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PubMedDate not supplied

Implementation of an Italian multicentric care network for early HIV infection diagnosis: 1999-2001 report.

BACKGROUND: Diagnosis of a new HIV infection during the primary phase (PHI) is sometimes misleading in a primary care setting. Since 1999 the Italian network for the study of acute HIV infection (ISAI) has been operative. At the time of PHI diagnosis the case is reported to the coordinating centre and enrolled in the National Register which records all epidemiological, demographic and clinical information. PATIENTS AND METHODS: From 1999 to September 2001, 51 symptomatic or asymptomatic patients with diagnosis of primary HIV infection were signalled to the coordinating centre. At screening, assessments were: interview to collect demographic and epidemiological data, clinical history (regarding PHI signs and symptoms) and, if available, relevant index case information; physical examination; routine hematology and chemistry; lymphocyte count; plasma HIV-RNA. In a subset of patients PBMC HIV-DNA, HIV-RNA, resistance genotyping and HIV subtype characterization were assessed. RESULTS: 74.5% of patients were males and all but four were Italian. Hetero and homosexual contacts were the prevalent route of HIV transmission. Forty-five patients (89%) were symptomatic and the most frequent signs and symptoms were: fever, lymphadenopathy, malaise and pharyngodinia. Baseline reverse-transcriptase (RT) and protease (PR) genotyping analysis was available for 29 patients. Only one of 29 patients harbored a virus with a resistance-associated mutation in the RT region (215Y); NNRTI mutations were identified in 3 of 29 patients. In the remaining 20 (69%) patients no mutations were found in the RT region. Sequence data from PR region were successfully obtained in 21 patients. Only one of these had a high-level resistance mutation (46L); in an additional 10 cases 1 or more secondary mutations were identified. The remaining 10 patients harbored a PR region wild type virus. One patient presenting two secondary mutations in the PR region, even if highly adherent and tolerant to drug regimen, showed a slow viral load decrease. CONCLUSIONS: Our cohort confirms the uptrend of new infections through unsafe sexual contacts involving both homosexual and heterosexual couples. Genotype sequencing for antiretroviral resistant viral variants describes a low prevalence of RT resistance-associated mutations, as well as primary mutations in the PR region. On the contrary, a higher prevalence of PR gene polymorphisms and mutations is not known with any certainty to confer resistance to NRTI and NNRTI. The identification of antiretroviral drug resistant HIV strains is strategic for clinical and therapeutical intervention, even though from a public health point of view cost-efficacy must be considered.

AIDS Serodiagnosis↗

PubMed2006

Foscarnet salvage therapy for patients with late-stage HIV disease and multiple drug resistance.

OBJECTIVE: To evaluate the efficacy of foscarnet on HIV infection in patients with late-stage HIV disease and multiple drug resistance. METHODS: Three drugs experienced patients with plasma viral load (pVL) > 50,000 copies/ml and CD4+ T-cell counts < 100/mm3 were eligible for this open-label, single-arm, add-on pilot study. Foscarnet induction therapy consisted of 5 g intravenously twice daily for 6 weeks, in addition to a stable antiretroviral regimen. Patients with at least 1 log10 decrease in pVL at week 6 (W6), were given foscarnet 5 g intravenously twice daily on two consecutive days each week. Primary endpoint was the virological response rate at W6. RESULTS: Eleven patients were enrolled with a median baseline pVL at 5.16 log10 copies/ml, median CD4+ T-cell count at 10/mm3 and median number of mutations of 9, 2 and 12 associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs and protease inhibitors, respectively. One patient discontinued foscarnet at W2 because of renal toxicity. In an intent-to-treat analysis, the median change in pVL from baseline was -1.99 log10 copies/ml at W2 and -1.79 log10 copies/ml at W6. Eight out of eleven patients had a fall in pVL of at least 1 log10 at W6, and six started maintenance therapy. The median fall in pVL after 12 weeks of maintenance therapy was -0.85 log10 copies/ml in the four patients who reached W12, and the median increase of CD4+ T-cell count was 60/mm3. CONCLUSION: In patients with HIV mutations conferring resistance to all antiretroviral drug classes, foscarnet markedly reduced plasma HIV load and improved immunological status.

Adult↗

PubMed2006

Options for a second-line antiretroviral regimen for HIV type 1-infected patients whose initial regimen of a fixed-dose combination of stavudine, lamivudine, and nevirapine fails.

BACKGROUND: A fixed-dose combination of stavudine, lamivudine, and nevirapine is extensively used as an antiretroviral regimen in developing countries because of its affordability. Virological failure with this regimen has become more common, and a second-line regimen needs to be prepared in the national program. METHODS: Genotypic resistance testing was conducted among human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced treatment failure with their first antiretroviral regimen (a fixed-dose combination of stavudine, lamivudine, and nevirapine) during 2003-2005. Patterns of resistance mutations and options for a second-line regimen were studied. RESULTS: We studied 98 patients (mean age, 35.2 years), of whom, 63% were male. The median duration of antiretroviral therapy was 20 months. The median HIV-1 RNA load at the time of virological failure detection was 4.1 log copies/mL. The prevalences of patients with > or =1 major mutation conferring drug resistance to nucleoside reverse-transcriptase inhibitors and nonnucleoside reverse-transcriptase inhibitors were 95% and 92%, respectively. M184V was the most common nucleoside reverse-transcriptase inhibitor resistance mutation (observed in 89% of patients). Thymidine analogue mutations, K65R, and Q151M were observed in 37%, 6%, and 8% of patients, respectively. Patients with an HIV-1 RNA load of >4 log copies/mL at the time of treatment failure had higher prevalence of thymidine analogue mutations (P=.041), K65R (P=.031), and Q151M (P=.008) mutations. The second-line regimen was determined in a resource-limited setting where tenofovir and enfuvirtide are not available; the options were limited for 48% of patients. CONCLUSIONS: After experiencing treatment failure with a fixed-dose combination of stavudine, lamivudine, and nevirapine, almost all patients have lamivudine and nonnucleoside reverse-transcriptase inhibitor resistance. The options for a second-line regimen are limited for one-half of these patients. In resource-limited settings where availability of antiretroviral agents is limited, strategies for prevention of HIV-1 resistance are crucial. Early detection of virological failure may provide more options and better treatment outcomes.

Adult↗

PubMed1995

Tyrosine 114 is essential for the trimeric structure and the functional activities of human proliferating cell nuclear antigen.

In order to study the effect of trimerization of proliferating cell nuclear antigen (PCNA) on its interaction with DNA polymerase (pol) delta and its loading onto DNA by replication factor C (RF-C) we have mutated a single tyrosine residue located at the subunit interface (Tyr114) to alanine. This mutation (Y114A) had a profound effect on PCNA, since it completely abolished trimer formation as seen by glycerol gradient sedimentation and native gel electrophoresis. Furthermore, the mutant protein was unable to stimulate DNA synthesis by pol delta and did not compete effectively with wild-type PCNA for pol delta, although it was able to oligomerize and could to some extent interact with subunits of functionally active PCNA. We thus conclude that PCNA molecules that are not part of a circular trimeric complex cannot interact with the pol delta core. furthermore, the mutant protein could not be loaded onto DNA by RF-C and did not compete with wild-type PCNA for loading onto DNA, indicating that PCNA trimerization may also be a prerequisite for its recognition by RF-C. The adverse effects caused by this single mutation suggest that trimerization of PCNA is essential for the monomers to keep their overall structure and that the structural changes imposed by trimerization are important for interaction with other proteins.

Alanine↗

PubMed2002

Subtle decreases in stavudine phenotypic susceptibility predict poor virologic response to stavudine monotherapy in zidovudine-experienced patients.

To identify the level of phenotypic susceptibility for stavudine (d4T) that is associated with a diminished virologic response to d4T therapy, phenotyping was performed on archived baseline HIV isolates from 26 subjects who received d4T monotherapy in AIDS Clinical Trials Group (ACTG) 302 who had received >3 years of prior zidovudine (ZDV) monotherapy. Seven of 26 subjects achieved a virologic response of >0.3-log10 copies/mL reduction in plasma HIV RNA after 8 weeks of d4T. Responders had lower fold changes in susceptibility to d4T (1.0 vs. 1.6, p=.003), lower baseline viral loads (4.26 vs. 4.74 log10 copies/mL, p=.004), and fewer thymidine analog mutations (TAMS) (1 vs. 2, p=.059). Lower baseline d4T fold change in susceptibility predicted greater reductions in HIV RNA from baseline to week 8 after adjusting for baseline HIV RNA, ZDV fold change in susceptibility, and number of TAMS. Using the same phenotypic assay, drug susceptibility among 240 antiretroviral-naive patients found all HIV isolates to have d4T susceptibility <or=1.4-fold change. Using <or=1.4 as the d4T cutoff, the positive predictive value for a virologic response in this study was 44%, and the negative predictive value was 100%. d4T susceptibility greater than 1.4-fold change was associated with failure to achieve significant viral load reduction after 8 weeks of d4T monotherapy.

Adult↗

PubMed2006

A prospective study of the evolution of lamivudine resistance mutations in patients with chronic hepatitis B treated with lamivudine.

Lamivudine resistance has been described in subjects with chronic hepatitis B infections, associated with mutations in the viral polymerase gene. The objective of this study was to estimate the emergence rate of lamivudine-resistant viral strains and their consequences over a 2-year period. We evaluated 283 lamivudine-naïve subjects with chronic hepatitis B. Clinical and virological features were assessed at inclusion and every 6 months thereafter. Viral DNA was characterized using polymerase chain reaction (PCR)-based sequencing. Potential risk factors for the emergence of lamivudine resistance mutations were assessed using logistic regression analysis. The annualized incidence rate for viral polymerase mutations was 22%. The only independent risk factor identified was high viral load, at inclusion. Detectable viral DNA and elevated transaminases were more frequent in subjects harbouring mutant viral strains, and these underwent a lower rate of hepatitis B e seroconversion. All subjects responded favourably to treatment, with no difference in symptoms between the two groups. This prospective cohort study identified lamivudine-resistant mutations emerging in 22% of subjects, yearly, which were apparently not associated with clinical aggravation over the study period.

Adolescent↗

PubMed2003

Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy.

BACKGROUND: Whether ventricular remodeling from hypertrophic cardiomyopathy (HCM), systemic hypertension, or other pathologies arises through a common signaling pathway or through independent molecular mechanisms is unknown. To study this, we assessed cardiac hypertrophy in a mouse model of HCM subjected to increased left ventricular (LV) load. METHODS AND RESULTS: Transverse aortic banding of mice with or without an Arg403Gln cardiac myosin heavy chain mutation (alphaMHC403/+) produced similarly elevated LV pressures (120+/-30 versus 112+/-14 mm Hg; P=NS). No mice developed heart failure, and mortality (26% alphaMHC403/+, 35% wild-type) was comparable. Load-induced hypertrophy was identical in banded 129SvEv alphaMHC403/+ mice (LV anterior wall [LVAW]=1.28+/-0.11) and 129SvEv wild-type mice (LVAW=1.29+/-0.11 mm; P=NS). Genetically outbred Black Swiss (BS) alphaMHC403/+ mice showed only mildly exaggerated hypertrophy in response to aortic banding (BS alphaMHC403/+ LVAW=1.30+/-0.13 mm; BS wild-type LVAW=1.17+/-0.15 mm; P=0.03), suggesting some effect from a BS genetic locus that modifies hypertrophy induced by the cardiac MHC Arg403Gln mutation. Histopathology and molecular markers of hypertrophy were comparable in all banded 129SvEv or BS mice. Banded alphaMHC403/+ mice had potential for greater hypertrophy, because cyclosporin A treatment markedly augmented hypertrophy. CONCLUSIONS: The uniform hypertrophic response to increased ventricular load in wild-type and alphaMHC403/+ mice indicates independent cardiac remodeling pathways and predicts that coexistent hypertension and HCM should not profoundly exacerbate cardiac hypertrophy. In contrast, sarcomere mutation and cyclosporin A-mediated calcineurin inhibition stimulate a shared hypertrophic signaling pathway. Defining distinct signaling pathways that trigger myocyte growth should help to tailor therapies for cardiac hypertrophy.

Animals↗

PubMed2006

Expertise of laboratories in viral load quantification, genotyping, and precore mutant determination for hepatitis B virus in a multicenter study.

A national evaluation study was performed in 14 specialized laboratories with the objective of assessing their capacities to provide (i) hepatitis B virus (HBV) viral loads (VL), (ii) HBV genotypes, and(iii) identification of precore/core mutants. The panel consisted of 12 HBV DNA-positive samples with VLs from 2.8 to 9.1 log(10) copies/ml, different HBV genotypes (A to F), and 3 mutant and 9 wild-type samples at nucleotide 1896. The coefficients of variation of the mean VLs ranged from 2.4% to 10.4% with the Cobas HBV Monitor assay, from 1.8% to 5.5% with the Cobas TaqMan 48, from 1.5 to 26.2% with RealArt HBV PCR, and from 0 to 7% with branched DNA (bDNA). The Cobas Monitor assay underestimated the VLs of genotype F samples, with differences ranging from 1.4 to 2.4 log(10) copies/ml. The accuracies of genotype determinations ranged from 33% to 100%, and those of precore mutant determinations ranged from 25 to 100%. This study showed some drawbacks of two widely used assays: (i) Cobas Monitor has a narrow dynamic range and underestimates genotype F sample VLs and (ii) bDNA shows poor sensitivity and may fail to identify patients with low VLs. With higher performance in terms of analytical sensitivity combined with a larger dynamic range and an ability to quantify the main genotypes equally, real-time PCR methods appear more appropriate for accurate monitoring of HBV DNA quantification. Furthermore, the clinical implications of HBV genotyping and the determination of precore/core mutants need to be clearly stated to justify the standardization of these methods.

France↗

PubMedDate not supplied

Zidovudine resistance mutations and human immunodeficiency virus type 1 DNA burden: longitudinal evaluation of six patients under treatment.

Zidovudine (ZDV) is by far the most widely used drug to counteract human immunodeficiency virus type 1 (HIV-1) infection, both in monotherapy and in combination therapy regimens. However, the majority of patients under prolonged ZDV therapy have been shown to harbour HIV-1 mutant genomes displaying reduced sensitivity to the drug in vitro. In order to investigate the pathogenic role of in vitro resistance to ZDV, six HIV-1-infected ZDV-treated subjects were evaluated longitudinally (mean follow-up 28.5 months, range 12-39 months) for HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) and for the presence of HIV-1 pol gene mutations responsible for ZDV resistance. Quantitation of HIV-1 DNA was performed by competitive polymerase chain reaction (cPCR) and the pol genotype was determined by direct sequencing of PCR products. All of the six patients developed one or more of the HIV-1 pol mutations known to confer resistance to ZDV in vitro (Met41-->Leu, Asp67-->Asn, Lys70-->Arg, Thr215-->Phe/Tyr, Lys219-->Gln/Glu). A temporal association was found between HIV-1 DNA burden and the level of ZDV resistance, as predicted on the basis of the pol genotype (genotypic resistance). Both virus load and ZDV resistance were inversely correlated with CD4+ cell counts. These results are compatible with a direct in vivo pathogenetic role for pol gene mutations shown to be involved in resistance to ZDV in vitro. Monitoring the degree of genotypic resistance to ZDV and to other antiretroviral drugs should be considered in designing protocols for the management of treated patients.

Adult↗

PubMed2005

Identification of the critical region in replication factor C from Pyrococcus furiosus for the stable complex formation with proliferating cell nuclear antigen and DNA.

Replication factor C (RFC) and proliferating cell nuclear antigen (PCNA) are accessory proteins essential for processive DNA synthesis. The function of RFC is to load PCNA, a processivity factor of replicative DNA polymerases, onto primed DNA templates. The central hole of the PCNA homo-trimeric ring encircles doublestranded DNA, so that DNA polymerases can operate for DNA synthesis with PCNA along a DNA template. The Pyrococcus furiosus RFC (PfuRFC) consists of a small subunit (RFCS, 37kDa) and a large subunit (RFCL, 55kDa), which show significant sequence identity to the eukaryotic homologs. The C-terminal region of RFCL has an acidic cluster of about 30 amino acids, which consists mainly of glutamic acid residues, and a following basic cluster of 10 amino acids, which consists mainly of lysine residues. These clusters of charged amino acids, which precede the C-terminal consensus sequence, PIP (PCNA interacting protein)-box, are conserved in several archaeal RFCLs. The series of mutant PfuRFC containing the C-terminal deletions in RFCL were constructed. The mutational analyses showed that the charged cluster is not essential for loading of PCNA onto DNA. However, the region containing the basic cluster is important for the stable ternary (RFC-PCNA-DNA) complex formation.

Amino Acid Sequence↗

PubMed2005

Viral load change and sequential evolution of entire hepatitis C virus genome in Irish recipients of single source-contaminated anti-D immunoglobulin*.

In hepatitis C virus (HCV) infection, serum viral load is important in the prediction of therapeutic efficacy. However, factors that affect the viral load remain poorly understood. To identify viral genomic elements responsible for the viral load, we investigated samples from a population of Irish women who were iatrogenically infected from a single HCV source by administration of HCV 1b-contaminated anti-D immune globulin between 1977 and 1978 (Kenny-Walsh, N Engl J Med 1999; 340: 1228). About 15 patients were divided into two groups, viral load increasing group (11 patients) and decreasing group (4 patients). Pairs of sera were collected from each patient at interval between 1.1 and 5.8 years. Full-length sequences of HCV genome were determined, and analyzed for changes in each patient. Sliding window analysis showed that the decreasing group had significantly higher mutation rates in a short segment of NS5B region that may affect the activity of RNA-dependent RNA polymerase. By comparing each coding regions, significantly higher mutation numbers were accumulated in NS5A region in the increasing group than the decreasing group (0.92 vs 0.16 nucleotides/site/year, P = 0.021). The mutation in certain positions of the HCV genome may be determinant factors of the viral load in a relatively homogeneous patient population.

Amino Acid Sequence↗

PubMed1996

Technical note: use of a PCR-single strand conformation polymorphism (PCR-SSCP) for detection of a point mutation in the swine ryanodine receptor (RYR1) gene.

We used the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis for screening the point mutation (C1843 to T) in the porcine ryanodine receptor (RYR1) gene. The PCR products (659 bp) were heat-denatured and separated by polyacrylamide gel electrophoresis. On silver-stained gels, the point mutation within the RYR1 gene could be detected clearly by mobility shifts. The best conditions for detecting the point mutation were by using a 5% polyacrylamide gel without glycerol and loading at 3 degrees C. The RYR1 genotypes diagnosed by PCR-SSCP were identical to the genotypes diagnosed by restriction enzyme fragment length polymorphism in all cases examined (n = 606).

Animals↗

PubMed2005

Low frequency of mutations in the X gene, core promoter and precore region of hepatitis B virus infected Vietnamese.

Numerous mutations in the hepatitis B virus (HBV) genome have been described, but in most cases their role in the pathogenesis of HBV infection is still unclear. Therefore, we analysed specific mutations in HBV-infected Vietnamese patients and assessed their potential relationship with their clinical outcome. A total of 153 HBV-infected Vietnamese patients with well-characterised clinical profiles were enrolled. None of the study participants had a history of alcohol or drug use and none received any antiviral or immunosuppressive therapy before or during the course of this study. The HBx- and core promoter regions were analysed by sequencing. The majority of isolates corresponded to genotype A. The presence of hepatitis B e antigen (HBeAg) was associated with significantly higher viral loads in the chronic HBV-infection group (P = 0.026). Double mutations in the core promoter (1762/1764) were more frequent in those with cancer than in noncancer patients (P < 0.01). Mutations at nucleotide (nt) 1766/1773 were found at low prevalence but with no obvious association to clinical presentation. Cytosine at nt 1858 was predominant but the stop codon mutation in the precore region was not detected. In the study, 4/48 hepatocellular carcinoma (HCC) patients revealed truncated HBx, whilst the serine to alanine mutation (codon 31) of HBx was more prevalent in cancer patients than in asymptomatic HBV carriers (P < 0.01). Thus, the low frequency of mutations indicates the relation of the absence of antiviral pressure in this population. The exclusively found prevalence of certain mutations detected in those with HBV-related carcinoma nevertheless indicates a degree of association with disease progression.

Adult↗

PubMed1997

Frequency of spontaneous and induced micronuclei in the peripheral blood of aging mice.

The mouse peripheral blood micronucleus assay, a measure of DNA damage in erythroblastic cells, was used to determine: (1) the incidence of spontaneously occurring micronucleated reticulocytes (MNRETs) as a function of age, and (2) the induction of micronuclei following treatment of young and old animals with mitomycin C. Male C57BL/6 mice, 92 weeks of age, exhibited a significantly higher frequency of spontaneously occurring peripheral blood MNRETs than mice that were 6 or 10 weeks of age. Mice that were 5-6 weeks or 91-92 weeks old were treated with one dose, or two consecutive doses of mitomycin C; this resulted in dose-related increases in the frequency of MNRETs. Mitomycin C, at a single dose of 1 or 2 mg/kg, induced one-third as many MNRETs in the older animals as compared to the younger animals. When treated with a split dose of mitomycin C (total dose 0.5 to 2 mg/kg), older animals displayed on average two-thirds the mutagenic response of the younger animals. However, analysis of variance performed on these data indicated that the age of the animals did not have a significant effect on their mutagenic response to mitomycin C at any dose level. It appears that aging mice may not be more sensitive to the mutagenic effects of chemically-induced DNA damage than younger mice, suggesting that the higher spontaneous mutation frequency in older mice could be the result of an increased load of accumulated DNA damage.

Aging↗

PubMed2002

Phenylalanine hydroxylase mutations and phenylalanine-tyrosine metabolism in heterozygotes for phenylalanine hydroxylase deficiency.

UNLABELLED: The aim of this study was to determine whether any relationship exists between the severity of mutation of the phenylalanine hydroxylase (PAH) gene and the plasma concentrations of phenylalanine (Phe) and tyrosine (Tyr) under fasting and semifasting conditions among heterozygotes in a matched case-control study. Parents of patients affected by PAH deficiency (n = 25) detected through the Italian Neonatal Screening Program and referred from January 1994 to June 2000, and parents of healthy children were investigated. In total, 68 subjects without any disease, 34 hyperphenylalaninaemia (HPA) heterozygous parents and 34 age- and gender-matched controls, were recruited. Plasma concentrations of Phe and Tyr in fasting and semifasting (1600 mg Phe oral load) conditions were the main outcome measures. DNA analysis for PAH mutations was performed in all 68 subjects. Compared with controls, heterozygotes showed higher fasting and semifasting Phe concentrations (p < 0.0001), lower semifasting Tyr concentrations (p = 0.015), lower Tyr variations (p = 0.003) and a higher Phe/Tyr ratio (p < 0.0001) in switching from fasting to semifasting conditions. Heterozygotes carrying a severe mutation showed semifasting plasma Tyr concentrations lower than controls (p = 0.019) but not significantly different from Tyr levels found in non-severe carriers (p = 0.197). The Tyr variations were minor in severe carriers than controls (p < 0.001) and non-severe carriers too, although with lower significance (p = 0.089). In six carriers of A403V mutation, parents of mild hyperphenylalaninaemics on an unrestricted diet, significant differences in variations from fasting to semifasting conditions were found compared with parents of patients on a diet. CONCLUSION: Although the great heterogeneity of PAH mutations limits any general conclusion, the results suggest that monitoring plasma Tyr variations may be more sensitive than plasma Phe in assessing the severity of PAH mutations in HPA heterozygotes.

Adult↗

PubMed2003

Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation.

Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone. The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. Evidence from transgenic mouse models indicates that hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from macrophages. The key role of hepcidin is confirmed by the presence of nonsense mutations in the hepcidin gene, homozygous in the affected members, in 2 families with severe juvenile hemochromatosis. Recent evidence shows that deficient hepcidin response to iron loading may contribute to iron overload even in the much milder common form of hemochromatosis, from mutations in the HFE gene. In anemia of inflammation, hepcidin production is increased up to 100-fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.

Anemia↗

PubMed2004

Prevention of gastrointestinal tumors based on adenomatous polyposis coli gene mutation by dendritic cell vaccine.

Here we describe the effect of immunization with dendritic cells loaded with syngeneic tumor cells (DC/Ts) by polyethylene glycol treatment, on tumor development in adenomatous polyposis coli (APC) gene mutant mouse models, APC1309 and APC(Min-/+), in which adenomatous polyps of the gastrointestinal tracts develop with a high incidence. Treatment with DC/Ts prevented the development of gastrointestinal tumors, and coadministration of DC/Ts and IL-12 caused a further reduction in tumor incidence. Splenocytes from APC1309 mice treated with DC/Ts and IL-12 showed no cytotoxic activity toward the tumor cells, but serum antibody specific to them was detected. IgG from the treated mice exhibited cytotoxic activity against the tumor cells in vitro. Predominance of Th2 cell response over Th1 response was also suggested by ELISPOT assays in the treated mice. Depletion in vivo of CD4(+) T cells, not CD8(+) T cells, by the intraperitoneal administration of corresponding mAb's decreased the antitumor effect of DC/T inoculation. Immunofluorescence microscopic studies showed that Ig was attached to tumor cells in mice treated with DC/Ts and IL-12. These findings indicate that DC/T vaccination prevents tumor development through APC gene mutation and that its preventive effects are mediated by humoral antitumor immunity.

Animals↗

PubMed1997

HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial. The National Virology Groups. Delta Virology Working Group and Coordinating Committee.

BACKGROUND: The Delta trial showed that combination therapy (zidovudine plus didanosine and zidovudine plus zalcitabine) substantially lengthened life and reduced disease progression compared with zidovudine monotherapy. We did a nested virological study in three countries (France, the Netherlands, and the UK) to investigate changes in markers for viral load and antiretroviral-drug resistance during therapy. METHODS: 240 zidovudine-naive HIV-1-infected patients were randomly assigned zidovudine only (n = 87), zidovudine plus didanosine (n = 80), or zidovudine plus zalcitabine (n = 73). Viral load in peripheral-blood mononuclear cells and plasma was measured by quantitative culture. Plasma HIV-1 RNA was measured by reverse-transcriptase PCR amplification, and serum p24 antigen by ELISA. Resistance to antiretroviral drugs was measured phenotypically by culture and genotypically by detection and quantification of drug-related point mutations in the pol gene. Analyses were done by intention to treat. FINDINGS: The reduction in viral load was greatest 4-12 weeks after the start of therapy and was most pronounced in the combination-therapy study groups (median reductions of RNA at 4 weeks 1.58, 1.28, and 0.49 log10 copies/mL for zidovudine plus didanosine, zidovudine plus zalcitabine, and zidovudine only, respectively). RNA levels at 8 weeks were predictive of disease progression and death after allowance for baseline values. At 48 weeks, the proportion of participants with phenotypic zidovudine resistance was similar in all three groups: didanosine and zalcitabine resistance were rare; zidovudine genomic resistance correlated with phenotypic resistance (r = 0.54, p < 0.0001) and developed earlier in the combined-therapy groups. However, participants in the zidovudine monotherapy group had higher circulating loads of resistant virus than those in the combined-therapy groups. INTERPRETATION: Combined antiretroviral therapy was more efficient at lowering virus load than monotherapy. Although zidovudine resistance was common in monotherapy and combined-therapy groups, circulating concentrations of resistant virus were substantially lower in the combination groups, which is likely to be a result of the continued antiviral activity of didanosine or zalcitabine.

Anti-HIV Agents↗