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1.
Chin Med J (Engl) ; 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34759226

RESUMO

ABSTRACT: In the past 37 years, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has undergone various major transmission routes in China, with the world most complex co-circulating HIV-1 subtypes, even the prevalence is still low. In response to the first epidemic outbreak of HIV in injecting drug users and the second one by illegal commercial blood collection, China issued the Anti-Drug Law and launched the Blood Donation Act and nationwide nucleic acid testing, which has avoided 98,232 to 211,200 estimated infections and almost ended the blood product-related infection. China has been providing free antiretroviral therapy (ART) since 2003, which covered >80% of the identified patients and achieved a viral suppression rate of 91%. To bend the curve of increasing the disease burden of HIV and finally end the epidemic, China should consider constraining HIV spread through sexual transmission, narrowing the gaps in identifying HIV cases, and the long-term effectiveness and safety of ART in the future.

2.
Clin Chem Lab Med ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34533003

RESUMO

OBJECTIVES: Peripheral blood lymphocyte subsets are important parameters for monitoring immune status; however, lymphocyte subset detection is time-consuming and error-prone. This study aimed to explore a highly efficient and clinically useful autoverification system for lymphocyte subset assays performed on the flow cytometry platform. METHODS: A total of 94,402 lymphocyte subset test results were collected. To establish the limited-range rules, 80,427 results were first used (69,135 T lymphocyte subset tests and 11,292 NK, B, T lymphocyte tests), of which 15,000 T lymphocyte subset tests from human immunodeficiency virus (HIV) infected patients were used to set customized limited-range rules for HIV infected patients. Subsequently, 13,975 results were used for historical data validation and online test validation. RESULTS: Three key autoverification rules were established, including limited-range, delta-check, and logical rules. Guidelines for addressing the issues that trigger these rules were summarized. The historical data during the validation phase showed that the total autoverification passing rate of lymphocyte subset assays was 69.65% (6,941/9,966), with a 67.93% (5,268/7,755) passing rate for T lymphocyte subset tests and 75.67% (1,673/2,211) for NK, B, T lymphocyte tests. For online test validation, the total autoverification passing rate was 75.26% (3,017/4,009), with 73.23% (2,191/2,992) for the T lymphocyte subset test and 81.22% (826/1,017) for the NK, B, T lymphocyte test. The turnaround time (TAT) was reduced from 228 to 167 min using the autoverification system. CONCLUSIONS: The autoverification system based on the laboratory information system for lymphocyte subset assays reduced TAT and the number of error reports and helped in the identification of abnormal cell populations that may offer clues for clinical interventions.

4.
J Transl Med ; 18(1): 95, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093678

RESUMO

BACKGROUND: Despite the effective antiretroviral treatment (ART) of HIV-infected individuals, HIV persists in a small pool. Central memory CD4+ T cells (Tcm) make a major contribution to HIV persistence. We found that unlike HLA-DR, CD38 is highly expressed on the Tcm of HIV-infected subjects receiving ART for > 5 years. It has been reported that the half-life of total and episomal HIV DNA in the CD4+CD38+ T cell subset, exhibits lower decay rates at 12 weeks of ART. Whether CD38 contributes to HIV latency in HIV-infected individuals receiving long-term ART is yet to be addressed. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood of HIV-infected subjects receiving suppressive ART. The immunophenotyping, proliferation and apoptosis of CD4+ T cell subpopulations were detected by flow cytometry, and the level of CD38 mRNA and total HIV DNA were measured using real-time PCR and digital droplet PCR, respectively. A negative binomial regression model was used to determine the correlation between CD4+CD38+ Tcm and total HIV DNA in CD4+ T cells. RESULTS: CD38 was highly expressed on CD4+ Tcm cells from HIV infected individuals on long-term ART. Comparing with HLA-DR-Tcm and CD4+HLA-DR+ T cells, CD4+CD38+ Tcm cells displayed lower levels of activation (CD25 and CD69) and higher levels of CD127 expression. The proportion of CD38+ Tcm, but not CD38- Tcm cells can predict the total HIV DNA in the CD4+ T cells and the CD38+ Tcm subset harbored higher total HIV DNA copy numbers than the CD38- Tcm subset. After transfected with CD38 si-RNA in CD4+ T cells, the proliferation of CD4+ T cells was inhibited. CONCLUSION: The current date indicates that CD4+CD38+ Tcm cells contribute to HIV persistence in HIV-infected individuals on long-term ART. Our study provides a potential target to resolve HIV persistence.


Assuntos
Linfócitos T CD4-Positivos , Infecções por HIV , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Memória Imunológica , Leucócitos Mononucleares
5.
J Transl Med ; 18(1): 96, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093694

RESUMO

BACKGROUND: Disease progression in the absence of therapy varies significantly in mono-HIV and HCV infected individuals. Virus-specific CD8+ T cells play an important role in restricting lentiviral replication and determining the rate of disease progression during HIV and HCV mono- and co-infection. Thus, understanding the similarities in the characteristics of CD8+ T cells in mono-HIV and HCV infection at the transcriptomic level contributes to the development of antiviral therapy. In this study, a meta-analysis of CD8+ T cell gene expression profiles derived from mono-HIV and HCV infected individuals at different stages of disease progression, was conducted to understand the common changes experienced by CD8+ T cells. METHODS: Five microarray datasets, reporting CD8+ T cell mRNA expression of the mono-HIV and HCV infected patients, were retrieved from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified via integrative meta-analysis of expression data (INMEX) program. Network analysis methods were used to assess protein-protein interaction (PPI) networks, Gene Ontology (GO) terms and pathway enrichment for DEGs. MirDIP and miRDB online prediction tools were used to predict potential microRNAs (miRNAs) targeting hub genes. RESULTS: First, we identified 625 and 154 DEGs in the CD8+ T cells originating from mono-HIV and HCV chronic progressor patients, respectively, compared to healthy individuals. Among them, interferon-stimulated genes (ISGs) including ISG15, IFIT3, ILI44L, CXCL8, FPR1 and TLR2, were upregulated after mono-HIV and HCV infection. Pathway enrichment analysis of DEGs showed that the "cytokine-cytokine receptor interaction" and "NF-kappa B" signaling pathways were upregulated after mono-HIV and HCV infection. In addition, we identified 92 and 50 DEGs in the CD8+ T cells of HIV non-progressor and HCV resolver patients, respectively, compared with corresponding chronic progressors. We observed attenuated mitosis and reduced ISG expression in HIV non-progressors and HCV resolvers compared with the corresponding chronic progressors. Finally, we identified miRNA-143-3p, predicted to target both IFIT3 in HIV and STAT5A in HCV infection. CONCLUSIONS: We identified DEGs and transcriptional patterns in mono-HIV and HCV infected individuals at different stages of disease progression and identified miRNA-143-3p with potential to intervene disease progression, which provides a new strategy for developing targeted therapies.


Assuntos
Coinfecção , Infecções por HIV , Hepatite C , Linfócitos T CD8-Positivos , Perfilação da Expressão Gênica , Infecções por HIV/genética , Hepatite C/genética , Humanos
6.
Cytokine ; 125: 154801, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31442680

RESUMO

BACKGROUND: HIV rapid progressors (RPs) present with a rapid decline of CD4+ T cells within a few years of infection. Determining the underlying mechanisms throughout this decline is important to identify prognostic biomarkers and intervention strategies. Determining the numbers of CD4+ and CD8+ T cells is essential for monitoring the immune status of HIV infected patients. There are additional kinds of cell subtypes in T cells, but their relationship to the rapid progression of HIV disease is not well defined. METHODS: Nineteen RPs and twenty-one chronic progressors (CPs) were enrolled in this study. Based on the intensity of CD4 and CD8 expression, different T cell subtypes were identified, including CD4+CD8+T cells, CD4-CD8- T cells, CD4+CD8low T cells and CD4-CD8low T cells. Alterations in these T cell subtypes in early HIV infection (within 120 days of infection) between RPs and CPs were measured, and the relationships between these subtypes and HIV disease progression were investigated. In addition, expression of IFN-γ in T cell subtypes after PMA stimulation was analyzed by flow cytometry. RESULTS: We found that during early HIV infection, CD4+CD8low T cells both significantly decreased in numbers and percentages in RPs compared to CPs. Furthermore, baseline CD4+CD8low T cells positively correlated not only with baseline CD4+T cells but also with CD4+T cells 12 months after infection. Moreover, survival analysis indicated that low levels of baseline CD4+CD8low T cells significantly accelerated the decline in CD4+ T cells as well as increased viral loads. CD4+CD8low T cells secreted significantly more IFN-γ after PMA stimulation compared to CD4+CD8-T cells and CD4-CD8+T cells, which may be beneficial for the prevention of disease progression. CONCLUSIONS: Our results identified that in early stage HIV-1 infection, a subtype of T cells, CD4+CD8low, are associated with subsequent disease progression.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Adulto , Biomarcadores/sangue , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Doença Crônica , Correlação de Dados , Progressão da Doença , Humanos , Interferon gama/metabolismo , Masculino , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , Carga Viral/imunologia
7.
J Transl Med ; 17(1): 167, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118081

RESUMO

BACKGROUND: In human immunodeficiency virus (HIV) infection, 10-15% of individuals exhibit a rapid decline in CD4+ T cells and become rapid progressors (RPs). Overall, understanding the factors affecting rapid disease progression in early HIV infection (EHI) can aid in treatment initiation. Recent studies show that eIF3s, classic scaffold proteins during the translation initiation process, can directly promote or inhibit the translation of mRNA, therefore participating in the regulation of cell function. However, to our knowledge, it has not been addressed whether eIF3s are involved in the diverse prognosis of HIV infection. METHODS: Expression of eIF3s in primary cells from early or chronic HIV-infected patients was detected by real-time PCR. To investigate the potential mechanisms of eIF3d in the regulation of CD8+ T cell function, complete transcriptomes of eIF3d-inhibited Jurkat T cells were sequenced by RNA sequencing (RNA-Seq). Additionally, to examine the effect of eIF3d on CD8+ T cell function, eIF3d expression was inhibited alone or in combination with SOCS-7 knockdown by siRNA in isolated CD8+ T cells. CD8+ T cell proliferation, IFN-r secretion and apoptosis were detected by flow cytometry. Moreover, the effect of eIF3d on HIV replication was evaluated in Jurkat cells, peripheral blood mononuclear cells (PBMCs) and CD4+ T cells with eIF3d knockdown using a pNL4-3 pseudotyped virus. RESULTS: At approximately 100 days of infection, only eIF3d was markedly decreased in RPs compared with chronic progressors (CPs). Expression of eIF3d correlated significantly with disease progression in EHI. Based on in vitro analyses, reduced eIF3d expression led to decreased proliferation and IFN-γ secretion and increased apoptosis in CD8+ T cells. Inhibited expression of eIF3d caused enhanced expression of SOCS-7, and inhibiting SOCS-7 expression by siRNA rescued the attenuated CD8+ T cell function caused by eIF3d. Finally, when eIF3d was inhibited in Jurkat cells, PBMCs and CD4+ T cells, pNL4-3-VSV-G virus replication was enhanced. CONCLUSIONS: The current data highlight the importance of eIF3d in HIV infection by inhibiting CD8+ T cell function and promoting viral replication. Our study provides potential targets for improved immune intervention.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Progressão da Doença , Fator de Iniciação 3 em Eucariotos/metabolismo , Infecções por HIV/imunologia , Adulto , Apoptose , Proliferação de Células , Fator de Iniciação 3 em Eucariotos/genética , Feminino , Regulação da Expressão Gênica , Infecções por HIV/genética , Humanos , Interferon gama/metabolismo , Células Jurkat , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Replicação Viral
8.
Front Immunol ; 9: 2850, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564243

RESUMO

T cell responses were less functional and persisted in an exhausted state in chronic HIV infection. Even in early phase of HIV infection, the dysfunction of HIV-specific T cells can be observed in rapid progressors, but the underlying mechanisms are not fully understood. Cytokines play a central role in regulating T cell function. In this study, we sought to elucidate whether IL-33/ST2 axis plays roles in the regulation of T cell function in HIV infection. We found that the level of IL-33 was upregulated in early HIV-infected patients compared with that in healthy controls and has a trend associated with disease progression. In vitro study shows that IL-33 promotes the expression of IFN-γ by Gag stimulated CD4+ and CD8+T cells from HIV-infected patients to a certain extent. However, soluble ST2 (sST2), a decoy receptor of IL-33, was also increased in early HIV infected patients, especially in those with progressive infection. We found that anti-ST2 antibodies attenuated the effect of IL-33 to CD4+ and CD8+T cells. Our data indicates that elevated expression of IL-33 in early HIV infection has the potential to enhance the function of T cells, but the upregulated sST2 weakens the activity of IL-33, which may indirectly contribute to the dysfunction of T cells and rapid disease progression. This data broadens the understanding of HIV pathogenesis and provides critical information for HIV intervention.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Adulto , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Progressão da Doença , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/antagonistas & inibidores , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/antagonistas & inibidores , Interleucina-33/imunologia , Ativação Linfocitária , Masculino , Cultura Primária de Células , Minorias Sexuais e de Gênero , Regulação para Cima/imunologia , Adulto Jovem
9.
Front Immunol ; 9: 3140, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30687333

RESUMO

Human immunodeficiency virus (HIV)-infected long-term non-progressors (LTNPs) are of particular importance because of their unique disease progression characteristics. Defined by the maintenance of normal CD4+T cells after more than 8 years of infection, these LTNPs are heterogeneous. Some LTNPs exhibit ongoing viral production, while others do not and are able to control viral production. The underlying basis for this heterogeneity has not been clearly elucidated. In this study, the miRNA expression profiles of LTNPs were assessed. The levels of microRNA-19b (miR-19b) were found to be significantly increased in peripheral blood mononuclear cells of LTNPs with lower rather than higher viral load. We made clear that miR-19b may regulate CD8+T cell functions in HIV infection, which has not been addressed before. Overexpression of miR-19b promoted CD8+T cell proliferation, as well as interferon-γ and granzyme B expression, while inhibiting CD8+T cells apoptosis induced by anti-CD3/CD28 stimulation. The target of miR-19b was found to be the "phosphatase and tensin homolog", which regulates CD8+T cells function during HIV infections. Furthermore, we found that miR-19b can directly inhibit viral production in in-vitro HIV infected T cells. These results highlight the importance of miR-19b to control viral levels, which facilitate an understanding of human immunodeficiency virus pathogenesis and provide potential targets for improved immune intervention.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Terapia Antirretroviral de Alta Atividade , Apoptose/genética , Apoptose/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Resposta Viral Sustentada , Carga Viral , Replicação Viral
10.
J Transl Med ; 15(1): 191, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28899396

RESUMO

BACKGROUND: A small proportion of HIV-infected patients remain clinically and/or immunologically stable for years, including elite controllers (ECs) who have undetectable viremia (<50 copies/ml) and long-term nonprogressors (LTNPs) who maintain normal CD4+ T cell counts for prolonged periods (>10 years). However, the mechanism of nonprogression needs to be further resolved. In this study, a transcriptome meta-analysis was performed on nonprogressor and progressor microarray data to identify differential transcriptome pathways and potential biomarkers. METHODS: Using the INMEX (integrative meta-analysis of expression data) program, we performed the meta-analysis to identify consistently differentially expressed genes (DEGs) in nonprogressors and further performed functional interpretation (gene ontology analysis and pathway analysis) of the DEGs identified in the meta-analysis. Five microarray datasets (81 cases and 98 controls in total), including whole blood, CD4+ and CD8+ T cells, were collected for meta-analysis. RESULTS: We determined that nonprogressors have reduced expression of important interferon-stimulated genes (ISGs), CD38, lymphocyte activation gene 3 (LAG-3) in whole blood, CD4+ and CD8+ T cells. Gene ontology (GO) analysis showed a significant enrichment in DEGs that function in the type I interferon signaling pathway. Upregulated pathways, including the PI3K-Akt signaling pathway in whole blood, cytokine-cytokine receptor interaction in CD4+ T cells and the MAPK signaling pathway in CD8+ T cells, were identified in nonprogressors compared with progressors. In each metabolic functional category, the number of downregulated DEGs was more than the upregulated DEGs, and almost all genes were downregulated DEGs in the oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle in the three types of samples. CONCLUSIONS: Our transcriptomic meta-analysis provides a comprehensive evaluation of the gene expression profiles in major blood types of nonprogressors, providing new insights in the understanding of HIV pathogenesis and developing strategies to delay HIV disease progression.


Assuntos
Progressão da Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Regulação para Baixo/genética , Ontologia Genética , Humanos , Redes e Vias Metabólicas/genética , Transcriptoma/genética , Regulação para Cima/genética
11.
Front Immunol ; 8: 1122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28955339

RESUMO

Persistent activation and inflammation impair immune response and trigger disease progression in HIV infection. Emerging evidence supports the supposition that excessive production of interferon-inducible protein 10 (IP-10), a critical inflammatory cytokine, leads to immune dysfunction and disease progression in HIV infection. In this study, we sought to elucidate the cause of the upregulated production of IP-10 in HIV infection and explore the underlying mechanisms. Bolstering miR-21 levels using mimics resulted in the obvious suppression of lipopolysaccharide (LPS)-induced IP-10 in monocyte leukemia cells THP-1 and vice versa. The analysis of the primary monocytes of HIV patients revealed significantly less miR-21 than in healthy controls; this was opposite to the tendency of IP-10 levels in plasma. The secretion of IP-10 due to LPS stimulation was not affected by miR-21 modulation in the differentiated THP-1 macrophages (THP-1-MA). We found a novel switch, IFN-stimulated gene 15 (ISG15), which triggers the expression of IP-10 and is significantly upregulated during the differentiation of THP-1 into THP-1-MA. The inhibition of ISG15 can restore the regulation of IP-10 by miR-21. In summary, IP-10 expression in monocytes is regulated by miR-21, whereas in macrophages, this fine-tuning is attenuated by the enhanced expression of ISG15. This study paves the way to a comprehensive understanding of the molecular regulatory mechanism of IP-10, a key point in immune intervention strategy.

12.
J Acquir Immune Defic Syndr ; 76(2): 200-208, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28570288

RESUMO

OBJECTIVE: Events occurring during the initial phase of human immunodeficiency virus (HIV) infection are intriguing because of their dramatic impact on the subsequent course of the disease. In particular, the relationship between myeloid-derived suppressor cells (MDSCs) and HIV pathogenesis in primary infection remains unknown and the mechanism of MDSCs in HIV infection are incompletely defined. METHODS: The frequency of MDSC expression in patients with primary HIV infection (PHI) and chronic HIV infection was measured, and the association with disease progression was studied. Programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9) expression on MDSCs was measured and in vitro blocking experiments were performed to study the role of PD-L1 in MDSCs' inhibition. RESULTS: We found increased levels of HLA-DRCD14CD33CD11b granulocytic(G)-MDSCs in PHI individuals compared with normal controls, which correlated with viral loads and was negatively related to CD4 T-cell levels. When cocultured with purified G-MDSCs, both proliferation and interferon-γ secretion by T cell receptor (TCR)-stimulated CD8 T cells from HIV-infected patients were significantly inhibited. We also demonstrated that PD-L1, but not Gal-9, expression on HLA-DRCD14CD33CD11b cells increased during HIV infection. The suppressive activity of G-MDSCs from HIV-infected patients was attenuated by PD-L1 blockade. CONCLUSIONS: We found a significant increase in G-MDSCs in PHI patients that was related to disease progression and PD-L1 was used by MDSCs to inhibit CD8 T cells in HIV infection. Our data improve the understanding of HIV pathogenesis in PHI.


Assuntos
Antígeno B7-H1/metabolismo , Progressão da Doença , Galectinas/metabolismo , Infecções por HIV/tratamento farmacológico , Células Supressoras Mieloides/efeitos dos fármacos , Adulto , Antirreumáticos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Doença Crônica , Feminino , Galectinas/genética , HIV-1/efeitos dos fármacos , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Células Supressoras Mieloides/citologia , Carga Viral , Adulto Jovem
13.
Cytokine ; 91: 110-117, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28043029

RESUMO

INTRODUCTION: IL-21 enhances T and natural killer cells survival and antiviral functions without promoting T cell activation during HIV infection, which makes it a better adjuvant in anti-HIV immunotherapy. Due to the pleiotropy and redundancy of cytokines, it is vital to have a comprehensive knowledge of the role of IL-21 in the regulation of immune responses. Regulatory T cells (Tregs) play an important role in immune regulation and are a determinant of immune therapeutic efficacy in certain circumstances. In this study, we explored the direct effect of IL-21 on Tregs during HIV infection, which has not been addressed before. METHODS: Thirty-four HIV treatment-naïve patients were enrolled and the relationship between CD4+IL-21+T cells and Tregs were studied. The effects of IL-21 on CD4+CD25+CD127low Tregs' apoptosis, proliferation, and CTLA-4 and TGF-ß expression in HIV-infected patients was investigated and compared with the effect of other common γ-chain cytokines. RESULTS: We found the percentage and absolute numbers of CD4+IL-21+T cells were positively related to the frequency or absolute numbers of CD4+CD25+ or CD4+CD25+CD127low Tregs. Compared with the media-alone control, IL-21, IL-7, and IL-15 could significantly reduce apoptosis of Tregs (p<0.05). IL-21 did not promote the proliferation of Tregs as compared with media alone, while IL-2, IL-7, and IL-15 could significantly increase the proliferation of Tregs (p<0.05). IL-21 enhanced CTLA-4 expression by Tregs (p<0.05), but could not induce TGF-ß secretion of Tregs from HIV infected patients. There were no significant differences of the fold induction of apoptosis, proliferation, or CTLA-4 and TGF-ß expression by Tregs from HIV-infected patients and normal controls after IL-21 treatment. In vitro experiment showed that pretreatment with IL-21 significantly enhanced the suppressive effect of Tregs on CD8+ T cells' IFN-γ expression. CONCLUSION: We conclude that IL-21 promotes the survival and CTLA-4 expression of Tregs and enhanced the suppressive capacity of Tregs during HIV infection. These results broaden the understanding of HIV pathogenesis and provide critical information for HIV interventions.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Interleucinas/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Apoptose/imunologia , Antígeno CTLA-4/imunologia , Proliferação de Células , Sobrevivência Celular/imunologia , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/imunologia
14.
Biomed Res Int ; 2015: 916936, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25685816

RESUMO

PURPOSE: To explore the association between differential Tim-3 and PD-1 expression patterns and HIV disease progression, and to investigate the impact of common γ-chain cytokines on Tim-3 and PD-1 expression patterns on T cells. METHODS: Tim-3/PD-1 expression on the T cells of patients with early and chronic HIV infections was detected. The expression levels and functional profiles of T cells with differential Tim-3 and PD-1 expression patterns induced by γ-chain cytokines were studied. RESULTS: The elevation of differential Tim-3 and PD-1 expression patterns on T cells appeared early in HIV infection. Co-expression of Tim-3 and PD-1 (Tim-3+PD-1+) correlates with more severe exhaustion of T cells during HIV infection. In vitro stimulation of common γ-chain cytokines can induce differential expression patterns of Tim-3 and PD-1 on T cells. The enhancement of Tim-3 and PD-1 expression by common γ-chain IL-2 can inhibit the function of T cells re-stimulated by HIV gag and TCR, not by the re-stimulation of IL-2. CONCLUSIONS: The elevation of differential Tim-3 and PD-1 expression patterns on T cells represents a state of T cell exhaustion and can be induced by common γ-chain cytokines. These findings provide insights into HIV pathogenesis and help inform immune intervention strategies.


Assuntos
Regulação da Expressão Gênica , Infecções por HIV/metabolismo , HIV-1/metabolismo , Interleucina-2/metabolismo , Proteínas de Membrana/biossíntese , Receptor de Morte Celular Programada 1/biossíntese , Linfócitos T/metabolismo , Feminino , Infecções por HIV/patologia , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Masculino , Linfócitos T/patologia
15.
Clin Chem ; 59(8): 1175-86, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23592504

RESUMO

BACKGROUND: A substantial percentage (10%-15%) of HIV-infected individuals experience a sharp decline in CD4(+) T-cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) vs chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy. METHODS: mRNA and microRNA (miRNA) expression profiles in the peripheral blood mononuclear cells (PBMCs) of RPs and CPs were investigated at 111 (22) days [mean (SD)] of HIV infection. The association of mRNA and miRNA expression with disease progression was examined by ROC analysis and Kaplan-Meier survival analysis. RESULTS: Pathway enrichment analysis showed that genes with deregulated expression in RPs were primarily involved in apoptosis pathways. Furthermore, we found that 5 miRNAs (miR-31, -200c, -526a, -99a, and -503) in RPs were significantly decreased compared to those in CPs (P < 0.05). The decreased expression of these miRNAs was associated with a rapid disease of progression of HIV infection with a 94% predictive value as measured by the area under the curve. The upregulated predicted targets from the 5 signature miRNAs and all upregulated genes identified from mRNA microarray analysis converged to the apoptosis pathway. Moreover, overexpression of miR-31 in primary human T cells promoted their survival. CONCLUSIONS: Our results have identified a distinct transcriptomic signature in PBMCs of RPs and provided novel insights to the pathogenesis of HIV infection.


Assuntos
Infecções por HIV/sangue , Leucócitos Mononucleares/metabolismo , Transcriptoma , Adulto , Apoptose/genética , Estudos de Casos e Controles , Sobrevivência Celular , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Infecções por HIV/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/sangue , RNA Mensageiro/sangue , Curva ROC , Linfócitos T/metabolismo , Linfócitos T/patologia
16.
Zhonghua Yi Xue Za Zhi ; 92(17): 1159-64, 2012 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-22883001

RESUMO

OBJECTIVE: To explore the human leukocyte antigen (HLA)-associated mutations in Gag protein of B' clade (human immunodeficiency virus-1) HIV-1 infected Han Chinese people and evaluate the impact of HLA associated Gag mutations on the disease progression of HIV infection. METHODS: A total of 95 B' clade HIV-1 infected Han Chinese cases were recruited. The gag sequences were amplified from viral RNA and sequenced directly. HLA-I genotypes were detected with the assay of polymerase chain reaction-sequence specific primer (PCR-SSP). HLA-associated mutations were identified and the relationships between HLA-associated mutations and CD4+ T cell counts or plasma viral loads analyzed. RESULTS: Forty-seven kinds of mutations at 28 sites (15, 18, 26, 30, 34, 46, 62, 67, 81, 84, 90, 102, 118, 121, 122, 125, 146, 147, 173, 176, 252, 357, 374, 376, 437, 470, 471, 478) of Gag protein were significantly associated with particular HLA class I allelotypes (P < 0.05). Among which, 9 sites (26, 30, 81, 84, 125, 146, 147, 357, 437) were located within 13 known cytotoxic T-lymphocyte (CTL) epitopes or flanking regions. The number of HLA-associated mutations was significantly associated with both CD4 T cell counts (r = -0.318, P = 0.002) and viral loads (r = 0.360, P = 0.003). CONCLUSION: HLA-associated mutations may have a significant impact on HIV disease progression in B' clade HIV-1 infected Han Chinese population.


Assuntos
Síndrome de Imunodeficiência Adquirida/genética , Síndrome de Imunodeficiência Adquirida/virologia , Genes MHC Classe I , HIV-1/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , RNA Viral , Carga Viral , Adulto Jovem
17.
BMC Infect Dis ; 12: 5, 2012 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-22243920

RESUMO

BACKGROUND: Toll-like receptors (TLR) 7 and 8 are important in single-stranded viral RNA recognition and may play a role in HIV infection and disease progression. We analyzed TLR7/8 expression and signaling in monocytes from HIV-infected and uninfected subjects to investigate a pathway with new potential for the suppression of HIV replication. METHODS: Eighty-one HIV-infected and uninfected subjects from Liaoning and Henan provinces in China participated in this study. Monocytes were isolated from subjects' peripheral blood mononuclear cells by magnetic bead selection. TLR7 and TLR8 mRNA was measured using quantitative real-time reverse transcriptase PCR. R-848 (resiquimod) was used as a ligand for TLR7 and TLR8 in order to 1) assess TLR7/8-mediated monocyte responsiveness as indicated by IL-12 p40 and TNF-α secretion and 2) to examine HIV replication in cultured monocytes in the presence of R-848. RESULTS: We found that expression of TLR7/8 mRNA in peripheral blood monocytes decreased with disease progression. TLR7 expression was decreased with stimulation with the TLR7/8 agonist, R-848, in vitro, whereas TLR8 expression was unaffected. Following R-848 stimulation, monocytes from HIV-infected subjects produced significantly less TNF-α than those from uninfected subjects, but trended towards greater production of IL-12 than stimulated monocytes from uninfected subjects. R-848 stimulation also suppressed HIV replication in cultured monocytes. CONCLUSIONS: Our study provides evidence that the TLR7 and TLR8 triggering can suppress HIV replication in monocytes and lead to postpone HIV disease progression, thereby offering novel targets for immunomodulatory therapy.


Assuntos
HIV/crescimento & desenvolvimento , Imidazóis/farmacologia , Fatores Imunológicos/farmacologia , Monócitos/imunologia , Monócitos/virologia , Receptor 7 Toll-Like/biossíntese , Receptor 8 Toll-Like/biossíntese , Adulto , Células Cultivadas , China , Feminino , Perfilação da Expressão Gênica , HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Replicação Viral
18.
Chin Med J (Engl) ; 123(23): 3406-11, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22166522

RESUMO

BACKGROUND: Studies on human immunodeficiency virus type 1 (HIV-1) vaccines have recently focused on targeting the conserved neutralizing epitopes 2F5 and 4E10, and hence it is important to understand the extent of mutations in these two viral epitopes. Here, we investigated the amino acid mutations in epitopes of 2F5 (ELDKWA, HIV-1 HXB2 env 662 - 667 aa) and 4E10 (NWFDIT, HIV-1 HXB2 env 671 - 676 aa) in the membrane proximal-external region of gp41 from clade B' HIV-1-infected individuals living in Henan province, China. We also examined the frequency of a mutation and its relation to disease progression. METHODS: A cohort of 54 treatment-naïve HIV-1-infected individuals was recruited in this study, and 16 individuals were selected for a short-term longitudinal study on sequence evolution. The HIV-1 env gp41 gene was amplified, cloned, and sequenced, and predicted amino acid sequences were aligned for analysis. RESULTS: The mutations E662A and K665E on the 2F5 epitope and N671S and T676S on the 4E10 epitope were seen. Simultaneous RNA sequencing showed some discrepancies with proviral DNA sequences. In our longitudinal study, mutation levels of these two neutralizing epitopes were low but diverse and persistent. The frequencies of mutations within the 4E10 peptide NWFDIT in slow progressors were noticeably lower than those in AIDS patients (P < 0.05). CONCLUSIONS: Antigenic variation of the neutralizing epitopes 2F5 and 4E10 is limited in subtype B' infection, and that 4E10 peptide mutation is correlated with disease progression. Monitoring epitope mutations will offer useful data for development of the candidate 2F5-like and 4E10-like antibodies to prevent and treat AIDS.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Anticorpos Neutralizantes/genética , Epitopos/genética , Anticorpos Anti-HIV/genética , Proteína gp41 do Envelope de HIV/imunologia , HIV-1/imunologia , Mutação , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Progressão da Doença , Evolução Molecular , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/química
19.
Zhonghua Liu Xing Bing Xue Za Zhi ; 30(7): 663-7, 2009 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-19957585

RESUMO

OBJECTIVE: To better understand the prevalence and geographic distribution of genotypes/subtypes on HCV and the relationship between HCV genotypes/subtypes and HIV infection disease progression in the HIV-1/HCV co-infected individuals living in high HIV-1 prevalent areas in China. METHODS: 186 plasma samples were collected from HIV-1 seropositive individuals infected through paid blood donors (PBD), injecting drug users(IDUs) or sexual contact, living in most severely affected provinces, Henan, Yunnan, Xinjiang, Jilin and Liaoning provinces. Samples with HCV viral load >1000 cop/ml were amplified by RT-nested PCR, sequenced and phylogenetically analyzed for genotyping/subtyping of HCV. HIV-1, HCV viral loads and CD4+ T lymphocytes were measured for all subjects. RESULTS: (1) HCV were identified as 1a (1.7%), 1b (39.9%), 2a (17.9%), 3a (10.4%), 3b (15.6%), 6a (1.2%), 6n (6.4%), and a newly unclassified subtype (7.5%). HCV 2a and 1b subtypes predominated in PBD in Henan, 3a and 3b in IDUs in Xinjiang and Yunnan, and 6 genotype/subtypes in IDU in Yunnan. (2) There were no significant differences in CD4+ T cell counts among the different HCV subtypes. (3) The viral load of HCV RNA in 1b subtype was higher than that of non-1b subtype, however, no significant differences in HIV-1 viral loads and CD4+ T cell counts were found between 1b and non-lb subtype. Both HIV and HCV viral loads were lower in 2a than non-2a subtype. CONCLUSION: The prevalence of HCV genotype/subtype in HIV-1/HCV co-infected individuals was associated with geographic areas and transmission routes. HCV subtypes had no direct correlation with HIV infection disease progression.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/virologia , Infecções por HIV/complicações , HIV-1 , Hepacivirus/genética , Hepatite C/virologia , Coleta de Amostras Sanguíneas , Contagem de Linfócito CD4 , Comorbidade , Progressão da Doença , Genótipo , Hepacivirus/classificação , Hepatite C/complicações , Humanos , Prevalência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Viral
20.
Jpn J Infect Dis ; 61(5): 361-5, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18806342

RESUMO

This study sought to investigate the impacts of the antiretroviral (ARV) therapy regimens currently used in Chinese HIV-1-infected individuals. Seven hundred eighteen ARV-treated and treatment-naive HIV-1-infected individuals living in seven provinces were enrolled in 2005 by a multistage sampling approach according to a national cross-sectional survey program on HIV-1 drug resistance. All patients were investigated clinically, and CD4+ T cell counts and HIV-1 viral loads were measured while genotyping for drug resistance was determined by a home brew nested PCR. Viral inhibition in ARV-treated individuals was higher than that in ARV treatment-naive individuals. The overall prevalence of drug-resistant mutations was 37.8%. Higher frequencies of mutations in ARV-treated and drug withdrawal groups were found than in the ARV treatment-naive group (P<0.01). Of the four regimens currently used, the D4T/3TC/NVP regimen showed a higher-level viral inhibition. No statistical significance was found among the four regimens in drug-resistant mutations. The rate of resistance-associated mutations to non-nucleotide reverse transcriptase inhibitors (NNRTIs) was higher than that to nucleotide reverse transcriptase inhibitors (NRTIs) (P<0.01). The most common mutations conferring resistance to NNRTIs were K103N, Y181C and G190A, representing 56.5, 30.4 and 14.5%, respectively. Furthermore, higher viral inhibition and a lower rate of drug-resistant mutations were achieved in the good compliance group. This study revealed an efficient viral inhibition achieved with the current first-line regimens in China. Most of these regimens could rapidly result in emergence of drug-resistant mutations, suggesting that a second-line ARV therapy is urgently needed and that the compliance with treatment must be emphasized during long-term treatment.


Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral/genética , HIV-1/efeitos dos fármacos , Mutação/efeitos dos fármacos , Inibidores da Transcriptase Reversa , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , China/epidemiologia , Estudos Transversais , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/enzimologia , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Carga Viral
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