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1.
J Clin Invest ; 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31990684

RESUMO

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of thirty-five untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in systemic sclerosis patients. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction..

2.
BMC Med Res Methodol ; 19(1): 216, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775643

RESUMO

BACKGROUND: Antiretroviral therapy (ART) has significantly reduced HIV-related morbidity and mortality. However, therapeutic benefit of ART is often limited by delayed drug-associated toxicity. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of ART regimens. NRTIs compete with endogenous deoxyribonucleotide triphosphates (dNTPs) in incorporation into elongating DNA chain resulting in their cytotoxic or antiviral effect. Thus, the efficacy of NRTIs could be affected by direct competition with endogenous dNTPs and/or feedback inhibition of their metabolic enzymes. In this paper, we assessed whether the levels of ribonucleotides (RN) and dNTP pool sizes can be used as biomarkers in distinguishing between HIV-infected patients with ART-induced mitochondrial toxicity and HIV-infected patients without toxicity. METHODS: We used data collected through a case-control study from 50 subjects. Cases were defined as HIV-infected individuals with clinical and/or laboratory evidence of mitochondrial toxicity. Each case was age, gender, and race matched with an HIV-positive without evidence of toxicity. We used a range of machine learning procedures to distinguish between patients with and without toxicity. Using resampling methods like Monte Carlo k-fold cross validation, we compared the accuracy of several machine learning algorithms applied to our data. We used the algorithm with highest classification accuracy rate in evaluating the diagnostic performance of 12 RN and 14 dNTP pool sizes as biomarkers of mitochondrial toxicity. RESULTS: We used eight classification algorithms to assess the diagnostic performance of RN and dNTP pool sizes distinguishing HIV patients with and without NRTI-associated mitochondrial toxicity. The algorithms resulted in cross-validated classification rates of 0.65-0.76 for dNTP and 0.72-0.83 for RN, following reduction of the dimensionality of the input data. The reduction of input variables improved the classification performance of the algorithms, with the most pronounced improvement for RN. Complex tree-based methods worked the best for both the deoxyribose dataset (Random Forest) and the ribose dataset (Classification Tree and AdaBoost), but it is worth noting that simple methods such as Linear Discriminant Analysis and Logistic Regression were very competitive in terms of classification performance. CONCLUSIONS: Our finding of changes in RN and dNTP pools in participants with mitochondrial toxicity validates the importance of dNTP pools in mitochondrial function. Hence, levels of RN and dNTP pools can be used as biomarkers of ART-induced mitochondrial toxicity.

3.
Arthritis Rheumatol ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31612628

RESUMO

OBJECTIVE: Four autoantigens have been described recently in IgG4-related disease (IgG4-RD): prohibitin, annexin A11, laminin 511-E8, and galectin-3. However, no external validation has been performed and the possibility that some individuals break tolerance to more than one autoantigen has not been explored. METHODS: Autoantibody responses against prohibitin, annexin A11 and laminin 511-E8 were measured by ELISA among a clinically diverse cohort of IgG4-RD patients (n=100). Autoantibody responses were correlated with disease severity and organ distribution. RESULTS: The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511-E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti-galectin-3 antibody responses with 25 (29%) having IgG4 anti-galectin-3 antibodies. Among these 86 subjects, 32 (37%) had IgG4 antibodies to at least one of the 4 auto-antigens and 12 (14%) showed reactivity to ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total IgG1, IgG2, IgG4, and C-reactive protein levels; were more commonly hypocomplementemic; and were more likely to have visceral organ involvement. CONCLUSION: Antibodies against prohibitin, annexin A11, and laminin 511-E8 were found in only a small portion of patients with IgG4-RD. A subset of IgG4-RD patients, however, had IgG4 antibodies against ≥2 autoantigens. Patients with antibodies against ≥2 autoantigens present with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunological tolerance in IgG4-RD was associated with more severe disease.

4.
Sci Signal ; 12(604)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641080

RESUMO

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.

5.
J Virol ; 93(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31375576

RESUMO

BLT (bone marrow-liver-thymus) humanized mice, which reconstitute a functional human immune system, develop prototypic human virus-specific CD8+ T cell responses following infection with human immunodeficiency virus type 1 (HIV-1). We explored the utility of the BLT model for HIV-1 vaccine development by immunizing BLT mice against the conserved viral Gag protein, utilizing a rapid prime-boost protocol of poly(lactic-co-glycolic) acid microparticles and a replication-defective herpes simplex virus (HSV) recombinant vector. After HIV-1 challenge, the mice developed broad, proteome-wide gamma interferon-positive (IFN-γ+) T cell responses against HIV-1 that reached magnitudes equivalent to what is observed in HIV-1-infected individuals. The functionality of these responses was underscored by the consistent emergence of escape mutations in multiple CD8+ T cell epitopes during the course of infection. Although prechallenge vaccine-induced responses were largely undetectable, the Gag immunization increased both the magnitude and the kinetics of anamnestic Gag-specific T cell responses following HIV-1 infection, and the magnitude of these postchallenge Gag-specific responses was inversely correlated with acute HIV-1 viremia. Indeed, Gag immunization was associated with a modest but significant 0.5-log reduction in HIV-1 viral load when analyzed across four experimental groups of BLT mice. Notably, the HSV vector induced elevated plasma concentrations of polarizing cytokines and chemotactic factors, including interleukin-12p70 (IL-12p70) and MIP-1α, which were positively correlated with the magnitude of Gag-specific responses. Overall, these results support the ability of BLT mice to recapitulate human pathogen-specific T cell responses and to respond to immunization; however, additional improvements to the model are required to develop a robust system for testing HIV-1 vaccine efficacy.IMPORTANCE Advances in the development of humanized mice have raised the possibility of a small-animal model for preclinical testing of an HIV-1 vaccine. Here, we describe the capacity of BLT humanized mice to mount broadly directed HIV-1-specific human T cell responses that are functionally active, as indicated by the rapid emergence of viral escape mutations. Although immunization of BLT mice with the conserved viral Gag protein did not result in detectable prechallenge responses, it did increase the magnitude and kinetics of postchallenge Gag-specific T cell responses, which was associated with a modest but significant reduction in acute HIV-1 viremia. Additionally, the BLT model revealed immunization-associated increases in the plasma concentrations of immunomodulatory cytokines and chemokines that correlated with more robust T cell responses. These data support the potential utility of the BLT humanized mouse for HIV-1 vaccine development but suggest that additional improvements to the model are warranted.

7.
J Clin Microbiol ; 57(8)2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31189584

RESUMO

Tuberculous meningitis (TBM) is a devastating infection of the central nervous system lacking an adequate point-of-care diagnostic test. We conducted a prospective cohort study of 550 Zambian adults with suspected TBM to determine the diagnostic accuracy of cerebrospinal fluid (CSF) Xpert MTB/RIF, CSF lipoarabinomannan (LAM), urine LAM, CSF total protein, and CSF glucose compared with the gold standard of CSF culture. We categorized patients with a positive CSF tuberculosis (TB) culture as definite TBM. We also assessed inpatient and 1-year mortality on definite TBM patients when CSF Xpert MTB/RIF results were available in real time to treating physicians relative to a historical comparison cohort in whom Xpert results were not available in real time. Of the 550 patients, 474 (86.2%) were HIV-infected and 105/550 (19.1%) had definite TBM based on a positive CSF culture. The sensitivity/specificity of the diagnostic tests were CSF Xpert MTB/RIF, 52.9%/94.2%; CSF LAM, 21.9%/94.2%; urine LAM, 24.1%/76.1%; and CSF glucose <40 mg/dl, and total protein, >100 mg/dl, 66.3%/90%. A model including CSF Xpert MTB/RIF, CSF LAM, CSF glucose, and CSF total protein demonstrated an area under the receiver operating curve of 0.90. The inpatient and 1-year mortality for definite TBM was 43% and 57%, respectively. There was low sensitivity for the diagnosis of TBM across all diagnostics tests. CSF Xpert MTB/RIF and CSF LAM are highly specific for the diagnosis of TBM. Despite the use of Xpert MTB/RIF for diagnostic purpose in real time, TBM was still associated with a high mortality in Zambian patients.

8.
J Math Stat ; 15(1): 55-64, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31186621

RESUMO

The percentage CD4+ T-lymphocytes is used to monitor pediatric HIV disease. However, in resource-limited settings, enumerating the percentage of CD4+ T-lymphocytes is hampered by the lack of laboratory infrastructure and trained technicians. In this paper, we investigated the performances of the percentage and absolute CD4+ T-lymphocytes as markers of pediatric HIV disease progression using data from HIV-infected children enrolled through the Yale Prospective Longitudinal Pediatric Cohort study. A Lehmann family of Receiver Operating Characteristic (ROC) curves were used to estimate and compare the performance of the two biomarkers in monitoring pediatric HIV disease progression. The area under the ROC (AUC) curve and its empirical estimator have previously been used to assess the performance of biomarkers for a cross-sectional data. However, there is a paucity of literature on the AUC for correlated longitudinal biomarkers. Previous works on the estimation and inference of the AUC for longitudinal biomarkers have largely focused on independent biomarkers or failed to consider the effect of covariates. The Lehmann approach allowed us to estimate the AUC of the aforementioned correlated longitudinal biomarkers as functions of explanatory variables. We found that the overall performance of the two biomarkers was comparable. The area under the ROC curves for CD4+ T cell count and percentage were 0.681 [SE = 0.029; 95% CI: 0.624-0.737] and 0.678 [SE = 0.024; 95% CI:0.630-0.725], respectively. Our results suggest that absolute CD4+ T-lymphocyte counts could be used as a proxy for percentage of CD4+ T-lymphocytes in monitoring pediatric HIV in resource-limited settings.

9.
Science ; 364(6439): 480-484, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31048489

RESUMO

Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies network theory to HIV protein structure data to quantitate the topological importance of individual amino acid residues. Mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes presented by protective human leukocyte antigen (HLA) class I alleles. Moreover, CD8+ T cell targeting of highly networked epitopes distinguished individuals who naturally control HIV, even in the absence of protective HLA alleles. This approach thereby provides a mechanistic basis for immune control and a means to identify CD8+ T cell epitopes of topological importance for rational immunogen design, including a T cell-based HIV vaccine.


Assuntos
Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Síndrome de Imunodeficiência Adquirida/prevenção & controle , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , HIV-1/imunologia , Alelos , Sequência Conservada , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Mutação , Proteoma/genética , Proteoma/imunologia , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana
10.
Biostatistics ; 20(3): 433-451, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29608649

RESUMO

The receiver operating characteristic (ROC) curve is a commonly used graphical summary of the discriminative capacity of a thresholded continuous scoring system for a binary outcome. Estimation and inference procedures for the ROC curve are well-studied in the cross-sectional setting. However, there is a paucity of research when both biomarker measurements and disease status are observed longitudinally. In a motivating example, we are interested in characterizing the value of longitudinally measured CD4 counts for predicting the presence or absence of a transient spike in HIV viral load, also time-dependent. The existing method neither appropriately characterizes the diagnostic value of observed CD4 counts nor efficiently uses status history in predicting the current spike status. We propose to jointly model the binary status as a Markov chain and the biomarkers levels, conditional on the binary status, as an autoregressive process, yielding a dynamic scoring procedure for predicting the occurrence of a spike. Based on the resulting prediction rule, we propose several natural extensions of the ROC curve to the longitudinal setting and describe procedures for statistical inference. Lastly, extensive simulations have been conducted to examine the small sample operational characteristics of the proposed methods.


Assuntos
Biomarcadores , Bioestatística/métodos , Modelos Estatísticos , Curva ROC , Infecções por HIV/sangue , Humanos , Estudos Longitudinais , Carga Viral
11.
AIDS ; 32(10): 1207-1217, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29620716

RESUMO

OBJECTIVE: Postinfection HIV viral control and immune correlates analysis of the RV144 vaccine trial indicate a potentially critical role for Fc receptor-mediated antibody functions. However, the influence of functional antibodies in clade C infection is largely unknown. DESIGN: Plasma samples from 361 chronic subtype C-infected, antiretroviral therapy-naive participants were tested for their HIV-specific isotype and subclass distributions, along with their Fc receptor-mediated functional potential. METHOD: Total IgG, IgG subclasses and IgA binding to p24 clade B/C and gp120 consensus C proteins were assayed by multiplex. Antibody-dependent uptake of antigen-coated beads and Fc receptor-mediated natural killer cell degranulation were evaluated as surrogates for antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), respectively. RESULTS: p24 IgG1 was the only subclass associated with viral control (P = 0.01), with higher p24-specific ADCP and ADCC responses detected in individuals with high p24 IgG1. Although p24 IgG1 levels were enriched in patients with elevated Gag-specific T-cell responses, these levels remained an independent predictor of low-viral loads (P = 0.04) and high CD4+ cell counts (P = 0.004) after adjusting for Gag-specific T-cell responses and for protective HLA class I alleles. CONCLUSION: p24 IgG1 levels independently predict viral control in HIV-1 clade C infection. Whether these responses contribute to direct antiviral control via the recruited killing of infected cells via the innate immune system or simply mark a qualitatively superior immune response to HIV, is uncertain, but highlights the role of p24-specific antibodies in control of clade C HIV-1 infection.


Assuntos
Genótipo , Anticorpos Anti-HIV/sangue , Proteína do Núcleo p24 do HIV/imunologia , HIV-1/imunologia , Imunoglobulina G/sangue , Receptores Fc/metabolismo , Carga Viral , Citotoxicidade Celular Dependente de Anticorpos , Degranulação Celular , Estudos de Coortes , Anticorpos Anti-HIV/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Humanos , Imunoglobulina G/metabolismo , Células Matadoras Naturais/imunologia , Fagocitose
12.
Nat Immunol ; 19(5): 475-486, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29670239

RESUMO

CD4+ T lymphocytes are the principal target of human immunodeficiency virus (HIV), but infected macrophages also contribute to viral pathogenesis. The killing of infected cells by CD8+ cytotoxic T lymphocytes (CTLs) leads to control of viral replication. Here we found that the killing of macrophages by CTLs was impaired relative to the killing of CD4+ T cells by CTLs, and this resulted in inefficient suppression of HIV. The killing of macrophages depended on caspase-3 and granzyme B, whereas the rapid killing of CD4+ T cells was caspase independent and did not require granzyme B. Moreover, the impaired killing of macrophages was associated with prolonged effector cell-target cell contact time and higher expression of interferon-γ by CTLs, which induced macrophage production of pro-inflammatory chemokines that recruited monocytes and T cells. Similar results were obtained when macrophages presented other viral antigens, suggestive of a general mechanism for macrophage persistence as antigen-presenting cells that enhance inflammation and adaptive immunity. Inefficient killing of macrophages by CTLs might contribute to chronic inflammation, a hallmark of chronic disease caused by HIV.


Assuntos
Linfócitos T CD4-Positivos/virologia , Citotoxicidade Imunológica/imunologia , Infecções por HIV/imunologia , Macrófagos/virologia , Linfócitos T Citotóxicos/imunologia , Células Cultivadas , Humanos
13.
Lancet HIV ; 5(1): e35-e44, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28978417

RESUMO

BACKGROUND: HIV incidence among young women in sub-Saharan Africa remains high and their inclusion in vaccine and cure efforts is crucial. We aimed to establish a cohort of young women detected during Fiebig stage I acute HIV infection in whom treatment was initiated immediately after diagnosis to advance research in this high-risk group. METHODS: 945 women aged 18-23 years in KwaZulu-Natal, South Africa, who were HIV uninfected and sexually active consented to HIV-1 RNA testing twice a week and biological sampling and risk assessment every 3 months during participation in a 48-96 week life-skills and job-readiness programme. We analysed the effect of immediate combination antiretroviral therapy (ART) on viraemia and immune responses, sexual risk behaviour, and the effect of the socioeconomic intervention. FINDINGS: 42 women were diagnosed with acute HIV infection between Dec 1, 2012, and June 30, 2016, (incidence 8·2 per 100 person-years, 95% CI 5·9-11·1), of whom 36 (86%) were diagnosed in Fiebig stage I infection with a median initial viral load of 2·97 log10 copies per mL (IQR 2·42-3·85). 23 of these 36 women started ART at a median of 1 day (1-1) after detection, which limited the median peak viral load to 4·22 log10 copies per mL (3·27-4·83) and the CD4 nadir to 685 cells per µL (561-802). ART also suppressed viral load (to <20 copies per mL) within a median of 16 days (12-26) and, in 20 (87%) of 23 women, prevented seroconversion, as shown with western blotting. 385 women completed the 48 week socioeconomic intervention, of whom 231 were followed up for 1 year. 202 (87%) of these 231 women were placed in jobs, returned to school, or started a business. INTERPRETATION: Frequent HIV screening combined with a socioeconomic intervention facilitated sampling and risk assessment before and after infection. In addition to detection of acute infection and immediate treatment, we established a cohort optimised for prevention and cure research. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, International AIDS Vaccine Initiative, Wellcome Trust, Howard Hughes Medical Institute.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Feminino , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Estudos Prospectivos , Fatores Socioeconômicos , África do Sul , Carga Viral , Adulto Jovem
14.
Artigo em Inglês | MEDLINE | ID: mdl-28584150

RESUMO

A case-control study of the effect of antiretroviral therapy (ART) on apoptosis pathway genes comprising 16 cases (HIV infected with mitochondrial toxicity) and 16 controls (HIV uninfected) was conducted. A total of 26 of 84 genes of the apoptosis pathway were differentially expressed. Two of the upregulated genes, DFFA and TNFRSF1A, classified 75% of study participants correctly as either a case or control. Thus, apoptosis may be in the causal pathway of ART-associated mitochondrial toxicity. These two genes could be markers for detecting and monitoring ART-induced mitochondrial toxicity.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Mitocôndrias/patologia , Adulto , Idoso , Fármacos Anti-HIV/farmacologia , Proteínas Reguladoras de Apoptose/genética , Estudos de Casos e Controles , Citocromos c/sangue , DNA Mitocondrial/efeitos dos fármacos , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Análise de Componente Principal , Receptores Tipo I de Fatores de Necrose Tumoral/genética
15.
Immunity ; 46(1): 29-37, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28087240

RESUMO

Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus-dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa.


Assuntos
Colo do Útero/microbiologia , Infecções por HIV/microbiologia , Vagina/microbiologia , Animais , Bactérias Anaeróbias , Linfócitos T CD4-Positivos/imunologia , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Lactobacillus , Camundongos , Microbiota/imunologia , Prevotella , África do Sul
16.
Cell ; 167(2): 433-443.e14, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27667685

RESUMO

While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.


Assuntos
Anticorpos Antibacterianos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Humoral , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Adulto , Feminino , Glicosilação , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Polissacarídeos/imunologia , Análise Serial de Proteínas , Receptores de IgG/imunologia , Adulto Jovem
17.
Hum Immunol ; 77(12): 1147-1153, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27521484

RESUMO

Differences in HLA-C expression are inversely correlated with HIV viral load set-point and slower progression to AIDS, linked to enhanced cytotoxic T cell immunity. Yet, beyond T cells, HLA-C serves as a dominant ligand for natural killer (NK) cell killer immunoglobulin-like receptors (KIR). Thus, we speculated that HLA-C expression levels may also impact NK activity, thereby modulating HIV antiviral control. Phenotypic and functional profiling was performed on freshly isolated PBMCs. HLA-C expression was linked to changes in NK subset distribution and licensing, particularly in HLA-C1/C1, KIR2DL3+2DL2-individuals. Moreover, high levels of HLA-C, were associated with reduced frequencies of anergic CD56neg NKs and lower frequencies of KIR2DL1/2/3+ NK cells, pointing to an HLA-C induced influence on the NK cell development in the absence of disease. In HIV infection, several spontaneous controllers, that expressed higher levels of HLA-C demonstrated robust NK-IFN-γ secretion in response to target cells, highlighting a second disease induced licensing phenotype. Thus this population study points to a potential role for HLA-C levels both in NK cell education and development.


Assuntos
Infecções por HIV/imunologia , HIV-1/fisiologia , Antígenos HLA-C/metabolismo , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Adolescente , Adulto , Doenças Assintomáticas , Estudos de Coortes , Citotoxicidade Imunológica , Feminino , Frequência do Gene , Infecções por HIV/genética , Antígenos HLA-C/genética , Haplótipos , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Células Matadoras Naturais/virologia , Ativação Linfocitária , Subpopulações de Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Receptores KIR/genética , Receptores KIR/metabolismo , Carga Viral , Adulto Jovem
18.
J Leukoc Biol ; 100(6): 1425-1433, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27406996

RESUMO

Mechanisms modulating HIV-specific CD8+ T cell-mediated viral inhibition are not well defined. To delineate features of effective control, we compared the ability of CD8+ T cells from HIV ECs and CPs to inhibit HIV ex vivo. ECs showed superior inhibition compared to HAART-treated or untreated CPs in a typical VIA in which CD8+ T cells are rested 3 d before use (P = 0.025). In contrast, comparable antiviral activity was observed in freshly thawed cells. Rested CD8+ T cells underwent apoptosis with preferential loss of HIV-specific cells. EC CD8+ T cells showed greater capacity to sustain polyfunctionality ex vivo compared with those of CPs, and incubation of CD8+ T cells with IL-15 augmented inhibition. These results indicate that superior ex vivo inhibition of viral replication by CD8+ T cells from ECs is associated with enhanced retention of functional qualities and that in vitro antiviral function is enhanced by IL-15.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV/imunologia , Subpopulações de Linfócitos T/imunologia , Terapia Antirretroviral de Alta Atividade , Apoptose , Células Cultivadas , Criopreservação , Citotoxicidade Imunológica , Progressão da Doença , HIV/fisiologia , Infecções por HIV/tratamento farmacológico , Humanos , Interleucina-15/farmacologia , Especificidade do Receptor de Antígeno de Linfócitos T , Replicação Viral
19.
J Infect Dis ; 214(4): 612-6, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27357340

RESUMO

Humanized mice reconstituted with a human immune system can be mucosally infected with human immunodeficiency virus (HIV), opening up the possibility of studying HIV transmission in a small-animal model. Here we report that passive immunization with the broadly neutralizing antibody b12 protected humanized mice against repetitive intravaginal infection in a dose-dependent manner. In addition, treatment with the antibody PGT126, which is more potent in vitro, was more efficacious in vivo and provided sterilizing protection. Our results demonstrate that humanized mice can be used as a small-animal model to study the efficacy and mechanism of broadly neutralizing antibody protection against HIV acquisition.


Assuntos
Anticorpos Neutralizantes/administração & dosagem , Modelos Animais de Doenças , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , Imunização Passiva/métodos , Animais , Relação Dose-Resposta Imunológica , Feminino , Camundongos , Camundongos SCID , Resultado do Tratamento
20.
J AIDS Clin Res ; 7(4)2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27379199

RESUMO

BACKGROUND: The clinical consequences of the magnitude and the duration of detectable viremia in HIV-infected children have not been well characterized. We examined the predictors and immunologic consequences over time of frequent episodes of detectable viremia in HIV-infected children followed at Yale-New Haven Hospital. METHODS: We analyzed the CD4+ T-cell and HIV viral load over a 19-year period (1996 to 2013) of 104 HIV-infected children enrolled in the Yale Prospective Longitudinal Pediatric HIV Cohort. Both CD4+ T-lymphocytes and HIV viral load were measured at clinic visits every 3 to 4 months. Longitudinal data analyses using polynomial random coefficients models were conducted to examine overtime changes in CD4+ T-cell counts by frequency of episodes of detectable viremia. Moreover, regression analyses using logistic regression models were used to assess the predictors of frequent episodes of detectable viremia. RESULTS: One hundred and four (104) HIV-infected children with more than one HIV viral load measurement between 1996 and November 2013 were included in the analysis. Over 80% (N=86) of the children had detectable viral load (HIV RNA viral load ≥50 copies/ml) during more than 50% of their clinic visits. Children with infrequent episodes of detectable viremia had significantly higher CD4+ T-cell counts overtime compared to those with frequent episodes of detectable viremia (P<0.0001). CONCLUSIONS: Both frequency and magnitude of episodes of detectable viremia had effect on CD4+ T-cells. Strict adherence to a treatment goal of undetectable HIV viremia in children is likely to be beneficial.

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