the latter pattern indicates that unparasitized parthenogens have temporarily escaped these virulent parasites, but recolonization of these populations by trematodes results in high infection levels (> 40%), possibly due to reduced variation in resistance genes. I also examined whether the survivorship of juvenile sexuals and parthenogens varied under different stress levels. Sexual juveniles had twofold higher survivorship in all environments. Compared to polyploid parthenogens, autodiploid parthenogens may be less buffered against the effects of deleterious recessive alleles. I propose that the combined effects of higher parasitism and reduced juvenile survivorship of these autodiploid parthenogens accounts for the spatial distribution of sexual and parthenogenetic C. limum in the Atlantic coastal plain. Parthenogens may persist by higher dispersal rates into marginal habitats where there is a temporary escape from digenetic trematodes and competition with sexuals.

Animals↗
PubMed2004

Understanding HIV resistance, fitness, replication capacity and compensation: targeting viral fitness as a therapeutic strategy.

The increasingly prevalent emergence of drug-resistant virus strains in patients being treated with highly active antiretroviral regimens and the increasing rates of transmission of drug-resistant virus strains have focused attention on the critical need for additional antiretroviral agents with novel mechanisms of action and enhanced potency. Furthermore, novel means of employing highly active antiretroviral therapy are needed to reduce or eliminate the virological treatment failures that currently occur. Over the past several years, evidence has mounted supporting the fact that the emergence of resistant strains is associated with reductions in viral fitness, yielding decreases in plasma virus load in treated patients harbouring resistant populations of the virus. Additional mutations that serve to modify fitness (compensatory mutations) and mutations that impact the viral replication capacity also emerge under the selective pressure of drug treatment, and have both negative and positive effects on virus growth. Fitness is generally accepted to refer to the ability of HIV to replicate in a defined environment and thus is used to describe the viral replication potential in the absence of the drug. Although viral fitness and replication capacity are related in some ways, it is important to recognise that viral fitness is not the same as viral replication capacity. This review will assess the recent literature on antiviral drug resistance, viral fitness and viral replication capacity, and discuss means by which the adaptability of HIV to respond rapidly to antiviral treatment through mutation may be used against it. This would be done by treating patients with an aim to lock the deleterious mutations into the resistant virus genome, resulting in a positive therapeutic outcome despite the presence of resistance to the selecting agents. The review will specifically discuss the literature on nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, as well as other biological factors involved in viral fitness.

Anti-Retroviral Agents↗
PubMed2005

[Primary resistance to antiretroviral therapy in patients with HIV/AIDS in Chile].

BACKGROUND: Resistance to antiretroviral therapy is a determining factor for therapeutic failure in HIV/AIDS. The prevalence of primary resistance (i.e. in those patients that have not received treatment) varies in different parts of the world. AIM: To study the prevalence of primary resistance to antiretroviral drugs in patients living in Northern Santiago. PATIENTS AND METHODS: Viral load, lymphocyte subpopulations by flow cytometry and genotypic resistance testing were assessed in blood samples from 60 HIV-1 infected patients (mean age 37 years, 54 male). RESULTS: Mean CD4 cell count and viral load was 200 cells/ml and 142,840 RNA copies/ml respectively. Ten mutations were identified: V179D, L10I/V, M361, L63P, A71T/V, Y115F, V118I and K20R. None of these mutations is associated to a high degree of resistance to reverse transcriptase inhibitors, nucleoside analogs (NRTI), non nucleoside analogs (NNRTI) or viral protease inhibitors. CONCLUSIONS: This is a first approach to study antiretroviral resistance in Chilean patients. This study must be amplified, since the prevalence of resistance may experience changes with time.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Theoretical rationale for the use of sequential single-drug antiretroviral therapy for treatment of HIV infection.

BACKGROUND: Subpopulations of HIV with mutations associated with resistance to antiretroviral drugs often have reduced replicative capacity, so virus with resistance mutations for all existing and new antiretroviral drugs is likely to be appreciably impaired. Issues of toxicity, quality of life and economics mean that the simultaneous use of all these drugs in combination is unrealistic. We aimed to explore the use of sequential monotherapy regimens using a mathematical model of quasi-species dynamics, to see if these could take advantage of the poor replicative capacity of highly resistant virus. METHODS: We assume for each of seven drugs that a single mutation is associated with the ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. Parameters included were drug efficacy, the cost of resistance mutations and the number of new target cells arising daily. RESULTS: The use of seven drugs in a daily/weekly sequential monotherapy cycle led to substantial viral suppression (in the presence of all resistant viral subpopulations) for a wider range of parameter values than a continuous five-drug regimen. Although on any one day/week there is a viral subpopulation with R > 1 (e.g. that with resistance only to the current drug), this subpopulation does not have time to grow sufficiently during the short period when that drug is being taken. CONCLUSION: These results provide a rationale for trials of sequential regimens, using as wide a number of drugs with different resistance-associated mutations as possible, as a potential 'resistance-proof' strategy for achieving significant viral load suppression.

Anti-HIV Agents↗
PubMed2001

Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.

Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.

Amino Acid Substitution↗
PubMed2004

Virological and immunological impact of non-nucleoside reverse transcriptase inhibitor withdrawal in HIV-infected patients with multiple treatment failures.

No significant changes in viral load and CD4 cell count were observed 2-4 weeks after the withdrawal of non-nucleoside reverse transcriptase inhibitors (NNRTI) from the current therapy of patients exhibiting resistance mutations to this class of drugs. The data suggest that in the presence of specific resistance mutations NNRTIexert no residual antiretroviral activity and could be withdrawn without viral rebound.

CD4 Lymphocyte Count↗
PubMed2005

Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2007

Genome instability and DNA damage accumulation in gene-targeted mice.

Six major pathways for DNA repair have been identified. These include (1) DNA repair by direct reversal, (2) base excision repair, (3) mismatch repair, (4) nucleotide excision repair, (5) homologous recombination, and (6) non-homologous end-joining. In addition, several other cellular processes influence the response to DNA damage. The generation of gene-targeted organisms is crucial for assessing the relative contribution of single DNA repair proteins and DNA repair pathways in maintaining genome stability. In particular, the accumulation of DNA damage, mutations and cancer in unexposed gene-targeted animals illuminates the spontaneous load of a particular lesion and the relative significance of a single gene in a specific pathway. Strategies for the generation of gene-targeted mice have been available for 15 years and more than 100 different genes relevant to DNA repair have been targeted. This review describes some important progress made toward understanding spontaneous DNA damage and its repair, exemplified through one, or a few, gene-targeted mice from each major DNA repair pathway.

Animals↗
PubMed1996

Maintenance of growth factor signaling through Ras in human colon carcinoma cells containing K-ras mutations.

Fifty percent of human colon carcinomas contain activating mutations in the K-ras gene. However, whether these alterations in K-ras affect the function of Ras proteins in growth factor (GF) signal transduction is now known. Here we have characterized a previously defined human colon carcinoma cell model system for K-ras gene mutations and for altered levels of Ras protein expression and have examined whether these alterations affect Ras function in GF signal transduction. Sequence analysis of PCR-amplified K-ras gene fragments indicated that among the more aggressive cell lines, four had a normal K-ras sequence, whereas 3 others (isolated from the same human tumor) contained a mutation at codon 13. In contrast, all 7 of the less aggressive cell lines contained a mutation at either codon 12 or 13. In addition to the presence of a K-ras mutation, one cell line expressed higher levels of the K-Ras protein and displayed elevated Ras-GTP loading (in the absence of GF addition) compared with the other cell lines examined. Despite these alterations, the mitogenic GF combination epidermal growth factor + insulin + transferrin resulted in an activation of Ras and extracellular signal-regulated kinase 2. Collectively, our results indicate that the malignant phenotype of the cell lines was not correlated with the presence of K-ras mutations or with higher levels of Ras protein expression. Furthermore, K-ras mutations, high levels of K-Ras protein expression, and elevated Ras-GTP loading, as they occur naturally in human colon carcinomas, do not abolish the function of Ras in GF signaling.

Base Sequence↗
PubMedDate not supplied

Baseline antiretroviral drug susceptibility influences treatment response in patients receiving saquinavir-enhancing therapy.

PURPOSE: To relate baseline plasma HIV genotypic and virtual phenotypic antiretroviral drug susceptibility to subsequent virological response in patients receiving saquinavir (SQV)-enhancing therapy. Individuals were randomized to receive stavudine (d4T), SQV, and one of ritonavir, nelfinavir, or delavirdine to enhance SQV blood levels. METHOD: The protease and reverse transcriptase baseline sequences of 31 treatment-experienced patients were analyzed by genotype and virtual phenotype and were related to viral load at weeks 12 and 24. Genotypic resistance to SQV was defined by the presence of G48V and/or L90M mutations in the protease gene. Potential cross-resistance to d4T in zidovudine (ZDV)-experienced individuals was defined by the presence of thymidine-associated mutations in the reverse transcriptase gene. RESULTS: ZDV-associated mutations did not affect the virological response at 24 weeks. Individuals who were sensitive to SQV at baseline as determined by either genotyping or virtual phenotyping showed a greater decrease in viral load at week 24 than those resistant to SQV, irrespective of treatment arm. By genotyping, SQV-sensitive individuals had a median log decrease of 1.12 compared to 0.32 for those individuals who were SQV resistant. By virtual phenotyping, SQV-sensitive individuals had a median log decrease of 1.0 compared to a rise of 0.08 in resistant individuals. CONCLUSION: Thymidine analogue-associated mutations at baseline did not influence the response to subsequent therapy involving d4T. Individuals who were sensitive or resistant to SQV by genotyping or virtual phenotyping responded to SQV-enhancing regimens, but the virological response was greater in those who were sensitive.

Anti-HIV Agents↗
PubMed2006

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

Adult↗
PubMed2003

Moderate citrullinaemia without hyperammonaemia in a child with mutated and deficient argininosuccinate synthetase.

In a patient with microcephaly, feeding problems and restlessness, moderately increased serum and urine citrulline concentrations were observed. Protein and allopurinol loading did not result in additional indications for a urea cycle defect. The diagnosis of citrullinaemia was made at both the enzyme and DNA level, resulting from a novel mutation in the argininosuccinate synthetase gene. The fact that the patient has not suffered from severe deterioration, and that there were only minor abnormalities in metabolite concentrations, suggests that the argininosuccinate synthetase capacity was less affected in vivo than in vitro. In vitro nuclear magnetic resonance investigation suggested an active acetylation mechanism for citrulline. This case illustrates the importance of performing extensive biochemical and molecular investigations in order to reach a definitive diagnosis, particularly in instances of moderate citrullinaemia.

Amino Acids↗