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1.
Nat Med ; 27(11): 1893-1898, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34711975

RESUMO

Certain infected individuals suppress human immunodeficiency virus (HIV) in the absence of anti-retroviral therapy (ART). Elucidating the underlying mechanism(s) is of high interest. Here we present two contrasting case reports of HIV-infected individuals who controlled plasma viremia for extended periods after undergoing analytical treatment interruption (ATI). In Participant 04, who experienced viral blips and initiated undisclosed self-administration of suboptimal ART detected shortly before day 1,250, phylogenetic analyses of plasma HIV env sequences suggested continuous viral evolution and/or reactivation of pre-existing viral reservoirs over time. Antiviral CD8+ T cell activities were higher in Participant 04 than in Participant 30. In contrast, Participant 30 exhibited potent plasma-IgG-mediated neutralization activity against autologous virus that became ineffective when he experienced sudden plasma viral rebound 1,434 d after ATI due to HIV superinfection. Our data provide insight into distinct mechanisms of post-treatment interruption control and highlight the importance of frequent monitoring of undisclosed use of ART and superinfection during the ATI phase.

2.
PLoS Pathog ; 17(7): e1009732, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34280251

RESUMO

We have recently demonstrated that the function of T follicular helper (Tfh) cells from lymph nodes (LN) of HIV-infected individuals is impaired. We found that these cells were unable to provide proper help to germinal center (GC)-B cells, as observed by altered and inefficient anti-HIV antibody response and premature death of memory B cells. The underlying molecular mechanisms of this dysfunction remain poorly defined. Herein, we have used a unique transcriptional approach to identify these molecular defects. We consequently determined the transcriptional profiles of LN GC-Tfh cells following their interactions with LN GC-B cells from HIV-infected and HIV-uninfected individuals, rather than analyzing resting ex-vivo GC-Tfh cells. We observed that proliferating GC-Tfh cells from HIV-infected subjects were transcriptionally different than their HIV-uninfected counterparts, and displayed a significant downregulation of immune- and GC-Tfh-associated pathways and genes. Our results strongly demonstrated that MAF (coding for the transcription factor c-Maf) and its upstream signaling pathway mediators (IL6R and STAT3) were significantly downregulated in HIV-infected subjects, which could contribute to the impaired GC-Tfh and GC-B cell functions reported during infection. We further showed that c-Maf function was associated with the adenosine pathway and that the signaling upstream c-Maf could be partially restored by adenosine deaminase -1 (ADA-1) supplementation. Overall, we identified a novel mechanism that contributes to GC-Tfh cell impairment during HIV infection. Understanding how GC-Tfh cell function is altered in HIV is crucial and could provide critical information about the mechanisms leading to the development and maintenance of effective anti-HIV antibodies.


Assuntos
Infecções por HIV/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Células T Auxiliares Foliculares/imunologia , Adulto , Doença Crônica , Feminino , Centro Germinativo/imunologia , Humanos , Masculino , Transdução de Sinais/imunologia
3.
medRxiv ; 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34268520

RESUMO

SARS-CoV-2 mRNA vaccines are highly effective, although weak antibody responses are seen in some individuals with correlates of immunity that remain poorly understood. Here we longitudinally dissected antibody, plasmablast, and memory B cell (MBC) responses to the two-dose Moderna mRNA vaccine in SARS-CoV-2-uninfected adults. Robust, coordinated IgA and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses, but earlier and more intensely after dose two. Distinct antigen-specific MBC populations also emerged post-vaccination with varying kinetics. We identified antigen non-specific pre-vaccination MBC and post-vaccination plasmablasts after dose one and their spike-specific counterparts early after dose two that correlated with subsequent antibody levels. These baseline and response signatures can thus provide early indicators of serological efficacy and explain response variability in the population.

4.
Sci Adv ; 7(22)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34039612

RESUMO

Chronic infectious diseases have a substantial impact on the human B cell compartment including a notable expansion of B cells here termed atypical B cells (ABCs). Using unbiased single-cell RNA sequencing (scRNA-seq), we uncovered and characterized heterogeneities in naïve B cell, classical memory B cells, and ABC subsets. We showed remarkably similar transcriptional profiles for ABC clusters in malaria, HIV, and autoimmune diseases and demonstrated that interferon-γ drove the expansion of ABCs in malaria. These observations suggest that ABCs represent a separate B cell lineage with a common inducer that further diversifies and acquires disease-specific characteristics and functions. In malaria, we identified ABC subsets based on isotype expression that differed in expansion in African children and in B cell receptor repertoire characteristics. Of particular interest, IgD+IgMlo and IgD-IgG+ ABCs acquired a high antigen affinity threshold for activation, suggesting that ABCs may limit autoimmune responses to low-affinity self-antigens in chronic malaria.

5.
Commun Biol ; 4(1): 563, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980982

RESUMO

Innate Lymphoid Cells (ILCs) are immune cells typically found on mucosal surfaces and in secondary lymphoid organs where they regulate the immune response to pathogens. Despite their key role in the immune response, there are still fundamental gaps in our understanding of ILCs. Here we report a human ILC population present in the follicles of tonsils and lymph nodes termed follicular regulatory ILCs (ILCFR) that to our knowledge has not been previously identified. ILCFR have a distinct phenotype and transcriptional program when compared to other defined ILCs. Surprisingly, ILCFR inhibit the ability of follicular helper T (Tfh) cells to provide B cell help. The localization of ILCFR to the germinal centers suggests these cells may interfere with germinal center B cell (GC-B) and germinal center Tfh cell (GC-Tfh) interactions through the production of transforming growth factor beta (TGF-ß. Intriguingly, under conditions of impaired GC-Tfh-GC-B cell interactions, such as human immunodeficiency virus (HIV) infection, the frequency of these cells is increased. Overall, we predict a role for ILCFR in regulating GC-Tfh-GC-B cell interactions and propose they expand in chronic inflammatory conditions.


Assuntos
Centro Germinativo/imunologia , Centro Germinativo/fisiologia , Linfócitos/imunologia , Adolescente , Adulto , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Imunidade Inata/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária/imunologia , Linfócitos/metabolismo , Masculino , Tonsila Palatina/imunologia , Tonsila Palatina/metabolismo , Células T Auxiliares Foliculares/imunologia
6.
Cell ; 184(7): 1836-1857.e22, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713619

RESUMO

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.


Assuntos
COVID-19/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Expressão Gênica/imunologia , Células Matadoras Naturais/metabolismo , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , COVID-19/mortalidade , Estudos de Casos e Controles , Células Dendríticas/citologia , Feminino , Humanos , Células Matadoras Naturais/citologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transcriptoma/imunologia , Adulto Jovem
7.
J Infect Dis ; 224(9): 1599-1604, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33744939

RESUMO

Persistent exposure to antigen leads to T-cell exhaustion and immunologic dysfunction. We examined the immune exhaustion markers T cell immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) in human immunodeficiency virus (HIV)-infected and healthy individuals and the relationship with cytotoxic CD8+ T-lymphocyte activity. Frequencies of TIGIT but not PD-1 were positively correlated with CD8+ T-lymphocyte activity in HIV-aviremic and healthy individuals; however, there was no correlation in HIV-viremic individuals. Transcriptome analyses revealed up-regulation of genes associated with antiviral immunity in TIGIT+CD8+ versus TIGIT-CD8+ T cells. Our data suggest that TIGIT+CD8+ T cells do not necessarily represent a state of immune exhaustion and maintain an intrinsic cytotoxicity in HIV-infected individuals.

8.
J Infect Dis ; 223(4): 645-654, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33471124

RESUMO

CD4 expression identifies a subset of mature T cells primarily assisting the germinal center reaction and contributing to CD8+ T-cell and B-cell activation, functions, and longevity. Herein, we present a family in which a novel variant disrupting the translation-initiation codon of the CD4 gene resulted in complete loss of membrane and plasma soluble CD4 in peripheral blood, lymph node, bone marrow, skin, and ileum of a homozygous proband. This inherited CD4 knockout disease illustrates the clinical and immunological features of a complete deficiency of any functional component of CD4 and its similarities and differences with other clinical models of primary or acquired loss of CD4+ T cells. The first inherited loss of any functional component of CD4, including soluble CD4, is clinically distinct from any other congenital or acquired CD4 T-cell defect and characterized by compensatory changes in T-cell subsets and functional impairment of B cells, monocytes, and natural killer cells.


Assuntos
Antígenos CD4/deficiência , Antígenos CD4/genética , Síndromes de Imunodeficiência/genética , Iniciação Traducional da Cadeia Peptídica/genética , Doenças da Imunodeficiência Primária/genética , Medula Óssea/imunologia , Medula Óssea/metabolismo , Antígenos CD4/análise , Antígenos CD4/sangue , Linfócitos T CD4-Positivos/imunologia , Códon de Iniciação , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Íleo/imunologia , Íleo/metabolismo , Imunidade Inata , Síndromes de Imunodeficiência/imunologia , Células Matadoras Naturais/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária , Masculino , Monócitos/imunologia , Mutação de Sentido Incorreto , Linhagem , Doenças da Imunodeficiência Primária/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto Jovem
9.
J Infect Dis ; 222(10): 1655-1659, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32443148

RESUMO

Historical data regarding time to viral rebound following analytical treatment interruption (ATI) have been used to determine therapeutic efficacy in HIV cure trials; however, such data were collected from studies conducted a decade or more ago and included participants receiving older antiretroviral therapy (ART) regimens with infrequent virologic monitoring. We conducted a study of 22 HIV-infected participants receiving modern ART to determine the kinetics of plasma viral rebound following ATI. Our data suggest that modern ART does not alter kinetics of viral rebound when compared to previous regimens and that immunologic interventions may be necessary to achieve ART-free virologic remission. Clinical Trials Registration ClinicaTrials.gov identifier: NCT03225118.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Plasma/virologia , Adulto , Feminino , HIV-1/genética , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Carga Viral
10.
Immunity ; 52(5): 726-728, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32433944

RESUMO

Memory B cells (MBCs) expressing the transcription factor T-bet have been described in normal and dysregulated immune responses. In this issue of Immunity, Johnson et al. report that T-bet+ MBCs, formed in response to a primary influenza infection, contribute to protective antibody titers and persist mainly in the spleen with restricted trafficking between tissues.


Assuntos
Subpopulações de Linfócitos B , Animais , Especificidade de Anticorpos , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Humanos , Memória Imunológica , Camundongos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Distribuição Tecidual
11.
Nat Med ; 26(4): 618-629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32094927

RESUMO

Responses to vaccination and to diseases vary widely across individuals, which may be partly due to baseline immune variations. Identifying such baseline predictors of immune responses and their biological basis is of broad interest, given their potential importance for cancer immunotherapy, disease outcomes, vaccination and infection responses. Here we uncover baseline blood transcriptional signatures predictive of antibody responses to both influenza and yellow fever vaccinations in healthy subjects. These same signatures evaluated at clinical quiescence are correlated with disease activity in patients with systemic lupus erythematosus with plasmablast-associated flares. CITE-seq profiling of 82 surface proteins and transcriptomes of 53,201 single cells from healthy high and low influenza vaccination responders revealed that our signatures reflect the extent of activation in a plasmacytoid dendritic cell-type I IFN-T/B lymphocyte network. Our findings raise the prospect that modulating such immune baseline states may improve vaccine responsiveness and mitigate undesirable autoimmune disease activity.


Assuntos
Imunidade Adaptativa/genética , Formação de Anticorpos/genética , Vacinas contra Influenza/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transcriptoma , Vacina contra Febre Amarela/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Influenza Humana/prevenção & controle , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Transcriptoma/imunologia , Vacinação , Febre Amarela/prevenção & controle , Adulto Jovem
12.
J Clin Invest ; 130(4): 1669-1682, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874111

RESUMO

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.


Assuntos
Doenças Autoimunes , Interferon Tipo I , Interleucina-18 , Síndrome de Ativação Macrofágica , Mutação , Paniculite , Proteinose Alveolar Pulmonar , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Feminino , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/imunologia , Masculino , Paniculite/genética , Paniculite/imunologia , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/imunologia
13.
Sci Transl Med ; 11(520)2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776286

RESUMO

Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19hiT-bethi MBC in the peripheral blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear how these B cells arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. We addressed these questions by characterizing T-bet-expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among HIV-specific MBC associated with poor immunologic outcome. Confocal microscopy and quantitative imaging revealed that T-bethi B cells in LN of HIV-infected chronically viremic individuals distinctly accumulated outside germinal centers (GC), which are critical for optimal antibody responses. In single-cell analyses, LN T-bethi B cells of HIV-infected individuals were almost exclusively found among CD19hi MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19hiT-bethi MBC and displayed a distinct transcriptome, with features similar to CD19hiT-bethi MBC in blood and LN GC B cells (GCBC). LN CD19hiT-bethi MBC were also related to GCBC by B cell receptor (BCR)-based phylogenetic linkage but had lower BCR mutation frequencies and reduced HIV-neutralizing capacity, consistent with diminished participation in GC-mediated affinity selection. Thus, in the setting of chronic immune activation associated with HIV viremia, failure of HIV-specific B cells to enter or remain in GC may help explain the rarity of high-affinity protective antibodies.


Assuntos
Afinidade de Anticorpos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Infecções por HIV/imunologia , Proteínas com Domínio T/metabolismo , Adulto , Anticorpos Neutralizantes/imunologia , Antígenos CD19/metabolismo , Citocinas/metabolismo , Feminino , Infecções por HIV/genética , Humanos , Memória Imunológica , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Fenótipo , Receptores de Antígenos de Linfócitos B/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/genética , Adulto Jovem
14.
J Clin Invest ; 129(11): 4832-4837, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31589168

RESUMO

A number of highly potent and broadly neutralizing antibodies (bNAbs) against the human immunodeficiency virus (HIV) have recently been shown to prevent transmission of the virus, suppress viral replication, and delay plasma viral rebound following discontinuation of antiretroviral therapy in animal models and infected humans. However, the degree and extent to which such bNAbs interact with primary lymphocytes have not been fully delineated. Here, we show that certain glycan-dependent bNAbs, such as PGT121 and PGT151, bind to B, activated T, and natural killer (NK) cells of HIV-infected and -uninfected individuals. Binding of these bNAbs, particularly PGT121 and PGT151, to activated CD4+ and CD8+ T cells was mediated by complex-type glycans and was abrogated by enzymatic inhibition of N-linked glycosylation. In addition, a short-term incubation of PGT151 and primary NK cells led to degranulation and cellular death. Our data suggest that the propensity of certain bNAbs to bind uninfected/bystander cells has the potential for unexpected outcomes in passive-transfer studies and underscore the importance of antibody screening against primary lymphocytes.


Assuntos
Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Glucanos/imunologia , Anticorpos Anti-HIV/imunologia , Células Matadoras Naturais/imunologia , Feminino , Glicosilação , Humanos , Masculino
15.
Sci Transl Med ; 11(509)2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31488581

RESUMO

Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4ß7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4ß7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4ß7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4ß7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4ß7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Integrinas/imunologia , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Reservatórios de Doenças/virologia , Feminino , Infecções por HIV/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Viremia/sangue , Suspensão de Tratamento
16.
Curr Opin HIV AIDS ; 14(4): 240-245, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30973418

RESUMO

PURPOSE OF REVIEW: Numerous B-cell abnormalities in HIV-1 infection have been described over the past three decades yet have remained poorly defined mechanistically. We review recent studies that describe mechanisms of B-cell dysregulation in chronic HIV-1 infection associated with IgG3 and T-bet. RECENT FINDINGS: HIV-1 infection causes hypergammaglobulinemia and dysregulation of B-cell populations, including the expansion during chronic viremia of functionally impaired tissue-like memory (TLM) B cells. TLM B cells and B cells in other conditions of chronic activation and inflammation with similar phenotypes are characterized by increased expression of the transcription factor T-bet and preferential immunoglobulin class-switching to IgG3. However, defects in B-cell function during chronic HIV-1 viremia are also associated with the binding of soluble IgG3 to IgM-expressing B cells, with the highest intensities observed on TLM B cells. The consequence of IgG3 binding to TLM B cells is increased clustering of the IgM B-cell receptor and decreased response to stimulation. SUMMARY: The identification of T-bet and IgG3 as the regulators of B-cell function in chronic HIV-1 viremia could provide new targets for therapeutic intervention aimed at reversing the damaging effects of HIV-1-associated chronic immune activation.


Assuntos
Linfócitos B/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Imunoglobulina G/imunologia , Proteínas com Domínio T/imunologia , Animais , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Humanos , Memória Imunológica , Proteínas com Domínio T/genética , Viremia/genética , Viremia/imunologia , Viremia/virologia
17.
J Infect Dis ; 220(2): 270-274, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-30840763

RESUMO

Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)-infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Infecções por HIV/virologia , Humanos , Estudos Longitudinais , Prevenção Secundária/métodos
18.
J Exp Med ; 216(2): 384-406, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30674564

RESUMO

Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation. Based on these data and given their importance in autoimmunity, we conducted functional studies with B cells. We found that glucocorticoids impair upstream B cell receptor and Toll-like receptor 7 signaling, reduce transcriptional output from the three immunoglobulin loci, and promote significant up-regulation of the genes encoding the immunomodulatory cytokine IL-10 and the terminal-differentiation factor BLIMP-1. These findings provide new mechanistic understanding of glucocorticoid action and emphasize the multifactorial, cell-specific effects of these drugs, with potential implications for designing more selective immunoregulatory therapies.


Assuntos
Linfócitos B/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-10/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Glucocorticoides/imunologia , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/imunologia , Transcrição Genética/imunologia
20.
Nat Immunol ; 19(9): 1001-1012, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30104633

RESUMO

Immunoglobulin G3 (IgG3) has an uncertain role in the response to infection with and vaccination against human immunodeficiency virus (HIV). Here we describe a regulatory role for IgG3 in dampening the immune system-activating effects of chronic HIV viremia on B cells. Secreted IgG3 was bound to IgM-expressing B cells in vivo in HIV-infected chronically viremic individuals but not in early-viremic or aviremic individuals. Tissue-like memory (TLM) B cells, a population expanded by persistent HIV viremia, bound large amounts of IgG3. IgG3 induced clustering of B cell antigen receptors (BCRs) on the IgM+ B cells, which was mediated by direct interactions between soluble IgG3 and membrane IgM of the BCR (IgM-BCR). The inhibitory IgG receptor CD32b (FcγRIIb), complement component C1q and inflammatory biomarker CRP contributed to the binding of secreted IgG3 onto IgM-expressing B cells of HIV-infected individuals. Notably, IgG3-bound TLM B cells were refractory to IgM-BCR stimulation, thus demonstrating that IgG3 can regulate B cells during chronic activation of the immune system.


Assuntos
Linfócitos B/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Imunoglobulina G/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Células Cultivadas , Complemento C1q/metabolismo , Feminino , Humanos , Imunoglobulina M/metabolismo , Memória Imunológica , Imunomodulação , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Agregação de Receptores , Receptores de IgG/metabolismo , Adulto Jovem
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