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1.
J Infect Dis ; 219(3): 429-436, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30165648

RESUMO

Background: Chronic inflammation is associated with AIDS-defining and non-AIDS-defining conditions. Limited research has considered how food insecurity influences chronic inflammation among people living with human immunodeficiency virus (HIV). We examined whether food insecurity was associated with higher levels of inflammation among women living with HIV (WWH) in the United States. Methods: We analyzed cross-sectional data collected in 2015 from 421 participants on antiretroviral therapy from the Women's Interagency HIV Study. The exposure was any food insecurity. The outcome was inflammation, measured by proinflammatory cytokine interleukin-6 (IL-6) and tumor necroses factor receptor 1 (TNFR1) levels. We conducted multivariable linear regressions, adjusting for sociodemographic, clinical, and nutritional factors. Results: Nearly one-third of participants (31%) were food insecure and 79% were virally suppressed (<20 copies/mL). In adjusted analyses, food insecurity was associated with 1.23 times the level of IL-6 (95% confidence interval [CI], 1.06-1.44) and 1.13 times the level of TNFR1 (95% CI, 1.05-1.21). Findings did not differ by HIV control (virally suppressed with CD4 counts ≥500 cells/mm3 or not) in adjusted stratified analyses. Conclusion: Food insecurity was associated with elevated inflammation among WWH regardless of HIV control. Findings support the need for programs that address food insecurity among WWH.


Assuntos
Abastecimento de Alimentos/estatística & dados numéricos , Infecções por HIV/epidemiologia , Inflamação/epidemiologia , Adulto , Índice de Massa Corporal , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Inflamação/imunologia , Interleucina-6/imunologia , Modelos Lineares , Pessoa de Meia-Idade , Análise Multivariada , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Estados Unidos/epidemiologia
2.
PLoS Pathog ; 12(4): e1005580, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27093273

RESUMO

People with HIV infection are at increased risk for community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections (SSTIs). Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified. We aimed to determine the immunologic perturbations that predispose HIV-infected people to MRSA SSTIs. Participants with or without HIV infection and with MRSA SSTI, MRSA colonization or negative for MRSA were enrolled. Peripheral blood and skin biopsies from study participants were collected. Flow cytometry, flow cytometry with microscopy, multiplex assays of cell culture supernatants and immunohistochemistry were used to evaluate the nature of the immune defect predisposing HIV-infected people to MRSA infections. We found deficient MRSA-specific IFNγ+ CD4 T-cell responses in HIV-infected people with MRSA SSTIs compared to MRSA-colonized participants and HIV-uninfected participants with MRSA SSTIs. These IFNγ+ CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs. However, IFNγ responses to cytomegalovirus and Mycobacterium avium antigens and MRSA-specific IL-17 responses by CD4 T cells were intact. Upon stimulation with MRSA, peripheral blood mononuclear cells from HIV-infected participants produced less IL-12 and IL-15, key drivers of IFNγ production. There were no defects in CD8 T-cell responses, monocyte responses, opsonization, or phagocytosis of Staphylococcus aureus. Accumulation of CD3 T cells, CD4 T cells, IL-17+ cells, myeloperoxidase+ neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry. Together, these results indicate that MRSA-specific IFNγ+ CD4 T-cell responses are essential for the control of initial and recurrent MRSA infections in HIV-infected people.


Assuntos
Coinfecção/imunologia , Infecções por HIV/imunologia , Hospedeiro Imunocomprometido/imunologia , Infecções Estafilocócicas/imunologia , Células Th1/imunologia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Staphylococcus aureus Resistente à Meticilina , Estudos Prospectivos
4.
Gastroenterology ; 144(1): 112-121.e2, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23041322

RESUMO

BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS: Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS: Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient's height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS: Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224.


Assuntos
Hipertensão Portal/fisiopatologia , Cirrose Hepática/congênito , Cirrose Hepática/patologia , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Colangiopancreatografia por Ressonância Magnética , Endoscopia Gastrointestinal , Varizes Esofágicas e Gástricas/etiologia , Feminino , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/complicações , Lactente , Transplante de Rim , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/genética , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Mutação , Tamanho do Órgão , Contagem de Plaquetas , Rim Policístico Autossômico Recessivo/complicações , Pressão na Veia Porta , Tempo de Protrombina , Albumina Sérica , Índice de Gravidade de Doença , Esplenomegalia/diagnóstico por imagem , Ultrassonografia Doppler em Cores , Adulto Jovem , gama-Glutamiltransferase/sangue
5.
PLoS Pathog ; 8(11): e1003014, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23144619

RESUMO

Progressive multifocal leukoencephalopathy (PML) induced by JC virus (JCV) is a risk for natalizumab-treated multiple sclerosis (MS) patients. Here we characterize the JCV-specific T cell responses in healthy donors and natalizumab-treated MS patients to reveal functional differences that may account for the development of natalizumab-associated PML. CD4 and CD8 T cell responses specific for all JCV proteins were readily identified in MS patients and healthy volunteers. The magnitude and quality of responses to JCV and cytomegalovirus (CMV) did not change from baseline through several months of natalizumab therapy. However, the frequency of T cells producing IL-10 upon mitogenic stimulation transiently increased after the first dose. In addition, MS patients with natalizumab-associated PML were distinguished from all other subjects in that they either had no detectable JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production. Additionally, IL-10 levels were higher in the CSF of individuals with recently diagnosed PML. Thus, natalizumab-treated MS patients with PML have absent or aberrant JCV-specific T cell responses compared with non-PML patients, and changes in T cell-mediated control of JCV replication may be a risk factor for developing PML. Our data suggest further approaches to improved monitoring, treatment and prevention of PML in natalizumab-treated patients.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Celular/efeitos dos fármacos , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Esclerose Múltipla/imunologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Feminino , Humanos , Interleucina-10/imunologia , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Natalizumab , Fatores de Risco
6.
Gastroenterology ; 141(4): 1220-30, 1230.e1-3, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21726511

RESUMO

BACKGROUND & AIMS: Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes. METHODS: In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment. RESULTS: Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively). CONCLUSIONS: LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection.


Assuntos
Translocação Bacteriana , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Interações Hospedeiro-Patógeno , Intestinos/virologia , Cirrose Hepática/virologia , Monócitos/virologia , Biomarcadores/sangue , Biópsia , Morte Celular , Progressão da Doença , Doença Hepática Terminal/microbiologia , Doença Hepática Terminal/virologia , Enterócitos/microbiologia , Enterócitos/patologia , Enterócitos/virologia , Ensaio de Imunoadsorção Enzimática , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/microbiologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/imunologia , Hepatite C Crônica/microbiologia , Humanos , Hipertensão Portal/microbiologia , Hipertensão Portal/virologia , Interleucina-6/sangue , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Células de Kupffer/microbiologia , Células de Kupffer/virologia , Teste do Limulus , Receptores de Lipopolissacarídeos/sangue , Lipopolissacarídeos/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/imunologia , Cirrose Hepática/microbiologia , Modelos Logísticos , Masculino , Maryland , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/microbiologia , Razão de Chances , Estudos Retrospectivos , Índice de Gravidade de Doença
7.
J Infect Dis ; 203(6): 780-90, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21252259

RESUMO

BACKGROUND: Chronic human immunodeficiency virus (HIV) infection is associated with intestinal permeability and microbial translocation that contributes to systemic immune activation, which is an independent predictor of HIV disease progression. The association of microbial translocation with clinical outcome remains unknown. METHODS: This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples. RESULTS: Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2-16.1; P<.001), with minimal change after adjustment for inflammatory markers, CD4(+) T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D-dimer. CONCLUSIONS: sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.


Assuntos
Infecções por HIV/sangue , Infecções por HIV/mortalidade , Receptores de Lipopolissacarídeos/sangue , Adulto , Biomarcadores/sangue , Linfócitos T CD4-Positivos , Estudos de Casos e Controles , Causas de Morte , Proteínas de Ligação a Ácido Graxo/sangue , Humanos , Lipopolissacarídeos/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , RNA Viral , Adulto Jovem
8.
Vaccine ; 31(49): 5879-88, 2013 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-24099872

RESUMO

Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques.


Assuntos
Salmonelose Animal/prevenção & controle , Vacinas contra Salmonella/imunologia , Salmonella typhimurium/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/microbiologia , Animais , Derrame de Bactérias , Coinfecção , Modelos Animais de Doenças , Fezes/microbiologia , Doenças Transmitidas por Alimentos/microbiologia , Doenças Transmitidas por Alimentos/prevenção & controle , Imunidade Humoral , Hospedeiro Imunocomprometido , Mucosa Intestinal/patologia , Receptores de Lipopolissacarídeos/sangue , Lipopolissacarídeos/sangue , Macaca mulatta , Salmonelose Animal/complicações , Salmonelose Animal/imunologia , Vacinas Atenuadas/imunologia
9.
PLoS One ; 6(7): e21692, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21779334

RESUMO

Much of what is known regarding Riftia pachyptila physiology is based on the wealth of studies of tubeworms living at diffuse flows along the fast-spreading, basalt-hosted East Pacific Rise (EPR). These studies have collectively suggested that Riftia pachyptila and its chemoautotrophic symbionts are physiologically specialized, highly productive associations relying on hydrogen sulfide and oxygen to generate energy for carbon fixation, and the symbiont's nitrate reduction to ammonia for energy and biosynthesis. However, Riftia also flourish in sediment-hosted vents, which are markedly different in geochemistry than basalt-hosted systems. Here we present data from shipboard physiological studies and global quantitative proteomic analyses of Riftia pachyptila trophosome tissue recovered from tubeworms residing in the EPR and the Guaymas basin, a sedimented, hydrothermal vent field. We observed marked differences in symbiont nitrogen metabolism in both the respirometric and proteomic data. The proteomic data further suggest that Riftia associations in Guaymas may utilize different sulfur compounds for energy generation, may have an increased capacity for energy storage, and may play a role in degrading exogenous organic carbon. Together these data reveal that Riftia symbionts are far more physiologically plastic than previously considered, and that--contrary to previous assertions--Riftia do assimilate reduced nitrogen in some habitats. These observations raise new hypotheses regarding adaptations to the geochemical diversity of habitats occupied by Riftia, and the degree to which the environment influences symbiont physiology and evolution.


Assuntos
Poliquetos/metabolismo , Silicatos , Animais , Crescimento Quimioautotrófico , Nitrogênio/metabolismo , Poliquetos/fisiologia , Compostos de Enxofre/metabolismo , Simbiose
10.
J Clin Invest ; 121(6): 2391-400, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21555857

RESUMO

High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4⁺ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1-induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4⁺ and CD8⁺ T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4⁺ T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Cercocebus atys/genética , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica , Infecções por HIV/genética , Sobreviventes de Longo Prazo ao HIV , HIV-1 , Macaca mulatta/genética , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Vírus da Imunodeficiência Símia , Animais , Cercocebus atys/metabolismo , Progressão da Doença , Suscetibilidade a Doenças , Infecções por HIV/metabolismo , HIV-1/fisiologia , Humanos , Macaca mulatta/metabolismo , Fenótipo , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Vírus da Imunodeficiência Símia/fisiologia , Especificidade da Espécie , Regulação para Cima , Carga Viral , Viremia/genética , Viremia/metabolismo , Replicação Viral
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