Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
J Acquir Immune Defic Syndr ; 79(2): 269-276, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211778

RESUMO

BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting antiretroviral therapy (ART) <6 months of age. METHODS: Total HIV-1 DNA was measured from 51 long-term suppressed children aged 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS: At ART initiation, children were aged median [IQR] 2.3 [1.2-4.1] months, CD4% 37 [24-45] %, CD8% 28 [18-36] %, log10 plasma viral load (VL) 5.4 [4.4-5.9] copies per milliliter. Time to viral suppression was 7.98 [4.6-19.3] months. After suppression, 13 (25%) children had suboptimal response [≥2 consecutive VL 50-400 followed by VL <50] and/or experienced periods of virological failure [≥2 consecutive VL ≥400 followed by VL <50]. Median total HIV-1 DNA was 43 [6195] copies/10 PBMC. Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, P = 0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, P = 0.0022) and the absence of viral failure/suboptimal response (AC 0.34 for those with fail/suboptimal response, P = 0.0483) were associated with lower total HIV-1 DNA. CONCLUSIONS: Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1-infected children minimize the size of viral reservoir.

2.
Front Immunol ; 9: 1033, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29881378

RESUMO

Estradiol-based therapies predispose women to vaginal infections. Moreover, it has long been known that neutrophils are absent from the vaginal lumen during the ovulatory phase (high estradiol). However, the mechanisms that regulate neutrophil influx to the vagina remain unknown. We investigated the neutrophil transepithelial migration (TEM) into the vaginal lumen. We revealed that estradiol reduces the CD44 and CD47 epithelial expression in the vaginal ectocervix and fornix, which retain neutrophils at the apical epithelium through the estradiol receptor-alpha. In contrast, luteal progesterone increases epithelial expression of CD44 and CD47 to promote neutrophil migration into the vaginal lumen and Candida albicans destruction. Distinctive to vaginal mucosa, neutrophil infiltration is contingent to sex hormones to prevent sperm from neutrophil attack; although it may compromise immunity during ovulation. Thus, sex hormones orchestrate tolerance and immunity in the vaginal lumen by regulating neutrophil TEM.

3.
BMC Med ; 16(1): 30, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29490663

RESUMO

BACKGROUND: Despite long-lasting HIV replication control, a significant proportion of elite controller (EC) patients may experience CD4 T-cell loss. Discovering perturbations in immunological parameters could help our understanding of the mechanisms that may be operating in those patients experiencing loss of immunological control. METHODS: A case-control study was performed to evaluate if alterations in different T-cell homeostatic parameters can predict CD4 T-cell loss in ECs by comparing data from EC patients showing significant CD4 decline (cases) and EC patients showing stable CD4 counts (controls). The partial least-squares-class modeling (PLS-CM) statistical methodology was employed to discriminate between the two groups of patients, and as a predictive model. RESULTS: Herein, we show that among T-cell homeostatic alterations, lower levels of naïve and recent thymic emigrant subsets of CD8 cells and higher levels of effector and senescent subsets of CD8 cells as well as higher levels of exhaustion of CD4 cells, measured prior to CD4 T-cell loss, predict the loss of immunological control. CONCLUSIONS: These data indicate that the parameters of T-cell homeostasis may identify those EC patients with a higher proclivity to CD4 T-cell loss. Our results may open new avenues for understanding the mechanisms underlying immunological progression despite HIV replication control, and eventually, for finding a functional cure through immune-based clinical trials.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Homeostase , Adulto , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Nat Microbiol ; 2(11): 1513-1522, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28871089

RESUMO

In this study, we report that the tetraspanin CD81 enhances human immunodeficiency virus (HIV)-1 reverse transcription in HIV-1-infected cells. This is enabled by the direct interaction of CD81 with the deoxynucleoside triphosphate phosphohydrolase SAMHD1. This interaction prevents endosomal accumulation and favours the proteasome-dependent degradation of SAMHD1. Consequently, CD81 depletion results in SAMHD1 increased expression, decreasing the availability of deoxynucleoside triphosphates (dNTP) and thus HIV-1 reverse transcription. Conversely, CD81 overexpression, but not the expression of a CD81 carboxy (C)-terminal deletion mutant, increases cellular dNTP content and HIV-1 reverse transcription. Our results demonstrate that the interaction of CD81 with SAMHD1 controls the metabolic rate of HIV-1 replication by tuning the availability of building blocks for reverse transcription, namely dNTPs. Together with its role in HIV-1 entry and budding into host cells, the data herein indicate that HIV-1 uses CD81 as a rheostat that controls different stages of the infection.


Assuntos
Didesoxinucleotídeos/metabolismo , HIV-1/genética , Transcrição Reversa , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Tetraspanina 28/metabolismo , Replicação do DNA , HIV-1/fisiologia , Células HeLa , Humanos , Macrófagos/virologia , Proteína 1 com Domínio SAM e Domínio HD/genética , Tetraspanina 28/genética , Replicação Viral
5.
Pediatr Infect Dis J ; 35(11): 1175-1181, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27753763

RESUMO

BACKGROUND: Children are at higher risk of tuberculosis (TB) dissemination and extrapulmonary disease, contributing greatly to TB-associated morbidity and long-term sequelae. However, there are very few studies that assess the impact and clinical spectrum of pediatric extrapulmonary TB (EPTB) in low-prevalence regions. METHODS: Children <18 years of age diagnosed with TB in Madrid region (2005-2013) were reviewed. We compared the epidemiology, clinical characteristics and the performance of diagnostic tests in childhood extrapulmonary and pulmonary disease. We performed a multivariate logistic regression to identify factors associated with EPTB. RESULTS: During the study period, 93 of 526 pediatric TB cases had EPTB (17.7%). The most common site was lymphatic TB (34.5%). The source case was not identified in most extrapulmonary cases, contrary to pulmonary TB (28% vs. 63.3%; P < 0.001). The tuberculin-skin-test induration was smaller in EPTB cases (<5 mm 22% vs. 5%; P < 0.001), but the sensitivity of interferon-gamma-release-assays was similar (76.9% vs. 79.4%). Children with EPTB presented higher rate of bacteriologic confirmation (66% vs. 49.4%; P < 0.01), and higher incidence of multidrug resistant TB (8.2% vs. 1.6%; P = 0.03). Complications were present in 40.2% extrapulmonary cases. EPTB was associated with the child's foreign origin [odds ratio (OR) 2.3 (1.1-5.3)], immune disorders [OR 5.8 (1.9-17.1)] and drug resistance [OR 2.4 (1.1-5.4)]. CONCLUSIONS: In our low-prevalence region, childhood EPTB was linked to immigrant status, immune disorders and drug resistance, and presented high rate of complications. Our study underscores the relevance of improved diagnostic tools and systematic TB screening in high risk populations.


Assuntos
Tuberculose/diagnóstico , Tuberculose/epidemiologia , Antituberculosos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Prevalência , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Tuberculose/fisiopatologia
6.
J Infect Dis ; 213(3): 476-84, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26238687

RESUMO

Estradiol-based contraceptives and hormonal replacement therapy predispose women to Candida albicans infections. Moreover, during the ovulatory phase (high estradiol), neutrophil numbers decrease in the vaginal lumen and increase during the luteal phase (high progesterone). Vaginal secretions contain chemokines that drive neutrophil migration into the lumen. However, their expression during the ovarian cycle or in response to hormonal treatments are controversial and their role in vaginal defense remains unknown.To investigate the transepithelial migration of neutrophils, we used adoptive transfer of Cxcr2(-/-) neutrophils and chemokine immunofluorescence quantitative analysis in response to C. albicans vaginal infection in the presence of hormones.Our data show that the Cxcl1/Cxcr2 axis drives neutrophil transepithelial migration into the vagina. Progesterone promotes the Cxcl1 gradient to favor neutrophil migration. Estradiol disrupts the Cxcl1 gradient and favors neutrophil arrest in the vaginal stroma; as a result, the vagina becomes more vulnerable to pathogens.


Assuntos
Quimiocinas/metabolismo , Estrogênios/farmacologia , Neutrófilos/imunologia , Neutrófilos/fisiologia , Progesterona/farmacologia , Vagina/citologia , Adulto , Animais , Candida albicans/imunologia , Candidíase/imunologia , Movimento Celular , Células Cultivadas , Quimiocinas/genética , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Camundongos , Camundongos Knockout , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Vagina/imunologia
7.
AIDS ; 30(4): 553-62, 2016 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-26558724

RESUMO

BACKGROUND: The causes of HIV-vaccines failure are poorly understood. Therapeutic vaccination with modified vaccinia Ankara (MVA)-B in HIV-1-infected individuals did not control the virus upon analytical treatment interruption (ATI). We investigated whether the functional characteristics of HIV-specific CD8 T-cell responses stimulated by this vaccine, and the level of exhaustion of these cells might explain these results. METHODS: Twenty-one HIV-1 chronically infected patients on combination antiretroviral therapy, included in the therapeutic vaccine trial RISVAC03, were studied: 13 immunized and eight controls. Functional characteristics, cytotoxic potential and exhaustion of HIV-specific CD8 T cells, were evaluated by polychromatic flow cytometry. Differences between groups were tested using nonparametric tests. RESULTS: MVA-B vaccine induced an increase in HIV-specific CD8 T-cell response, but also increased their levels of exhaustion. At week 18 (following three immunizations) the level of response increased with respect to baseline (P = 0.02). A significant increase at weeks 18 and 24 (ATI) in granzyme B content was also observed. Interestingly, an increase in expression of exhaustion markers was found at weeks 18 (P = 0.006) and 24 (P = 0.01). However, there was no significant change in the functional profile of vaccine-induced CD8 cells. At week 36, in parallel to the rebound of plasma viremia after 12 weeks ATI, a significant increase in the level of CD8 response, in granzyme B content and in exhaustion markers expression, was observed in both groups. CONCLUSION: We show that therapeutic vaccination with MVA-B tilts the balance between activation and regulation of the response of HIV-specific CD8 T cells towards regulation, which impacts on the viral rebound after ATI.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/terapia , HIV-1/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Adulto , Portadores de Fármacos , Feminino , Citometria de Fluxo , Vetores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vírus Vaccinia/genética
8.
J Acquir Immune Defic Syndr ; 68(4): 386-95, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25559603

RESUMO

BACKGROUND: CXCR3A-associated chemokines (CXCL9-11) are implicated in the pathogenesis of hepatitis C virus (HCV) infection. We analyzed the association between CXCL9-11 polymorphisms and significant liver fibrosis in human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: We performed a cross-sectional study in 220 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using GoldenGate assay. Three outcome variables related to liver fibrosis were studied: (1) F ≥ 2; (2) APRI ≥ 2; and (3) FIB-4 ≥ 3.25. RESULTS: The percentage of patients with significant liver fibrosis (F ≥ 2, APRI ≥ 2, and FIB-4 ≥ 3.25) was significantly higher for CXCL9 rs10336 TT (P = 0.046, P = 0.010, and P = 0.046, respectively), CXCL10 rs3921 GG (P = 0.046, P = 0.011, and P = 0.049, respectively), and CXCL11 rs4619915 AA (P = 0.035, P = 0.014, and P = 0.057, respectively) genotypes. Moreover, the greater likelihood of having significant liver fibrosis (F ≥ 2, APRI ≥ 2, and FIB-4 ≥ 3.25) was found in carriers of CXCL9 rs10336 TT and CXCL10 rs3921 GG [adjusted odds ratio (aOR) > 2 (P < 0.05)]. These trends were significantly more pronounced in patients infected with HCV-genotype 1 (GT1) [aOR > 3 (P < 0.05)]. Moreover, TGA haplotype showed higher odds for having values of APRI ≥ 2 (aOR = 2.4; P = 0.012) when we considered all patients. This elevated risk for significant liver fibrosis was better represented in patients infected with HCV-GT1, where TGA haplotype had increased odds for having values of F ≥ 2 (aOR = 1.9; P = 0.045), APRI ≥ 2 (aOR = 3.2; P = 0.009), and FIB-4 ≥ 3.25 (aOR = 3.3; P = 0.026). CONCLUSIONS: The homozygosity for the minor alleles CXCL9 rs10336 (T), CXCL10 rs3921 (G), and CXCL11 rs4619915 (A) is associated with the higher likelihood of significant liver fibrosis in HIV-infected patients coinfected with HCV-GT1.


Assuntos
Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Cirrose Hepática/epidemiologia , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Adulto , Coinfecção/complicações , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Técnicas de Genotipagem , Homozigoto , Humanos , Masculino
9.
Nanoscale ; 7(9): 3857-66, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25254497

RESUMO

Tumor microenvironment favors the escape from immunosurveillance by promoting immunosuppression and blunting pro-inflammatory responses. Since most tumor-associated macrophages (TAM) exhibit an M2-like tumor cell growth promoting polarization, we have studied the role of 2G-03NN24 carbosilane dendrimer in M2 macrophage polarization to evaluate the potential application of dendrimers in tumor immunotherapy. We found that the 2G-03NN24 dendrimer decreases LPS-induced IL-10 production from in vitro generated monocyte-derived M2 macrophages, and also switches their gene expression profile towards the acquisition of M1 polarization markers (INHBA, SERPINE1, FLT1, EGLN3 and ALDH1A2) and the loss of M2 polarization-associated markers (EMR1, IGF1, FOLR2 and SLC40A1). Furthermore, 2G-03NN24 dendrimer decreases STAT3 activation. Our results indicate that the 2G-03NN24 dendrimer can be a useful tool for antitumor therapy by virtue of its potential ability to limit the M2-like polarization of TAM.


Assuntos
Dendrímeros/química , Compostos de Organossilício/química , Silanos/química , Biomarcadores/metabolismo , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dendrímeros/farmacologia , Humanos , Imunoterapia , Interleucina-10/metabolismo , Células K562 , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/citologia , Neoplasias/imunologia , Neoplasias/terapia , Compostos de Organossilício/farmacologia , Fagocitose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo
10.
J Acquir Immune Defic Syndr ; 66(3): 265-9, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24732875

RESUMO

We assessed high-density lipoprotein (HDL) anti-inflammatory properties in a cohort of vertically HIV-infected adolescents. We hypothesized that proatherogenic mechanisms related to inflammation and immune activation during HIV infection may impair HDL functionality and impact on the atherosclerotic burden. Compared with healthy controls, HDL from HIV-infected adolescents presented impaired functionality, as determined by its ability to inhibit monocyte chemotaxis in vitro, which correlated with detectable viral loads (P = 0.044), lower CD4 nadir (P = 0.043), increased levels of CD4 T-cell activation (P = 0.018), higher C-reactive protein (P = 0.009), and a tendency toward thicker carotid intima-media thickness (P = 0.071).


Assuntos
Doenças Cardiovasculares/etiologia , Infecções por HIV/complicações , Lipoproteínas HDL/fisiologia , Ativação Linfocitária , Linfócitos T/imunologia , Adolescente , Proteína C-Reativa/metabolismo , Contagem de Linfócito CD4 , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/fisiopatologia , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Quimiotaxia/fisiologia , Feminino , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , Humanos , Masculino , Monócitos/fisiologia , Carga Viral
11.
Bioinformation ; 9(13): 673-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23930018

RESUMO

The pandemic influenza AH1N1 (2009) caused an outbreak of human infection that spread to the world. Neuraminidase (NA) is an antigenic surface glycoprotein, which is essential to the influenza infection process, and is the target of anti-flu drugs oseltamivir and zanamivir. Currently, NA inhibitors are the pillar pharmacological strategy against seasonal and global influenza. Although mutations observed after NA-inhibitor treatment are characterized by changes in conserved amino acids of the enzyme catalytic site, it is possible that specific amino acid substitutions (AASs) distant from the active site such as H274Y, could confer oseltamivir or zanamivir resistance. To better understand the molecular distribution pattern of NA AASs, we analyzed NA AASs from all available reported pandemic AH1N1 NA sequences, including those reported from America, Africa, Asia, Europe, Oceania, and specifically from Mexico. The molecular distributions of the AASs were obtained at the secondary structure domain level for both the active and catalytic sites, and compared between geographic regions. Our results showed that NA AASs from America, Asia, Europe, Oceania and Mexico followed similar molecular distribution patterns. The compiled data of this study showed that highly conserved amino acids from the NA active site and catalytic site are indeed being affected by mutations. The reported NA AASs follow a similar molecular distribution pattern worldwide. Although most AASs are distributed distantly from the active site, this study shows the emergence of mutations affecting the previously conserved active and catalytic site. A significant number of unique AASs were reported simultaneously on different continents.

12.
J Biol Chem ; 288(39): 28382-97, 2013 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-23926103

RESUMO

HIV-1 contact with target cells triggers F-actin rearrangements that are essential for several steps of the viral cycle. Successful HIV entry into CD4(+) T cells requires actin reorganization induced by the interaction of the cellular receptor/co-receptor complex CD4/CXCR4 with the viral envelope complex gp120/gp41 (Env). In this report, we analyze the role of the actin modulator drebrin in HIV-1 viral infection and cell to cell fusion. We show that drebrin associates with CXCR4 before and during HIV infection. Drebrin is actively recruited toward cell-virus and Env-driven cell to cell contacts. After viral internalization, drebrin clustering is retained in a fraction of the internalized particles. Through a combination of RNAi-based inhibition of endogenous drebrin and GFP-tagged expression of wild-type and mutant forms, we establish drebrin as a negative regulator of HIV entry and HIV-mediated cell fusion. Down-regulation of drebrin expression promotes HIV-1 entry, decreases F-actin polymerization, and enhances profilin local accumulation in response to HIV-1. These data underscore the negative role of drebrin in HIV infection by modulating viral entry, mainly through the control of actin cytoskeleton polymerization in response to HIV-1.


Assuntos
Actinas/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Neuropeptídeos/metabolismo , Actinas/química , Antígenos CD4/metabolismo , Citoesqueleto/metabolismo , Humanos , Células Jurkat , Microscopia Confocal , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Receptores CXCR4/metabolismo , Internalização do Vírus
13.
J Infect Dis ; 207(8): 1221-5, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23322858

RESUMO

Levels of soluble CD14 (sCD14) were longitudinally measured in 85 human immunodeficiency virus (HIV)-infected subjects during long-term receipt of suppressive combined antiretroviral therapy (cART) and compared to those in young and elderly HIV-negative control subjects. cART did not normalize sCD14 levels; rather, the HIV-infected group displayed a significantly higher sCD14 level at baseline (ie, before cART initiation), 1 year after cART initiation, and 5 years after cART initiation, compared with both control groups. Furthermore, the baseline CD4(+) T-cell count was inversely associated with the baseline sCD14 level. Our results point to the necessity of complementary therapies to treat the activated/inflamed status associated with chronic HIV infection and to the benefits of early initiation of cART.


Assuntos
Antirretrovirais/uso terapêutico , Cicloexanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Receptores de Lipopolissacarídeos/sangue , Triazóis/uso terapêutico , Adulto , Idoso , Antirretrovirais/farmacologia , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Cicloexanos/farmacologia , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , HIV-1/patogenicidade , Humanos , Estudos Longitudinais , Masculino , Maraviroc , Pessoa de Meia-Idade , RNA Viral/sangue , Solubilidade , Fatores de Tempo , Resultado do Tratamento , Triazóis/farmacologia , Carga Viral
14.
AIDS ; 26(15): 1885-94, 2012 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-22992577

RESUMO

OBJECTIVES: The stability of the reservoir of latently infected memory CD4 T-cells may be associated with continuous replenishment from residual HIV-1, not completely eliminated by otherwise successful antiretroviral therapy (ART). Treatment intensification could help to control residual virus and to modify the latent reservoir. The objective of this work is to assess the effect of intensifying therapy with raltegravir on the HIV-1 cell reservoir. DESIGN: A pilot open-label phase-II clinical trial was performed to analyze ART intensification with raltegravir after 48 weeks in chronically HIV-1-infected patients on stable ART. METHODS: We measured the number of latently infected memory CD4 T cells, residual viremia, 2-long terminal repeat circles, CD4/CD8 T-cell activation, lymphocyte subpopulations, gut homing receptor, and bacterial translocation. RESULTS: A significant decay of HIV-1 latent reservoir was observed after intensification in the nine patients included (P = 0.021). No variation was found in either residual viremia or 2-long terminal repeat circles, whereas CD8 T-cell activation decreased at week 36 (P = 0.028). No differences were found in naive T-cell or effector memory cell counts, and the frequencies of gut homing receptor on activated or effector memory CD8 T cells. Bacterial translocation was stable, with the exception of a late decrease in lipopolysaccharide levels. CONCLUSIONS: In this pilot noncomparative trial, treatment intensification with raltegravir significantly decreased the latent cellular HIV-1 reservoir and CD8 T-cell activation. Despite the limitations inherent to trial design, our results suggest that ART intensification should be considered as an adjuvant strategy to eradicate HIV-1 infection.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , HIV-1/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Pirrolidinonas/administração & dosagem , Latência Viral/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida/imunologia , Síndrome de Imunodeficiência Adquirida/fisiopatologia , Adulto , Fármacos Anti-HIV/farmacologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Esquema de Medicação , Feminino , HIV-1/fisiologia , Humanos , Hospedeiro Imunocomprometido , Memória Imunológica , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Pirrolidinonas/farmacologia , RNA Viral/efeitos dos fármacos , Raltegravir Potássico , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/virologia
15.
Pharmacogenomics ; 11(12): 1715-23, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21142915

RESUMO

AIM: To find out whether SNPs in the transporter gene ATP-binding casette B1 (ABCB1) were related to adverse effects in colorectal cancer patients treated with 5-fluorouracil (5-FU) or capecitabine. MATERIALS & METHODS: Patients treated with a 5-FU-based therapy (n = 67) or a capecitabine-based therapy (n = 74) were recruited and genotyped for the ABCB1 SNPs rs1128503 (C1236T), rs2032592 (G2677T/A) and rs1045642 (C3435T). Clinical data and adverse reactions were recorded. ABCB1 genotypes of patients were statistically analyzed for association with the most frequent adverse reactions. RESULTS: Statistical associations were observed, suggesting a lower risk of neutropenia (p = 0.013) and hand-foot syndrome (HFS; p = 0.027) for the carriers of T variation for rs1128503 in capecitabine-treated patients, carriers of T variation for rs1045642 treated with capecitabine had a lower risk of HFS (p = 0.033), while those treated with 5-FU had a higher risk of diarrhea (p = 0.035), and carriers of T variation for rs2032592 treated with capecitabine were at less risk of developing HFS (p = 0.033). CONCLUSION: This is the first time evidence has been found of differing pharmacogenetic markers for capecitabine and 5-FU treatments. Genotyping of SNPs in the ABCB1 gene prior to chemotherapy administration could help reduce adverse reactions in colorectal cancer patients.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP , Idoso , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Capecitabina , Neoplasias Colorretais/genética , DNA/sangue , DNA/genética , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos
16.
Biomaterials ; 31(33): 8749-58, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20832111

RESUMO

Dendritic cells (DCs) play a major role in development of cell-mediated immunotherapy due to their unique role in linking innate and adaptive immunities. In spite of improvement in this area, strategies employing ex vivo generated DCs have shown limited efficacy in clinical trials. Dendrimers have been proposed as new carriers for drug delivery in aim to ameliorate DCs antigen loading that is a pivotal point in DCs approaches. In this study, we have investigated the phenotypic and functional characteristics of human monocytes-derived dendritic cells after HIV-derived peptides uptake in vitro. We have found that iDCs and mDCs were able to capture efficiently water soluble carbosilane (CBS) dendrimer 2 G-NN16 and did not induce changes in maturation markers levels at the DCs surface. Therefore, CBS 2 G-NN16-loaded mDCs migrated as efficiently as unloaded DCs towards CCL19 or CCL21. Furthermore, DCs viability, activation of allogenic naïve CD4 + T cells by mDCs and secretion of cytokines were not significantly changed by 2 G-NN16 loading. Summing up, our data indicate that CBS 2 G-NN16 has no negative effects on the pivotal properties of DCs in vitro. It should therefore be feasible to further develop this antigen loading strategy for clinical use in immunotherapy against viral infections.


Assuntos
Dendrímeros/farmacologia , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Monócitos/citologia , Silanos/farmacologia , Biomarcadores/metabolismo , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Dendrímeros/toxicidade , Humanos , Ativação Linfocitária/efeitos dos fármacos , Peptídeos/metabolismo , Fenótipo , Silanos/toxicidade
17.
BMC Infect Dis ; 10: 244, 2010 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-20723207

RESUMO

BACKGROUND: Hyaluronic acid (HA) serum levels correlate with the histological stages of liver fibrosis in hepatitis C virus (HCV) monoinfected patients, and HA alone has shown very good diagnostic accuracy as a non-invasive assessment of fibrosis and cirrhosis. The aim of this study was to evaluate serum HA levels as a simple non-invasive diagnostic test to predict hepatic fibrosis in HIV/HCV-coinfected patients and to compare its diagnostic performance with other previously published simple non-invasive indexes consisting of routine parameters (HGM-1, HGM-2, Forns, APRI, and FIB-4). METHODS: We carried out a cross-sectional study on 201 patients who all underwent liver biopsies and had not previously received interferon therapy. Liver fibrosis was determined via METAVIR score. The diagnostic accuracy of HA was assessed by area under the receiver operating characteristic curves (AUROCs). RESULTS: The distribution of liver fibrosis in our cohort was 58.2% with significant fibrosis (F≥2), 31.8% with advanced fibrosis (F≥3), and 11.4% with cirrhosis (F4). Values for the AUROC of HA levels corresponding to significant fibrosis (F≥2), advanced fibrosis (F≥3) and cirrhosis (F4) were 0.676, 0.772, and 0.863, respectively. The AUROC values for HA were similar to those for HGM-1, HGM-2, FIB-4, APRI, and Forns indexes. The best diagnostic accuracy of HA was found for the diagnosis of cirrhosis (F4): the value of HA at the low cut-off (1182 ng/mL) excluded cirrhosis (F4) with a negative predictive value of 99% and at the high cut-off (2400 ng/mL) confirmed cirrhosis (F4) with a positive predictive value of 55%. By utilizing these low and high cut-off points for cirrhosis, biopsies could have theoretically been avoided in 52.2% (111/201) of the patients. CONCLUSIONS: The diagnostic accuracy of serum HA levels increases gradually with the hepatic fibrosis stage. However, HA is better than other simple non-invasive indexes using parameters easily available in routine clinical practice only for the diagnosing of cirrhosis.


Assuntos
Infecções por HIV/complicações , Hepatite C Crônica/complicações , Ácido Hialurônico/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Adulto , Biomarcadores/sangue , Biópsia , Estudos Transversais , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/patologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/patologia , Humanos , Fígado/patologia , Masculino , Valor Preditivo dos Testes , Soro/química , Índice de Gravidade de Doença
18.
An Pediatr (Barc) ; 67(2): 104-8, 2007 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-17692254

RESUMO

INTRODUCTION: The development of resistance to antiretroviral therapy (ART) reduces the effectiveness of these drugs in HIV-infected children. METHODS: We performed a cross-sectional study in 86 vertically HIV-infected children, divided into four groups according to prior treatment: group 1: nucleoside reverse transcriptase inhibitor (NRTI), group 2: NRTI and non-nucleoside reverse transcriptase inhibitor (NNRTI), group 3: NRTI and protease inhibitor (PI), group 4: NRTI, NNRTI and PI. RESULTS: In group 1 (11 children), the median treatment duration was 35 months (26 to 108). Nucleoside-associated mutations (NAMs) were found in 10 of these patients and the Q151M multiresistance mutation was found in two. The three children in group 2 were treated for 9, 32 and 42 months with NRTI and NNRTI. One child showed three NAMs and another showed Q151M. Two children had the K103N mutation. Group 3 (36 children) received treatment with NRTI and PI for 48.0 +/- 27.6 and 23.0 +/- 14.6 months, respectively. NAMs were observed in 94 % of the patients in this group, and one child showed the Q151M mutation. In group 4 (36 children) total treatment duration was 70.0 +/- 36.1 months (13.0 +/- 12.1 months with NNRTI, and 39.0 +/- 14.3 months with PI). NAMs were observed in all patients in this group, and Q151M was found in three children. K103N and Y181C were detected in 24 (67%) and 10 (28%) of the children respectively, while 32 (90%) showed primary mutations to PI. CONCLUSIONS: A high prevalence of resistance mutations to NRTI and early appearance of resistance to NNRTI were observed in treated children.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Antirretrovirais/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/transmissão , Fatores Etários , Antirretrovirais/administração & dosagem , Criança , Estudos Transversais , Interpretação Estatística de Dados , Farmacorresistência Viral Múltipla/genética , Farmacorresistência Viral/genética , Infecções por HIV/transmissão , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/uso terapêutico , Humanos , Transmissão Vertical de Doença Infecciosa , Mutação , Prevalência , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Espanha , Fatores de Tempo
19.
BMC Infect Dis ; 6: 112, 2006 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-16839416

RESUMO

BACKGROUND: Recent advances in characterizing the immune recovery of HIV-1-infected people have highlighted the importance of the thymus for peripheral T-cell diversity and function. The aim of this study was to investigate differences in immune reconstitution profiles after highly active antiretroviral therapy (HAART) between HIV-children and adults. METHODS: HIV patients were grouped according to their previous clinical and immunological status: 9 HIV-Reconstituting-adults (HIV-Rec-adults) and 10 HIV-Reconstituting-children (HIV-Rec-children) on HAART with viral load (VL) or=500 cells/microL at least during 6 months before the study and CD4+

Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Adolescente , Adulto , Biomarcadores/análise , Criança , Estudos Transversais , HIV/efeitos dos fármacos , Infecções por HIV/virologia , Humanos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Timo/imunologia , Carga Viral
20.
BMC Infect Dis ; 6: 10, 2006 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-16433913

RESUMO

BACKGROUND: The effects of HAART may differ between children and adults because children have a developing immune system, and the long-term immunological outcome in HIV-infected children on HAART is not well-known. A major aim of our study was to determine CD4+ evolution associated with long-term VL control during 4 years of observation on HAART. METHODS: We carried out a retrospective study on a cohort of 160 vertically HIV-infected children. It was carried out from 1996 to 2004 in six large Spanish pediatric referral hospitals. We compared 33 children who had long-term VL suppression (VL < or = 400 copies/ml) in the first 12 months of follow-up and maintained that level throughout follow-up (Responders-group), and 127 children with persistently detectable VL in spite of ART switches (Non-Responders-group). RESULTS: We observed a quick initial and significant increase in CD4+ counts from the baseline to 12 months on HAART in both groups (p < 0.01). The Non-Responders group sustained CD4+ increases and most of these children maintained high CD4+ level counts (> or = 25%). The Non-Responders group reached a plateau between 26% and 27% CD4+ at the first 12 months of follow-up that remained stable during the following 3 years. However, the Responders group reached a plateau between 30% and 32% CD4+ at 24, 36 and 48 months of follow-up. We found that the Responders group had higher CD4+ count values and higher percentages of children with CD4+ > or = 25% than the Non-Responders group (p < 0.05) after month 12. CONCLUSION: Long-term VL suppression in turn induces large beneficial effects in immunological responses. However, it is not indispensable to recover CD4+ levels.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Adolescente , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Infecções por HIV/imunologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Carga Viral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA