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BACKGROUND: Progression rates from initial HIV-1 infection to advanced AIDS vary significantly among infected individuals. A distinct subgroup of HIV-1-infected individuals-termed viremic non-progressors (VNP) or controllers-do not seem to progress to AIDS, maintaining high CD4+T cell counts despite high levels of viremia for many years. Several studies have evaluated multiple host factors, including immune activation, trying to elucidate the atypical HIV-1 disease progression in these patients; however, limited work has been done to characterize viral factors in viremic controllers. METHODS: We analyzed HIV-1 isolates from three VNP individuals and compared the replicative fitness, near full-length HIV-1 genomes and intra-patient HIV-1 genetic diversity with viruses from three typical (TP) and one rapid (RP) progressor individuals. RESULTS: Viremic non-progressors and typical patients were infected for >10 years (range 10-17 years), with a mean CD4+T-cell count of 472 cells/mm3(442-529) and 400 cells/mm3(126-789), respectively. VNP individuals had a less marked decline in CD4+cells (mean -0.56, range -0.4 to -0.7 CD4+/month) than TP patients (mean -10.3, -8.2 to -13.1 CD4+/month). Interestingly, VNP individuals carried viruses with impaired replicative fitness, compared to HIV-1 isolates from the TP and RP patients (p < 0.05, 95% CI). Although analyses of the near full-length HIV-1 genomes showed no clear patterns of single-nucleotide polymorphisms (SNP) that could explain the decrease in replicative fitness, both the number of SNPs and HIV-1 population diversity correlated inversely with the replication capacity of the viruses (r = -0.956 andr = -0.878,p < 0.01, respectively). CONCLUSION: It is likely that complex multifactorial parameters govern HIV-1 disease progression in each individual, starting with the infecting virus (phenotype, load, and quasispecies diversity) and the intrinsic ability of the host to respond to the infection. Here we analyzed a subset of viremic controller patients and demonstrated that similar to the phenomenon observed in patients with a discordant response to antiretroviral therapy (i.e., high CD4+cell counts with detectable plasma HIV-1 RNA load), reduced viral replicative fitness seems to be linked to slow disease progression in these antiretroviral-naïve individuals.
- MeSH
- dlouhodobě přežívající nosiči HIV * MeSH
- dospělí MeSH
- genetická variace MeSH
- genetická zdatnost * MeSH
- genom virový MeSH
- HIV infekce virologie MeSH
- HIV-1 klasifikace genetika izolace a purifikace fyziologie MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- replikace viru * MeSH
- sekvenční analýza DNA MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Complement is thought to play a role in immunoglobulin A nephropathy (IgAN), though the activating mechanisms are unknown. This study focused on the gene expression of CD46 and CD55, two key molecules for regulating C3 convertase activity of lectin and alternative complement pathways at a cellular level. METHODS: The transcriptional expression in peripheral white blood cells (WBCs) of CD46 and CD55 was investigated in 157 patients enrolled by the Validation of the Oxford Classification of IgAN group, looking for correlations with clinical and pathology features and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous median follow-up of 6.4 (interquartile range 2.8-10.7) years and were divided into progressors and non-progressors according to the median value of their velocity of loss of renal function per year (-0.41 mL/min/1.73 m2/year). RESULTS: CD46 and CD55 messenger RNA (mRNA) expression in WBCs was not correlated with eGFR values or proteinuria at sampling. CD46 mRNA was significantly correlated with eGFR decline rate as a continuous outcome variable (P = 0.014). A significant difference was found in CD46 gene expression between progressors and non-progressors (P = 0.013). CD46 and CD55 mRNA levels were significantly correlated (P < 0.01), although no difference between progressors and non-progressors was found for CD55 mRNA values. The prediction of progression was increased when CD46 and CD55 mRNA expressions were added to clinical data at renal biopsy (eGFR, proteinuria and mean arterial blood pressure) and Oxford MEST-C (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, presence of any crescents) score. CONCLUSIONS: Patients with progressive IgAN showed lower expression of mRNA encoding for the complement inhibitory protein CD46, which may implicate a defective regulation of C3 convertase with uncontrolled complement activation.
- MeSH
- antigeny CD46 krev genetika MeSH
- biologické markery krev MeSH
- dospělí MeSH
- IgA nefropatie krev diagnóza genetika MeSH
- inhibitory komplementu krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA krev genetika MeSH
- prognóza MeSH
- progrese nemoci MeSH
- regulace genové exprese MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
ADPKD is the most common hereditary renal disease. IGAN is a mesangial proliferative glomerulonephritis characterized by diffuse mesangial deposition of immunoglobulin A. ET-1 has been suggested to be a major disease-promoting factor in renal diseases. The vasoconstrictor effect of ET-1 is mediated by the ET-A receptor. We have investigated the influence of C/T polymorphism in exon 8 of the EDNRA gene. A total number of 193 patients (87 males, 106 females) with ADPKD entered into this study. Patients were divided into three groups: 1. 47 pts with ESRD later than in 63 years (slow progressors), 2. 49 pts with ESRD before 45 (rapid progressors) and 3. 97 pts with ESRD between 45–63 years. Moreover, we examined a group of 153 pts with histologically proven IGAN (116 males, 37 females). Pts were divided into two groups: 1. 79 pts with ERSD during 5 years of the study (IGAN rapid progressors) and 2. 74 patients with normal renal function (IGAN slow progressors). As a control group we used 100 genetically unrelated healthy subjects. The distribution of C/T polymorphism did not significantly differ between rapid and slow progressors of ADPKD and IGAN. The comparison of ESRD ages showed that CC females with ADPKD failed significantly later than CT heterozygotes: CC (57.4 ± 8.1 years), CT (53.0 ± 9.1 years) and TT (54.5 ± 6.4years) (t-test, P = 0.018). To conclude, the CC genotype could be protective in ADPKD females. This genotype was described to be associated with lower pulse pressure.
- MeSH
- finanční podpora výzkumu jako téma MeSH
- genotyp MeSH
- IgA nefropatie genetika MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- polycystické ledviny autozomálně dominantní genetika MeSH
- progrese nemoci MeSH
- receptor endotelinu A genetika MeSH
- senioři MeSH
- věkové rozložení MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
BACKGROUND: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. OBJECTIVE: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. METHODS: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm ( n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. RESULTS: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors' times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. CONCLUSION: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.
- MeSH
- časové faktory MeSH
- chronicko-progresivní roztroušená skleróza diagnóza patofyziologie MeSH
- chůze fyziologie MeSH
- dospělí MeSH
- horní končetina patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- postižení rehabilitace MeSH
- posuzování pracovní neschopnosti MeSH
- progrese nemoci MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND; A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD), the most common renal hereditary disease. Endothelin-1 (ET-1) has been suggested to be an important disease-promoting factor of the kidney. Endothelin-converting enzyme-1 (ECE-1) is the main protease responsible for ET-1 generation by cleavage of its functionally inactive precursor. We examined the influence of the ECE-1b C-338A polymorphism on the progression of ADPKD toward end-stage renal disease (ESRD). The A allele was suggested to be associated with higher plasma level of ET-1. METHODS: 200 ADPKD patients (107 males, 93 females) who had reached ESRD were analyzed. Patients were divided into three groups: (1) 47 patients (23 males, 24 females) with ESRD later than in 63 yr (slow progressors); (2) 71 patients (38 males, 33 females) with ESRD before 45 yr (rapid progressors); and (3) 82 patients (46 males, 36 females) with ESRD between 45-63 yr. Moreover, we analyzed 160 genetically unrelated healthy Czech subjects as the control group (82 males, 78 females, mean age 51.4 +/- 8.2 yr). DNA samples from collected blood were genotyped for ECE-1b C-338A polymorphism using described polymerase chain reaction (PCR) followed by restriction enzyme digestion. We compared the frequencies of different genotypes between the groups of slow and rapid progressors and the ages of ESRD with regard to different genotypes. RESULTS: The ECE-1b C-338A genotype distribution showed no differences among the groups of slow progressors, rapid progressors, ADPKD group with ESRD between 45-63 yr and control group. Comparing the ages of ESRD of all patients, we did not find significant differences in the ages with regard to different genotypes: CC (51.5 +/- 10.1 yr), AC (51.6 +/- 11.4 yr), AA (48.2 +/- 5.9 yr). There was a tendency to lower age of ESRD in AA homozygotes in comparison with other genotypes (t-test, p = 0.12). We found no influence of gender. CONCLUSION: We excluded the effect of ECE-1b C-338A polymorphism on the progression of ADPKD. We could observe a mild tendency toward faster decline of renal function in AA homozygous individuals.
- MeSH
- aspartátové endopeptidasy genetika MeSH
- chronické selhání ledvin etiologie MeSH
- financování organizované MeSH
- lidé středního věku MeSH
- lidé MeSH
- metaloendopeptidasy genetika MeSH
- polycystické ledviny autozomálně dominantní genetika komplikace MeSH
- polymorfismus genetický MeSH
- progrese nemoci MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Decrypting the B cell ontogeny of HIV-1 broadly neutralizing antibodies (bNAbs) is paramount for vaccine design. Here, we characterized IgA and IgG bNAbs of three distinct B cell lineages in a viremic controller, two of which comprised only IgG+ or IgA+ blood memory B cells; the third combined both IgG and IgA clonal variants. 7-269 bNAb in the IgA-only lineage displayed the highest neutralizing capacity despite limited somatic mutation, and delayed viral rebound in humanized mice. bNAbs in all three lineages targeted the N332 glycan supersite. The 2.8-Å resolution cryo-EM structure of 7-269-BG505 SOSIP.664 complex showed a similar pose as 2G12, on an epitope mainly composed of sugar residues comprising the N332 and N295 glycans. Binding and cryo-EM structural analyses showed that antibodies from the two other lineages interact mostly with glycans N332 and N386. Hence, multiple B cell lineages of IgG and IgA bNAbs focused on a unique HIV-1 site of vulnerability can codevelop in HIV-1 viremic controllers.
- MeSH
- epitopy MeSH
- genové produkty env - virus lidské imunodeficience MeSH
- HIV infekce * MeSH
- HIV protilátky MeSH
- HIV-1 * MeSH
- imunoglobulin A MeSH
- imunoglobulin G MeSH
- lidé MeSH
- myši MeSH
- neutralizující protilátky MeSH
- non-progresoři MeSH
- polysacharidy MeSH
- široce neutralizující protilátky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND/AIM: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. Endothelin-1 (ET-1) has been suggested to be a major promoting factor in renal diseases. The role of the ET-1 gene locus (EDN1) in the renal function in the general nondiabetic population was evaluated. We examined the influence of three single-nucleotide polymorphisms of the ET-1 gene (EDN1)--K198N, 3A/4A, and T-1370G--on the progression of ADPKD towards end-stage renal disease (ESRD). METHODS: Two hundred and five ADPKD patients (113 males and 92 females) who had reached ESRD were analyzed. The patients were divided into three groups: (1) 48 patients (23 males and 25 females) with ESRD later than 63 years of age (slow progressors), (2) 74 patients (41 males and 33 females) with ESRD before 45 years of age (rapid progressors), and (3) 83 patients (49 males and 34 females) with ESRD between 45 and 63 years old. DNA samples from collected blood were genotyped for three single-nucleotide polymorphisms of EDN1: K198N, 3A/4A, and T-1370G. Haplotype analysis was also done in 200 healthy individuals. We compared the frequencies of the different genotypes between the groups of slow and rapid progressors and the ages at the time of ESRD regarding the EDN1 genotypes. RESULTS: The EDN1 genotype distribution showed no differences among the groups of slow progressors, rapid progressors, the ADPKD group with ESRD between 45 and 63 years old, and the control group. Comparing the ages of ESRD of all patients, we did not find significant differences with regard to the different genotypes. Furthermore, we compared the combinations of the different haplotypes and the ages at the time of ESRD. We found no differences in ages at the time of ESRD in patients with different haplotypes in the endothelin promoter (T-1370G) in combination with 3A/4A or K198N polymorphisms. Comparing the ages at the time of ESRD in patients with different 3A/4A and K198N haplotypes, we found a significantly lower age at the time of ESRD (47.1 +/- 8.7 years) in the carriers of the 4A allele in combination with the 198N allele (4A/4A, 3A/4A + 198KN,NN) than in the carriers of the 4A allele homozygous for the K198 allele (52.9 +/- 10.9 years; 4A/4A, 3A/4A + 198KK; t test: p < 0.01) and in the carriers of the 198N allele homozygous for the 3A allele (53 +/- 11.2 years; 3A/3A + 198KN,NN; t test: p < 0.05). CONCLUSIONS: We excluded an effect of K198N, 3A/4A, and T-1370G polymorphisms of EDN1 on the progression of ADPKD. However, a deleterious effect of the combination of 4A and 198N alleles of EDN1 was observed in APKDK individuals. Copyright 2006 S. Karger AG, Basel.
- MeSH
- bodová mutace genetika MeSH
- chronické selhání ledvin genetika patofyziologie MeSH
- endotelin-1 genetika MeSH
- financování organizované MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- polycystické ledviny autozomálně dominantní genetika patofyziologie MeSH
- progrese nemoci MeSH
- rozdělení chí kvadrát MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
Systems of antigen delivery into antigen-presenting cells represent an important novel strategy in chicken vaccine development. In this study, we verified the ability of Rous sarcoma virus (RSV) antigens fused with streptavidin to be targeted by specific biotinylated monoclonal antibody (anti-CD205) into dendritic cells and induce virus-specific protective immunity. The method was tested in four congenic lines of chickens that are either resistant or susceptible to the progressive growth of RSV-induced tumors. Our analyses confirmed that the biot-anti-CD205-SA-FITC complex was internalized by chicken splenocytes. In the cytokine expression profile, several significant differences were evident between RSV-challenged progressor and regressor chicken lines. A significant up-regulation of IL-2, IL-12, IL-15, and IL-18 expression was detected in immunized chickens of both regressor and progressor groups. Of these cytokines, IL-2 and IL-12 were most up-regulated 14 days post-challenge (dpc), while IL-15 and IL-18 were most up-regulated at 28 dpc. On the contrary, IL-10 expression was significantly down-regulated in all immunized groups of progressor chickens at 14 dpc. We detected significant up-regulation of IL-17 in the group of immunized progressors. LITAF down-regulation with iNOS up-regulation was especially observed in the progressor group of immunized chickens that developed large tumors. Based on the increased expression of cytokines specific for activated dendritic cells, we conclude that our system is able to induce partial stimulation of specific cell types involved in cell-mediated immunity.
- MeSH
- antigeny virové imunologie MeSH
- buněčná imunita imunologie MeSH
- CD antigeny imunologie MeSH
- cytokiny fyziologie MeSH
- dendritické buňky imunologie virologie MeSH
- kur domácí imunologie virologie MeSH
- lektiny typu C imunologie MeSH
- protilátky bispecifické imunologie MeSH
- ptačí sarkom imunologie prevence a kontrola MeSH
- receptory buněčného povrchu imunologie MeSH
- vedlejší histokompatibilní antigeny imunologie MeSH
- virové vakcíny imunologie MeSH
- virus Rousova sarkomu imunologie MeSH
- zvířata kongenní imunologie virologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
