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1.
Front Immunol ; 12: 670616, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489929

RESUMO

Neutrophils are characterized by their heterogeneity. They fight against pathogens and are involved in tissue injury repair and immune system regulation. Neutrophils have an extremely short life span in the peripheral blood and undergo aging after being released from the bone marrow. The over-aggregation of aged neutrophils is associated with phenotypical and functional changes. Here, we aimed to investigate the dynamics of neutrophil aging and its relationship with T cell exhaustion in HIV-1 infection, as they are not well understood. In this study, we enrolled 23 treatment naïve (TN) patients, 23 individuals that had received antiretroviral therapy (ART), and 21 healthy controls (HC). In these cohorts, we measured the degree of neutrophil aging, and its possible correlation with T cell dysfunction. In TN patients, peripheral neutrophils showed a more distinct aging phenotype and were over-activated compared to those in ART-treated patients. The degree of neutrophil aging was positively correlated with HIV-1 RNA viral load and negatively correlated with CD4+ T cell count. Moreover, aged neutrophils had impaired reactive oxygen species (ROS) production after lipopolysaccharide (LPS) stimulation, and were characterized by increased PD-L1 and arginase-1 expression in a time-dependent manner. Aged neutrophils demonstrated an increased inhibition of IFN-γ and TNF-α secretion by CD8+ T cell compared to non-aged neutrophils. The inhibition effect could be partially reversed by blocking PD-L1 and arginase-1 in vitro, and LPS was identified as an important activator of neutrophil aging. These results provide evidence that dampening neutrophil aging may provide a novel approach to recover T cell dysfunction in patients with HIV-1 infection.

2.
Signal Transduct Target Ther ; 6(1): 339, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497264

RESUMO

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.


Assuntos
COVID-19/terapia , Lesão Pulmonar/terapia , Pulmão/imunologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/imunologia , COVID-19/patologia , Humanos , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/virologia , Células-Tronco Mesenquimais/patologia
3.
J Viral Hepat ; 28(11): 1554-1562, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34448324

RESUMO

The long-term benefits of interferon-α (IFN-α) treatment in children with chronic hepatitis B (CHB) remain unclear. We conducted a retrospective and real-world study to evaluate the safety and long-term clearance rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in CHB children who received IFN-α monotherapy for 72 weeks and were with 13-year follow-up visit. Participants treated with IFN-α (n = 316) were more likely to become HBeAg negatve (39.87% vs. 27.37%; p < .05) and HBsAg negative (11.08% vs. 3.16%; p < .05) by the end of the treatment period than untreated participants (n = 95). Treated participants also had higher cumulative rates of HBeAg loss (74.13% vs. 59.27%; p < .05) and HBsAg loss (46.95 vs. 33.11%; p < 0.05) than untreated participants in parallel by the end of 13-year follow-up. In particular, the cumulative rate of HBsAg loss was higher in treated children aged 1-7 years than in those aged 8-17 years (71.40% vs. 39.0%; p < .01). Children who were HBeAg-negative at the end of IFN-α treatment or who had serum alanine aminotransferase levels of ≥80 IU/L at baseline were likely to have higher cumulative HBsAg loss rates. Accordingly, HBeAg loss at 72 weeks was positively associated with the cumulative HBsAg loss rate in untreated children. There were no serious adverse events of IFN-α therapy for the treated patients throughout the study period. Overall, IFN-α therapy was effective in obtaining higher long-term cumulative rates of HBeAg and HBsAg loss in children with HBeAg-positive immune-active CHB, especially among those aged 1-7 years.

4.
Front Immunol ; 12: 700152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394094

RESUMO

Background: Mucosal-associated invariant T (MAIT) cells are considered to participate of the host immune response against acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, single-cell transcriptomic profiling of MAIT cells in patients with COVID-19 remains unexplored. Methods: We performed single-cell RNA sequencing analyses on peripheral MAIT cells from 13 patients with COVID-19 and 5 healthy donors. The transcriptional profiles of MAIT cells, together with assembled T-cell receptor sequences, were analyzed. Flow cytometry analysis was also performed to investigate the properties of MAIT cells. Results: We identified that differentially expressed genes (DEGs) of MAIT cells were involved in myeloid leukocyte activation and lymphocyte activation in patients with COVID-19. In addition, in MAIT cells from severe cases, more DEGs were enriched in adaptive cellular and humoral immune responses compared with those in moderate cases. Further analysis indicated that the increase of cell cytotoxicity (killing), chemotaxis, and apoptosis levels in MAIT cells were consistent with disease severity and displayed the highest levels in patients with severe disease. Interestingly, flow cytometry analysis showed that the frequencies of pyroptotic MAIT cells, but not the frequencies of apoptotic MAIT cells, were increased significantly in patients with COVID-19, suggesting pyroptosis is one of leading causes of MAIT cell deaths during SARS-CoV-2 infection. Importantly, there were more clonal expansions of MAIT cells in severe cases than in moderate cases. Conclusions: The results of the present study suggest that MAIT cells are likely to be involved in the host immune response against SARS-CoV-2 infection. Simultaneously, the transcriptomic data from MAIT cells provides a deeper understanding of the immune pathogenesis of the disease.


Assuntos
COVID-19/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , SARS-CoV-2/imunologia , Transcriptoma/genética , Sequência de Bases , COVID-19/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Ativação Linfocitária/genética , Piroptose/fisiologia , Análise de Sequência de RNA , Índice de Gravidade de Doença , Éxons VDJ/genética
5.
BMC Infect Dis ; 21(1): 818, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399709

RESUMO

BACKGROUND: Liver injuries have been reported in patients with coronavirus disease 2019 (COVID-19). This study aimed to investigate the clinical role played by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: In this multicentre, retrospective study, the parameters of liver function tests in COVID-19 inpatients were compared between various time-points in reference to SARS-CoV-2 shedding, and 3 to 7 days before the first detection of viral shedding was regarded as the reference baseline. RESULTS: In total, 70 COVID-19 inpatients were enrolled. Twenty-two (31.4%) patients had a self-medication history after illness. At baseline, 10 (14.3%), 7 (10%), 9 (12.9%), 2 (2.9%), 15 (21.4%), and 4 (5.7%) patients already had abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), albumin, and total bilirubin (TBIL) values, respectively. ALT and AST abnormal rates and levels did not show any significant dynamic changes during the full period of viral shedding (all p > 0.05). The GGT abnormal rate (p = 0.008) and level (p = 0.033) significantly increased on day 10 of viral shedding. Meanwhile, no simultaneous significant increases in abnormal ALP rates and levels were observed. TBIL abnormal rates and levels significantly increased on days 1 and 5 of viral shedding (all p < 0.05). Albumin abnormal decrease rates increased, and levels decreased consistently from baseline to SARS-CoV-2 clearance day (all p < 0.05). Thirteen (18.6%) patients had chronic liver disease, two of whom died. The ALT and AST abnormal rates and levels did not increase in patients with chronic liver disease during SARS-CoV-2 shedding. CONCLUSIONS: SARS-CoV-2 does not directly lead to elevations in ALT and AST but may result in elevations in GGT and TBIL; albumin decreased extraordinarily even when SARS-CoV-2 shedding ended.


Assuntos
COVID-19/complicações , Fígado/virologia , Adulto , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , COVID-19/sangue , COVID-19/epidemiologia , Feminino , Humanos , Fígado/patologia , Testes de Função Hepática/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença
6.
Hepatol Int ; 15(3): 602-610, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34240319

RESUMO

BACKGROUND: This study aimed to compare the diagnostic accuracy of transient elastography (TE) and biopsy for the detection of liver fibrosis in children with chronic hepatitis B (CHB). METHODS: This single-center prospective study included 157 CHB children aged 0-6 years. All patients underwent liver stiffness measurement (LSM) by TE and liver biopsy, separated by an interval of less than 1 week. RESULTS: The LSM, aspartate aminotransferase-platelet ratio index (APRI), and fibrosis-4 index (FIB-4) were positively correlated with activity grade and fibrosis stage in CHB children. The areas under the receiver operating characteristic curves (AUCs) of LSM for identifying significant (F ≥ 2) and advanced (F ≥ 3) fibrosis were 0.732 and 0.941, respectively. The cut-off values, specificity, and sensitivity for significant fibrosis were 5.6 kPa, 75.7%, and 67.4%, respectively; the corresponding values for advanced fibrosis were 6.9 kPa, 91.5%, and 81.3%, respectively. Compared to LSM, the overall diagnostic performances of APRI and FIB-4 for significant and advanced fibrosis were suboptimal, with low AUCs and sensitivity. Since LSM, platelet, and Log10 (hepatitis B surface antigen) were independent factors associated with the fibrosis stage (F < 2 and F ≥ 2), they were used to formulate the "LPS" index for the prediction of F ≥ 2. The AUC of LPS (for F ≥ 2) was higher than that of LSM (0.792 vs. 0.732, p < 0.05), and had an improved sensitivity (76.6% vs. 67.4%). CONCLUSIONS: TE is a promising technology for the diagnosis of advanced fibrosis in CHB children aged 0-6 years.

7.
Front Med (Lausanne) ; 8: 604242, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34322497

RESUMO

Objectives: Our objective was to explore the incidence and early predictive factors of acute kidney injury in coronavirus disease 2019 (COVID-19) patients. Method: We established a retrospective cohort of 408 patients who were admitted to Shenzhen Third People's Hospital in Shenzhen, China, between January 1 and March 31, 2020. Clinical outcomes and renal function were monitored until April 12, 2020, with a median follow-up duration of 21 days [interquartile range (IQR) = 14-33]. Results: When first admitted to hospital (baseline), 19.36% (79/408) presented renal dysfunction [estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2]. During follow-up, 3.9% (16/408) developed acute kidney injury (AKI). Age ≥60 years [hazard ratio (HR) = 4.78, 95% CI = 1.10-20.69], PaO2/FiO2 ratio <300 (HR = 3.48, 95% CI = 1.04-11.62), and higher creatinine (HR = 1.04, 95% CI = 1.01-1.07) at baseline independently predicted the risk of AKI. Respectively, 25.0% (102/408), 3.9% (16/408), 0.5% (2/408), 1.0% (4/408), and 0.2% (1/408) experienced G2, G3a, G3b, G4, and G5 as their most severe category during hospitalization, while 69.4% (283/408) had normal eGFRs throughout the follow-up period. When finally discharged from hospital, there were 12.5% (51/408) of patients with abnormal eGFRs. Conclusions: COVID-19 patients can be at risk of AKI and continuous eGFR decline during hospitalization, which can be early predicted by baseline factors. Some individuals still had renal dysfunction when finally discharged from hospital.

9.
J Clin Transl Hepatol ; 9(3): 324-334, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34221918

RESUMO

Background and Aims: Tenofovir alafenamide (TAF) has similar efficacy to tenofovir disoproxil fumarate (TDF) but with improved renal and bone safety in chronic hepatitis B patients studied outside of China. We report 3-year results from two phase 3 studies with TAF in China (Clinicaltrials.gov: NCT02836249 and NCT02836236). Methods: Chinese hepatitis B e antigen (HBeAg)-positive and -negative chronic hepatitis B patients with viremia and elevated alanine aminotransferase were randomized 2:1 to TAF or TDF treatment groups and treated in a double-blind fashion for 144 weeks (3 years). Efficacy responses were assessed by individual study while safety was assessed by a pooled analysis. Results: Of the 334 patients (180 HBeAg-positive and 154 HBeAg-negative) randomized and treated, baseline characteristics were similar between groups. The overall mean age was 38 years and 73% were male. The mean HBV DNA was 6.4 log10 IU/mL. The median alanine aminotransferase was 88 U/L, and 37% had a history of antiviral use. At week 144, the proportion with HBV DNA <29 IU/mL was similar among the two groups, with TAF at 83% vs. TDF at 79%, and TAF at 93% vs. TDF at 92% for the HBeAg-positive and -negative patients, respectively. In each study, higher proportions of TAF than TDF patients showed normalized alanine aminotransferase (via the American Association for the Study of Liver Diseases and the China criteria) and showed loss of HBsAg; meanwhile, the HBeAg seroconversion rates were similar. Treatment was well-tolerated among the TAF patients, who showed a smaller median decline in creatinine clearance (-0.4 vs. -3.2 mL/min; p=0.014) and less percentage change in bone mineral density vs. TDF at hip (-0.95% vs. -1.93%) and spine (+0.35% vs. -1.40%). Conclusions: In chronic hepatitis B patients from China, TAF treatment provided efficacy similar to TDF but with better renal and bone safety at 3 years.

10.
Front Immunol ; 12: 687296, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177939

RESUMO

Background: Targeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8+ T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8+ T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8+ T-cell subsets in chronic HIV-1 infection remain poorly understood. Methods: This study enrolled 72 HIV-1-infected patients, including 40 treatment naïve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8+ T cells defined by CD39 and/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and/or PD-1 signaling on CD8+ T cells. Results: The proportions of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells were significantly increased in treatment naïve patients but were partially lowered in patients on antiretroviral therapy. In treatment naïve patients, the proportions of PD-1+CD39+ CD8+ T cells were negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio, and were positively correlated with viral load. CD39+CD8+ T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39- counterparts. In vitro, a combination of blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8+ T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells. Conclusion: In patients with chronic HIV-1 infection there are increased frequencies of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells. In treatment naïve patients, the frequencies of PD-1+CD39+ CD8+ T cells are negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio and positively correlated with viral load. Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8+ T-cell function in HIV-1-infected patients.

11.
Clin Immunol ; 229: 108773, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34102315

RESUMO

BACKGROUND: The dynamics of viral reservoir decay and naïve CD4 T-cell recovery between immunological non-responders (INR) and complete responders (CR) during long-term antiretroviral treatment (ART) are not fully known. METHODS: Twenty-eight chronic HIV-infected individuals on 5-year ART were divided into two groups: INR (CD4 counts ≤350 cells/µL, n = 13) and CR (CD4 counts ≥500 cells/µL, n = 15). The levels of HIV DNA and cell-associated HIV RNA (CA-RNA), CD4 counts, naïve CD4 counts and their correlations were analyzed at baseline, years 1, 3 and 5 of ART between the two groups. Expression of PD-1 on CD4 T-cells was quantified by flow cytometry. Linear mixed effect models were used to estimate the change procession in repeated measurements over 5 years. Slopes of the above-mentioned indicators were estimated using participant-specific linear regressions, respectively. RESULTS: INR maintained higher levels of HIV DNA and CA-RNA with higher percentages of PD-1+CD4 T-cells compared with CR during 5-year ART, concurrent with lower naïve CD4 T-cells. However, the rates of HIV DNA and CA-RNA decay in INR were not different from that in CR over time, and INR had higher rates of naïve CD4 T-cell percentage recovery. The baseline levels of HIV DNA were positively associated with the 5-year levels of HIV DNA, but negatively associated with the 5-year naïve CD4 counts. CONCLUSIONS: INR maintained significantly higher viral reservoir and lower naïve CD4 T-cells compared with CR during 5-year ART, however, the rates of reservoir decay and naïve CD4 T-cell percentage growth within INR were not lower than that in CR over time.


Assuntos
Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Adulto , Contagem de Linfócito CD4 , China , DNA Viral/sangue , DNA Viral/genética , Progressão da Doença , HIV/efeitos dos fármacos , HIV/genética , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/genética , Fatores de Tempo , Carga Viral/efeitos dos fármacos
12.
Nat Metab ; 3(7): 909-922, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34158670

RESUMO

Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane1. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes2,3, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level. Here we conduct high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. Our study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. We also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. Our results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.


Assuntos
COVID-19/metabolismo , COVID-19/virologia , Vesículas Extracelulares/metabolismo , Lipidômica , Metabolômica , SARS-CoV-2 , Transporte Biológico , COVID-19/epidemiologia , Fracionamento Celular , Membrana Celular/metabolismo , Fracionamento Químico , Análise por Conglomerados , Biologia Computacional/métodos , Exossomos/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Lipidômica/métodos , Metaboloma , Metabolômica/métodos , Estudos Retrospectivos , SARS-CoV-2/genética , SARS-CoV-2/imunologia
13.
Signal Transduct Target Ther ; 6(1): 217, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34103473

RESUMO

We examined the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) infusion for immune non-responder (INR) patients with chronic HIV-1 infection, who represent an unmet medical need even in the era of efficient antiretroviral therapy (ART). Seventy-two INR patients with HIV were enrolled in this phase II randomized, double-blinded, multicenter, placebo-controlled, dose-determination trial (NCT01213186) from May 2013 to March 2016. They were assigned to receive high-dose (1.5 × 106/kg body weight) or low-dose (0.5 × 106/kg body weight) hUC-MSC, or placebo. Their clinical and immunological parameters were monitored during the 96-week follow-up study. We found that hUC-MSC treatment was safe and well-tolerated. Compared with baseline, there was a statistical increase in CD4+ T counts in the high-dose (P < 0.001) and low-dose (P < 0.001) groups after 48-week treatment, but no change was observed in the control group. Kaplan-Meier analysis revealed a higher cumulative probability of achieving an immunological response in the low-dose group compared with the control group (95.8% vs. 70.8%, P = 0.004). However, no significant changes in CD4/CD8+ T counts and CD4/CD8 ratios were observed among the three groups. In summary, hUC-MSC treatment is safe. However, the therapeutic efficacy of hUC-MSC treatment to improve the immune reconstitution in INR patients still needs to be further investigated in a large cohort study.

14.
Eur J Immunol ; 51(8): 2027-2039, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33974710

RESUMO

Immune deficiency is one of the hallmarks of HIV infection and a major cause of adverse outcomes in people living with HIV (PLWH). Long-lived memory CD8+ T cells (LLMCs) are essential executors of long-term protective immunity; however, the generation and maintenance of LLMCs during chronic HIV infection are not well understood. In the present study, we analyzed circulating LLMCs in healthy controls (HCs) and PLWH with different disease statuses, including treatment naïve patients (TNs), complete responders (CRs), and immunological nonresponders (INRs). We found that both TNs and INRs showed severely compromised LLMCs compared with HCs and CRs, respectively. The decrease of LLMCs in TNs correlated positively with the reduction of their precursors, namely memory precursor effector T cells (MPECs), which might be associated with elevated pro-inflammatory cytokines. Strikingly, INRs showed an accumulation of MPECs, which exhibited diminished responsiveness to interleukin 7 (IL-7), thereby indicating abrogated differentiation into LLMCs. Moreover, in vitro studies showed that treatment with dexamethasone could improve the IL7-phosphorylated (p)-signal transducer and activator of transcription (STAT5) response by upregulating the expression of the interleukin 7 receptor (IL-7Rα) on MPECs in INRs. These findings provide insights that will encourage the development of novel therapeutics to improve immune function in PLWH.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Memória Imunológica/imunologia , Interleucina-7/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Signal Transduct Target Ther ; 6(1): 174, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958574

RESUMO

Severely immunosuppressed AIDS patients with recurrent opportunistic infections (OIs) represent an unmet medical need even in the era of antiretroviral therapy (ART). Here we report the development of a human leukocyte antigen (HLA)-mismatched allogeneic adaptive immune therapy (AAIT) for severely immunosuppressed AIDS patients. Twelve severely immunosuppressed AIDS patients with severe OIs were enrolled in this single-arm study. Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis. Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients. Clinical, immunological, and virological parameters were monitored during a 12-month follow-up period. We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients. Improvements in clinical symptoms were evident throughout the study period. All patients exhibited a steady increase of peripheral CD4+ T cells from a median 10.5 to 207.5 cells/µl. Rapid increase in peripheral CD8+ T-cell count from a median 416.5 to 1206.5 cells/µl was found in the first 90 days since initiation of AAIT. In addition, their inflammatory cytokine levels and HIV RNA viral load decreased. A short-term microchimerism with donor cells was found. There were no adverse events associated with graft-versus-host disease throughout the study period. Overall, AAIT treatment was safe, and might help severely immunosuppressed AIDS patients to achieve a better immune restoration. A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

17.
J Clin Invest ; 131(6)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720048

RESUMO

Chronic HIV-1 infection is generally characterized by progressive CD4+ T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4+ T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells, which revealed that pyroptotic and apoptotic CD4+ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4+ T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1 , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Adolescente , Adulto , Apoptose/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Estudos de Casos e Controles , Caspase 1/metabolismo , Caspase 3/metabolismo , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Inflamassomos/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Modelos Imunológicos , Piroptose/imunologia , Espécies Reativas de Oxigênio/metabolismo , Carga Viral , Adulto Jovem
18.
Gastroenterol Rep (Oxf) ; 9(1): 49-58, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33747526

RESUMO

Background: The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus (HBV) infection remain largely undefined. The present study assessed the clinical characteristics of the CD39/CD73/adenosine pathway in patients with chronic hepatitis B (CHB). Methods: We examined CD39 and CD73 expression and adenosine production by B-cells from 202 HBV-infected patients. B-cell-activation phenotypes were assessed by flow cytometry after CpG+CD40 ligand stimulation with or without blockade and activation of the adenosine pathway. Results: CD39 and CD73 expression on circulating B-cells was decreased in CHB patients with high HBV DNA, HBeAg positivity, high HBsAg levels, and active liver inflammation, and was hierarchically restored in complete responders according to HBeAg seroconversion or HBsAg reduction. However, CD39 and CD73 expression on activated memory and tissue-like memory B-cell subsets in complete responders was not increased despite effective antiviral treatments. Furthermore, CD39 and CD73 expression on intra-hepatic B-cells was decreased in inflammatory livers. In vitro, B-cells from CHB patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular adenosine and expressed increased levels of activation markers after adenosine-production blockade. Contrastingly, metformin significantly reduced activation-marker expression via regulating AMP-activated protein kinase. Conclusions: The skewed CD39 and CD73 expression on B-cells was associated with a high viral burden, liver inflammation, and antiviral efficacy in CHB patients, and the skewed CD39/CD73/adenosine pathway contributed to B-cell hyperactivation. Regulation of the CD39/CD73/adenosine pathway using metformin may represent a therapeutic option to reverse HBV-induced immune pathogenesis.

19.
Emerg Microbes Infect ; 10(1): 416-423, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33620297

RESUMO

Morbidity and mortality of non-AIDS-defining diseases (NADs) have become the increasing burden of people living with HIV (PLWH) with long-term antiretroviral therapy (ART). We aimed to quantify the contribution of modifiable risk factors to NADs. We included PLWHs starting ART at the Third People's Hospital of Shenzhen (China) from Jan 1, 2010 to Dec 31, 2017. We defined NAD outcomes of interest as cardiovascular disease (CVD), end-stage liver disease (ESLD), advanced renal disease (ARD), and non-AIDS-defining cancers (NADCs). We estimated incidence of outcomes and population-attributable fractions (PAFs) of modifiable traditional and HIV-related risk factors for each outcome. Overall, 8,301 participants (median age at study entry, 31 years) contributed 33,146 person-years of follow-up (PYFU). Incidence of CVD (362/100,000 PYFU) was the highest among outcomes, followed by that of ARD (270/100,000 PYFU), ESLD (213/100,000 PYFU), and NADC (152/100,000 PYFU). Totally, 34.14% of CVD was attributable to smoking, 7.98% to hypertension, and 6.44% to diabetes. For ESLD, 24.57% and 25.04% of it could be avoided if chronic hepatitis B and C virus infection, respectively, did not present. The leading PAFs for ARD were declined estimated glomerular filtration rate (eGFR) (39.68%) and low CD4 count (39.61%), followed by diabetes (10.19%). PAFs of hypertension, diabetes, and smoking for CVD, and declined eGFR and diabetes for ARD increased with age. The contribution of traditional risk factors for these NADs far outweighed the HIV-related risk factors. Individual-level interventions and population-level policy-making is needed to focus on these factors to prevent NADs in long-term management of HIV infection.


Assuntos
Doenças Cardiovasculares/mortalidade , Infecções por HIV/epidemiologia , Falência Renal Crônica/mortalidade , Neoplasias/mortalidade , Adulto , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Feminino , Taxa de Filtração Glomerular , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Estudos Retrospectivos , Fatores de Risco
20.
World J Clin Cases ; 9(4): 927-934, 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33585641

RESUMO

BACKGROUND: Brucella infections in the shoulder joint are uncommon, and few have been reported in the literature. CASE SUMMARY: A 26-year-old male was admitted to our hospital with complaint of recurrent pain and limited movement of the right shoulder. The patient reported the pain to have first occurred as an isolated event 6 mo previously and to have reoccurred 5 mo later, when it was accompanied by limited movement of the shoulder. Findings from physical examination and magnetic resonance imaging (referred to as MRI) suggested the diagnosis of subacromial bursitis, and diagnostic paracentesis and arthroscopic debridement were performed. Surprisingly, synovial fluid culture detected brucella, and the finding was confirmed by mass spectrometry of a colony sample. The diagnosis was corrected to brucellosis of the shoulder joint, and antibiotic drug treatment (oral rifampicin and doxycycline) was administrated for 6 wk. The 4-mo postoperative follow-up examination (MRI) yielded normal findings. The 2-year follow-up showed no signs of recurrence. CONCLUSION: This rare case of brucellosis infection in shoulder highlights the importance of increasing awareness to help avoid misdiagnosis.

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