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Results for “mutation load”

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PubMed2002

Predictors of treatment failure during highly active antiretroviral therapy (racing trial).

PURPOSE: To determine factors associated with virological failure during long-term treatment with the triple combination of saquinavir soft gel capsule, zalcitabine and zidovudine. METHOD: Open-label, prospective, multicentre study undertaken in private practices and the outpatient department of the Auguste-Viktoria-Hospital. A total of 95 patients with plasma HIV RNA > 5000 copies/ml who had received no more than 6 months pre-treatment with NRTIs and no prior PI therapy received saquinavir soft gel, zalcitabine and zidovudine for 52 weeks, before being randomly assigned to either remain on therapy or switch to nelfinavir, lamivudine and zidovudine for further 52 weeks. RESULTS: Combination therapy with saquinavir, zalcitabine and zidovudine was found to be effective and well tolerated, with virological response to therapy maintained for up to 2 years. In patients responding to therapy, switching to a novel triple regimen did not result in a virological or immunological worsening, but it did not confer an additional clinical benefit. Factors predictive of early treatment failure (virological failure within 16 weeks of treatment initiation) included high viral load and presence of RT mutations at baseline (OR: 0.30, 95% CI 0.11 0.83 and OR 0.13, 95% CI 0.03 0.52, respectively), with baseline viral load and the development of genotypic mutations on therapy being predictive of late treatment failure (16 52 weeks; OR: 0.15, 95% 0.05 0.46 and OR: 0.26, 95% CI < 0.001 1.16, respectively). Plasma saquinavir concentration < 50 mg/ml at 4 weeks was also found to be an independent risk factor for both early and late treatment failure (OR: 1.80, 95% CI 1.23 2.64 and OR: 1.16, 95% CI 0.84 1.60, respectively). CONCLUSIONS: While antiretroviral drug resistance appears to be a principal cause of treatment failure, other factors such as inadequate drug plasma concentrations also play a role.

Adult↗

PubMed2025

Unraveling the Role of Mutations Outside the Basal Promoter and Precore Regions in the HBeAg-Negative Stage of Chronic Hepatitis B.

Hepatitis B e antigen (HBeAg) seroconversion is a crucial event in the natural history of chronic hepatitis B virus (HBV) infection, marked by a significant decrease in viral load and the emergence of mutations that suppress HBeAg expression. However, these mutations alone do not fully account for the reduction in viral load. This study investigated the biological features and pathogenic roles of mutations outside the basal core promoter (BCP) and precore regions during the HBeAg-negative stage of chronic infection. Full-length HBV genomes from HBeAg-positive (n = 180) and HBeAg-negative (n = 328) genotype D datasets were analyzed, revealing significantly higher genomic heterogeneity in HBeAg-negative sequences compared with HBeAg-positive genomes (50.4 ± 16.0 vs. 26.6 ± 10.5 nucleotide changes per genome). Twenty-six hotspot amino acid mutations associated with the HBeAg-negative stage were identified, with over half located in the Core region. Subsequently, full-length HBV genomes from six HBeAg-negative patient-derived serum samples were obtained by PCR amplification followed by Sanger sequencing. Infectious clones generated from these genomes, each carrying between 21 and 66 amino acid substitutions, were characterized, showing that mutations in this stage differentially affected viral fitness in vitro by up- or downregulating HBV-DNA levels (ranging from 0.2 to 5 times those of the wild-type isolate), modulating capsid assembly, and altering the expression, secretion, and subcellular localization of viral proteins. In conclusion, while mutations in the BCP and precore regions are the primary drivers of HBeAg seroconversion, mutations outside these regions significantly influence HBV biology and potentially contribute to viral pathogenicity, underscoring the complex interplay between host and virus during the HBeAg-negative stage of chronic infection.

Humans↗

PubMed2001

Mutations in the carcinoembryonic antigen gene in colorectal cancer patients: implications on liver metastasis.

Carcinoembryonic antigen (CEA) expression is used clinically to monitor patients with colorectal and other cancers. A subset of patients have extraordinarily high CEA levels that cannot be attributed solely to tumor load. We have shown mutations in the region of CEA (PELPK motif) responsible for its hepatic clearance in three of eight patients with high CEA levels. We used denaturing high-performance liquid chromatography to provide evidence of polymorphism in these patients. These mutations were scored by DNA cycle sequencing and shown to be heterozygous. The patients with mutations in the PELPK motif showed remarkably reduced circulatory clearance rates in an animal model. A patient without mutation in the region showed normal clearance rates. Mutations in PELPK may affect structural stability and binding affinity to the Kupffer cell receptor in the liver. These studies have implications for the role of CEA as a facilitator of hepatic metastasis.

Amino Acid Sequence↗

PubMed2003

Load-induced transcriptional activation of c-jun in rat myocardium: regulation by myocyte enhancer factor 2.

The increased expression of immediate-early genes is a key feature of the myocardial response to hypertrophic stimuli. In this study, we investigated whether pressure overload or phenylephrine treatment stimulated myocyte enhancer factor 2 (MEF2)-dependent transcriptional activation of c-jun in cardiac myocytes. Western blotting and immunohistochemical analysis of rat myocardium demonstrated that p70(MEF2) is highly expressed in the rat heart and is predominantly located at the nuclei of cardiac myocytes. Electrophoretic mobility shift assays of myocardial nuclear extracts revealed a consistent DNA binding activation of MEF2 after 1 and 2 hours of pressure overload. We further showed that pressure overload induced a progressive nuclear translocation and activation of extracellular signal-regulated kinase 5 (ERK5). Coimmunoprecipitation and in vitro kinase assays indicated that the activation of ERK5 was paralleled by increased association of ERK5/p70(MEF2) and by enhanced ability of ERK5 to phosphorylate p70(MEF2). Experiments with in vivo transfection of the left ventricle with the c-jun promoter reporter gene showed that pressure overload induced a consistent increase of c-jun transcriptional activity in the rat myocardium. Rendering the MEF2 site of the c-jun plasmid inactive by mutation abolished the load-induced activation of the c-jun promoter reporter gene. Mutation of the MEF2 site also abolished the phenylephrine-induced c-jun promoter activation in neonatal rat ventricular myocytes. In addition, we demonstrated that neonatal rat ventricular myocyte transfection with ERK5-antisense oligodeoxynucleotide inhibited the phenylephrine-induced c-jun promoter activation. These findings identify MEF2 as a potential regulator of c-jun transactivation and suggest that ERK5 might be an important mediator of MEF2 and c-jun promoter activation in response to hypertrophic stimuli in cardiac myocytes.

Animals↗

PubMed1975

Spontaneous recessive lethal mutations in the mouse.

The estimation of the load of recessive lethals in our inbred CBA strain is based on samples drawn from 1964 to 1971. 407 control F1 males were back-crossed to their daughters. The first examined females which for each F1 male gave 50 implants were included in the test. their rate of intra-uterine death was compared to that from lethal-free males. The distribution of the number of F1 males according to the number of dead in the first 50 implants were compared to a model of lüning. Three estimates of the proportion of lethal heterozygotes gave 4.2, 5.35 and 6.2% respectively. From the way the inbred strain was kept it was estimated that the mean load among F1 males was 11.5mu (mu equal to mutation rate per gamete). These data indicate that about 0.5% lethals occur per gamete with an upper limit of 1%. Comparisons are made with previous estimates of the spontaneous rate of lethal mutations per gamete. The low proportion of lethal mutations indicate that the number of loci giving lethal mutations is low. Both spontaneous and induced mutations give similar low numbers, more than one order of magnitude below the number commonly assumed. The uncertainties are stressed of estimating risk by multiplying mutation rate per locus and assumed number of loci.

Animals↗

PubMed2005

Dynamic treatment model to examine the association between phenotypic drug resistance and duration of HIV viral suppression.

Recent advances in the chemotherapy of HIV infection have been successful in delaying the progression of disease in many patients and are responsible for the decline in HIV-related deaths in the United States. Yet, there are many patients who fail to maintain suppressed viral loads on treatment. Means to extend the utility of currently available drugs include developing improved ways to assess the therapeutic impact of drug-resistant variants. A mathematical model to incorporate the presence of resistance mutations with either primary or secondary classifications is created as a means to explore the association between phenotypic resistance and duration of viral response to therapy. The model, which includes phenotypic and genotypic resistance information for each viral mutant, is presented here with a simplified five-codon genome. However, as additional experimental data and computational resources become available future users may adapt the model to be larger and more accurate. Secondary analyses suggest that, in this model, the resistance phenotypes of the strains with an intermediate number of mutations are the primary determinants of both the total duration of viral suppression with a single treatment and the difference between the durations of suppression of the forward and reverse sequential administrations of two treatments. These findings imply that a model including the resistance phenotype and in vivo response of genotypically-resistant viral strains may lead to a priori prediction of successful anti-HIV drug selection for an individual harboring drug-resistant virus.

Anti-HIV Agents↗

PubMed1999

Neutral evolution of mutational robustness.

We introduce and analyze a general model of a population evolving over a network of selectively neutral genotypes. We show that the population's limit distribution on the neutral network is solely determined by the network topology and given by the principal eigenvector of the network's adjacency matrix. Moreover, the average number of neutral mutant neighbors per individual is given by the matrix spectral radius. These results quantify the extent to which populations evolve mutational robustness-the insensitivity of the phenotype to mutations-and thus reduce genetic load. Because the average neutrality is independent of evolutionary parameters-such as mutation rate, population size, and selective advantage-one can infer global statistics of neutral network topology by using simple population data available from in vitro or in vivo evolution. Populations evolving on neutral networks of RNA secondary structures show excellent agreement with our theoretical predictions.

Evolution, Molecular↗

PubMed2001

Human immunodeficiency virus type 1 hypersusceptibility to amprenavir in vitro can be associated with virus load response to treatment in vivo.

The human immunodeficiency virus type 1 protease mutation N88S, which is occasionally selected by treatment with nelfinavir or indinavir, confers hypersusceptibility to amprenavir in vitro. The clinical relevance of this observation is unclear. We report a case of N88S developing after virologic failure of both indinavir- and nelfinavir-containing regimens that was managed successfully with a regimen that contained amprenavir.

Adult↗

PubMed2000

Deleterious mutations and the evolution of sex.

It has been suggested that sexual reproduction is maintained because it reduces the load imposed by recurrent deleterious mutations. If rates of deleterious mutation per diploid genome per generation (U) exceed 1, and mutations interact synergistically, then sexuals can overcome their inherent twofold disadvantage. We have tested this hypothesis by estimating genomic point mutation rates for protein-coding genes in a range of animal taxa. We find a positive linear relationship between U and generation time. In species with short generation times, U is predicted to be far below 1, suggesting that sex is not maintained by its capacity to purge the genome of deleterious mutations.

Animals↗

PubMed2004

Obstacles to successful antiretroviral treatment of HIV-1 infection: problems & perspectives.

Mutations in human immunodeficiency virus type 1 (HIV-1) are a major impediment to successful highly active antiretroviral therapy (HAART) and the design of anti-HIV vaccines. Although HAART has made long-term suppression of HIV a reality, drug resistance, drug toxicity, drug penetration, adherence to therapy, low levels of continued viral replication in cellular reservoirs and augmentation of host immune responses are some of the most important challenges that remain to be sorted out. Continuing viral replication in the face of HAART leads to the accumulation of drug resistance mutations, increase in viral loads and eventual disease progression. Patients who fail therapy have minimal options for their clinical management. Therefore, a clear understanding of the pathogenesis of drug-resistant HIV-1, and all of the issues that influence the success of HAART is urgently needed. In the present article, we discuss various obstacles to HIV therapy, and provide perspectives relating to these issues that are critical in determining the success or failure of HAART.

Anti-HIV Agents↗

PubMed2005

Mutations in the nonstructural region 5B of hepatitis C virus genotype 1b: their relation to viral load, response to interferon, and the nonstructural region 5A.

The nonstructural 5B (NS5B) protein of hepatitis C virus possesses RNA-dependent RNA polymerase activity and plays an essential role in viral replication. The mutations in NS5B were determined and the correlation with viral load and response to interferon (IFN) were assessed. The entire NS5B region in 33 patients and its thumb domain in 62 patients was sequenced. The number of amino acid substitutions in the NS5B protein, that in thumb domain and the substitution at aa 389 was correlated with viral load and the response to IFN. Multivariate analysis selected only mutation in IFN sensitivity determining region (ISDR) as a factor associated with the viral load and response to IFN. The number of substitutions in the thumb domain and the substitution at aa 389 correlated with the number of substitutions in the ISDR. These results suggest that mutations in NS5B, especially in the thumb domain and at aa 389, have an important effect on viral load and the response to IFN, although they were dependent on mutations in ISDR. Further studies on the relationship between NS5B and NS5A (ISDR) are necessary to elucidate the mechanism of the correlation with viral load and the response to IFN.

Adult↗

PubMed2006

The genetic architecture of life span and mortality rates: gender and species differences in inbreeding load of two seed-feeding beetles.

We examine the inbreeding load for adult life span and mortality rates of two seed beetle species, Callosobruchus maculatus and Stator limbatus. Inbreeding load differs substantially between males and females in both study populations of C. maculatus--life span of inbred females was 9-13% shorter than the life span of outbred females, whereas the life span of inbred males did not differ from the life span of outbred males. The effect of inbreeding on female life span was largely due to an increase in the slope of the mortality curve. In contrast, inbreeding had only a small effect on the life span of S. limbatus--life spans of inbred beetles were approximately 5% shorter than those of outbred beetles, and there was no difference in inbreeding load between the sexes. The inbreeding load for mean life span was approximately 0.4-0.6 lethal equivalents per haploid gamete for female C. maculatus and approximately 0.2-0.3 for both males and females of S. limbatus, all within the range of estimates commonly obtained for Drosophila. However, contrary to the predictions of mutation-accumulation models, inbreeding load for loci affecting mortality rates did not increase with age in either species, despite an effect of inbreeding on the initial rate of increase in mortality. This was because mortality rates decelerated with age and converged to a mortality plateau for both outbred and inbred beetles.

Animals↗

PubMed1999

Effect of selection against deleterious mutations on the decline in heterozygosity at neutral loci in closely inbreeding populations.

Transition matrices for selfing and full-sib mating were derived to investigate the effect of selection against deleterious mutations on the process of inbreeding at a linked neutral locus. Selection was allowed to act within lines only (selection type I) or equally within and between lines (type II). For selfing lines under selection type I, inbreeding is always retarded, the retardation being determined by the recombination fraction between the neutral and selected loci and the inbreeding depression from the selected locus, irrespective of the selection coefficient (s) and dominance coefficient (h) of the mutant allele. For selfing under selection type II or full-sib mating under both selection types, inbreeding is delayed by weak selection (small s and sh), due to the associative overdominance created at the neutral locus, and accelerated by strong selection, due to the elevated differential contributions between alternative alleles at the neutral locus within individuals and between lines (for selection type II). For multiple fitness loci under selection, stochastic simulations were run for populations with selfing, full-sib mating, and random mating, using empirical estimates of mutation parameters and inbreeding load in Drosophila. The simulations results are in general compatible with empirical observations.

Animals↗

PubMed1998

Mutational analysis of the four alpha-helix bundle iron-loading channel of rat liver ferritin.

We previously reported that the heavy chain of ferritin was required for loading it with iron using ceruloplasmin as a ferroxidase [J.-H. Guo, M. Abedi, and S. D. Aust (1996) Arch. Biochem. Biophys. 335, 197-204]. Site-directed mutagenesis, K58E and G61H, on recombinant rat liver L chain ferritin (rL-Ft) was performed to construct a proposed iron-loading channel in the alpha-helix bundle similar to rat liver H chain ferritin (rH-Ft). Conversely, the channel in rH-Ft was closed by mutations E62K and H65G to form a K62 to E107 salt bridge, which is believed to exist in the L chain. Both variants were expressed in insect cells and were soluble and able to form multi-subunit homopolymers. The rH-Ft mutant homopolymer could not be loaded, whereas the rL-Ft mutant homopolymer could be loaded with iron by ceruloplasmin. However, we found that the initial rate of iron loading into the rL-Ft mutant homopolymer by ceruloplasmin was less than that into the rH-Ft homopolymer. When 500 atoms of iron per ferritin were used for loading, 98% was loaded into the rH-Ft homopolymer by ceruloplasmin in 15 min, but only 30% was loaded into the rL-Ft mutant homopolymer in the same time. Moreover, the ferroxidase activity of ceruloplasmin was enhanced in the presence of the rH-Ft and the rH-Ft mutant homopolymers, but not in the presence of the rL-Ft or the rL-Ft mutant homopolymers. These observations suggested that the four alpha-helix bundle channel of ferritin is required for iron loading, but an additional factor, i.e. , a site which stimulate the ferroxidase activity of ceruloplasmin, is also essential.

Animals↗

PubMed2002

Predictive value of provirus load and DNA human immunodeficiency virus genotype for successful abacavir-based simplified therapy.

Of 75 human immunodeficiency virus (HIV) type 1-infected patients successfully responding to 2 nucleoside reverse-transcriptase inhibitors (NRTIs) plus 1 protease inhibitor (PI), 55 started a simplified abacavir (ABC)-based triple NRTI regimen. Influences of DNA load and DNA reverse-transcriptase (RT) mutations on virological responses were assessed at month 6 after initiation of therapy. Baseline heterogeneity was observed: peripheral blood mononuclear cell (PBMC) genotyping showed 31% RT mutations with 1-5 NRTI-related mutations, 78% protease mutations had 1-5 PI-related mutations; and HIV-1-DNA levels were 1.8-3.5 log(10) copies/10(6) PBMC. Outcomes for 49 patients on a regimen of 2 NRTIs plus ABC were as follows: 22 successes, 10 blips ("blip" defined as intermittent plasma HIV-1 RNA levels between 50 and 100 copies/mL and a return to an undetectable level), and 17 failures, whereas, for patients continuing on a regimen of 2 NRTIs plus 1 PI, there were 19 successes and 1 blip. Previous treatment regimens, baseline provirus level, and PBMC genotype predicted virological outcome.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Skewed segregation of the mtDNA nt 8993 (T-->G) mutation in human oocytes.

Rapid changes in mtDNA variants between generations have led to the bottleneck theory, which proposes a dramatic reduction in mtDNA numbers during early oogenesis. We studied oocytes from a woman with heteroplasmic expression of the mtDNA nt 8993 (T-->G) mutation. Of seven oocytes analyzed, one showed no evidence of the mutation, and the remaining six had a mutant load > 95%. This skewed expression of the mutation in oocytes is not compatible with the conventional bottleneck theory. A possible explanation is that, during amplification of mtDNA in the developing oocyte, mtDNA from one mitochondrion is preferentially amplified. Thus, subsequent mature oocytes may contain predominantly wild-type or mutant mitochondrial genomes.

Cryopreservation↗

PubMed2000

Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: clinical and genotypic predictors of virologic response.

OBJECTIVE: To determine the impact of prior nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy, genotypic resistance, and other variables on response to efavirenz (EFV)- and adefovir dipivoxil (ADV)-based salvage therapy. DESIGN: Retrospective clinical cohort study. SETTING: One university and one community-based HIV clinic. STUDY SUBJECTS: All 33 patients who were coenrolled in both the EFV and ADV expanded access programs. INTERVENTIONS: Patients received EFV 600 mg/day and ADV 120 mg/day in addition to other antiretroviral agents. OUTCOME MEASURE: HIV viral load (<500 copies/ml) at 12 and 24 weeks. RESULTS: 10 of 33 (30%) patients at 12 weeks and 8 of 33 (24%) patients at 24 weeks had viral loads <500 copies/ml. Prior NNRTI use and a history of any NNRTI-associated mutations predicted failure. Patients with Y181C or G190A single mutations had an initial greater magnitude of viral load suppression than those with K103N, but this advantage was short lived. No one with any NNRTI mutations responded with a viral load <500 copies/ml at 12 or 24 weeks. CONCLUSIONS: EFV/ADV-based salvage yielded viral load suppression at 24 weeks in 42% (8 of 19) of patients who were highly NRTI and protease inhibitor experienced but NNRTI naive. NNRTI-experienced study subjects had a poor response regardless of the specific NNRTI resistance mutation they harbored.

Adenine↗

PubMed2005

Biochemical and mutational analyses of a unique clamp loader complex in the archaeon Methanosarcina acetivorans.

Clamp loaders orchestrate the switch from distributive to processive DNA synthesis. Their importance in cellular processes is underscored by their conservation across all forms of life. Here, we describe a new form of clamp loader from the archaeon Methanosarcina acetivorans. Unlike previously described archaeal clamp loaders, which are composed of one small subunit and one large subunit, the M. acetivorans clamp loader comprises two similar small subunits (M. acetivorans replication factor C small subunit (MacRFCS)) and one large subunit (MacRFCL). The relatedness of the archaeal and eukaryotic clamp loaders (which are made up of four similar small subunits and one large subunit) suggests that the M. acetivorans clamp loader may be an intermediate form in the archaeal/eukaryotic sister lineages. The clamp loader complex reconstituted from the three subunits MacRFCS1, MacRFCS2, and MacRFCL stimulated DNA synthesis by a cognate DNA polymerase in the presence of its sliding clamp. We used site-directed mutagenesis in the Walker A and SRC motifs to examine the contribution of each subunit to the function of the M. acetivorans clamp loader. Although mutations in MacRFCL and MacRFCS2 did not impair clamp loading activity, any mutant clamp loader harboring a mutation in MacRFCS1 was devoid of the clamp loading property. Mac-RFCS1 is therefore critical to the clamp loading activity of the M. acetivorans clamp loader. It is our anticipation that the discovery of this unique replication factor C homolog will lead to critical insights into the evolution of more complex clamp loaders from simpler ones as more complex organisms evolved in the archaeal/eukaryotic sister lineages.

Amino Acid Sequence↗