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1.
Immunity ; 46(1): 148-161, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-27986455

RESUMO

Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.


Assuntos
Citometria de Fluxo/métodos , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Humanos , Imunidade Inata , Fenótipo
2.
Immunity ; 44(2): 391-405, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26850658

RESUMO

Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Interferon gama/metabolismo , Intestinos/patologia , Linfócitos/imunologia , Doença Aguda , Antivirais/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular , Células Cultivadas , Doença Crônica , Estudos de Coortes , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Humanos , Imunidade Inata , Interferon gama/genética , Intestinos/virologia , Linfócitos/efeitos dos fármacos , Linfócitos/virologia , Fatores de Tempo , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia
3.
Nature ; 570(7762): 528-532, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31168092

RESUMO

Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.


Assuntos
Imunidade Inata/imunologia , Linfócitos/classificação , Linfócitos/imunologia , Macrófagos Alveolares/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Animais , Quimiocina CXCL13/imunologia , Feminino , Granuloma/imunologia , Granuloma/patologia , Humanos , Interleucina-17/imunologia , Interleucinas/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Linfócitos/metabolismo , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Receptores CXCR5/imunologia , Transcriptoma/genética , Tuberculose Pulmonar/genética , Interleucina 22
5.
Immunity ; 43(3): 591-604, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26362266

RESUMO

CD8(+) T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) T cell response, with limited bystander activation of non-HIV memory CD8(+) T cells. HIV-specific CD8(+) T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8(+) T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Ativação Linfocitária/imunologia , Carga Viral/imunologia , Adolescente , Apoptose/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Feminino , Citometria de Fluxo , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Cinética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Viral/genética , RNA Viral/imunologia , Fatores de Tempo , Viremia/diagnóstico , Viremia/imunologia , Adulto Jovem , Receptor fas/imunologia , Receptor fas/metabolismo
6.
PLoS Pathog ; 17(9): e1009871, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34555123

RESUMO

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Linfócitos T/virologia , Adulto , Alcinos/uso terapêutico , Benzoxazinas/uso terapêutico , Ciclopropanos/uso terapêutico , Emtricitabina/uso terapêutico , Feminino , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/uso terapêutico
8.
J Infect Dis ; 219(9): 1407-1417, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30624717

RESUMO

BACKGROUND: Susceptibility to coinfections in human immunodeficiency virus (HIV)-infected patients remains increased despite antiretroviral therapy (ART). To elucidate mechanisms involved in immune reconstitution, we studied immune activation, immune exhaustion, and HIV- and copathogen-specific T-cell responses in children before and after ART. METHODS: We prospectively enrolled 25 HIV-infected children to study HIV-, cytomegalovirus (CMV)-, and tuberculosis (TB)-specific T-cell responses before and 1 year after initiation of ART using intracellular cytokine (interleukin-2, interferon-γ, tumor necrosis factor-α) staining assays after in vitro stimulation. We further measured expression of activation, immune exhaustion, and memory phenotype markers and studied proliferative responses after antigen stimulation. RESULTS: We observed differential, pathogen-specific changes after 1 year of ART in cytokine profiles of CD4 T-cell responses that were associated with shifts in memory phenotype and decreased programmed cell death 1 (PD-1) expression. The proliferative capacity of HIV- and PPD-specific responses increased after 1 year of ART. Of note, the recovery of CMV- and TB-specific responses was correlated with a decrease in PD-1 expression (r = 0.83, P = .008 and r = 0.81, P = .0007, respectively). CONCLUSIONS: Reconstitution of immune responses on ART is associated with alterations in T-cell phenotype, function, and PD-1 expression that are distinct for HIV, TB, and CMV. The PD-1 pathway represents a potential target for immunotherapy in HIV-infected patients on ART with insufficient immune reconstitution.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citomegalovirus/imunologia , Infecções por HIV/tratamento farmacológico , HIV/imunologia , Reconstituição Imune , Mycobacterium tuberculosis/imunologia , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/fisiologia , Proliferação de Células , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica , Ativação Linfocitária , Masculino , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos
10.
J Virol ; 90(19): 8552-62, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27440884

RESUMO

UNLABELLED: Tripartite motif-containing protein 5 (TRIM5) restricts human immunodeficiency virus type 1 (HIV-1) in a species-specific manner by uncoating viral particles while activating early innate responses. Although the contribution of TRIM5 proteins to cellular immunity has not yet been studied, their interactions with the incoming viral capsid and the cellular proteasome led us to hypothesize a role for them. Here, we investigate whether the expression of two nonhuman TRIM5 orthologs, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), both of which are potent restrictors of HIV-1, could enhance immune recognition of infected cells by CD8(+) T cells. We illustrate how TRIM5 restriction improves CD8(+) T-cell-mediated HIV-1 inhibition. Moreover, when TRIM5 activity was blocked by the nonimmunosuppressive analog of cyclosporine (CsA), sarcosine-3(4-methylbenzoate)-CsA (SmBz-CsA), we found a significant reduction in CD107a/MIP-1ß expression in HIV-1-specific CD8(+) T cells. This finding underscores the direct link between TRIM5 restriction and activation of CD8(+) T-cell responses. Interestingly, cells expressing RhT5 induced stronger CD8(+) T-cell responses through the specific recognition of the HIV-1 capsid by the immune system. The underlying mechanism of this process may involve TRIM5-specific capsid recruitment to cellular proteasomes and increase peptide availability for loading and presentation of HLA class I antigens. In summary, we identified a novel function for nonhuman TRIM5 variants in cellular immunity. We hypothesize that TRIM5 can couple innate viral sensing and CD8(+) T-cell activation to increase species barriers against retrovirus infection. IMPORTANCE: New therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The nonhuman TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8(+) T-cell-mediated inhibition through the direct activation of HIV-1-specific CD8(+) T-cell responses. We found that the potency in CD8(+) activation was stronger for RhT5 variants and capsid-specific CD8(+) T cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ciclofilina A/metabolismo , HIV-1/imunologia , Macaca mulatta/imunologia , Proteínas/metabolismo , Animais , Linhagem Celular , Humanos , Ubiquitina-Proteína Ligases
11.
PLoS Pathog ; 11(5): e1004849, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25945999

RESUMO

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRß bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-γ production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.


Assuntos
Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Animais , Epitopos de Linfócito T/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Interferon gama/imunologia , Camundongos Endogâmicos C57BL
12.
J Immunol ; 194(11): 5329-45, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25911754

RESUMO

Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8(+) T cells, these constrained epitope-targeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control immunodominance in vivo. In this study, we conducted an extensive analysis of CD8(+) T cell responses restricted by a single HLA class I molecule to evaluate the mechanisms that contribute to epitope-targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 epitopes restricted by HLA-B*42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide-HLA-B*42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide important insights into a potential link between shared TCR recruitment, immunodominance, and antiviral efficacy in a major human infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , HIV-1/imunologia , Epitopos Imunodominantes/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Adulto , Sequência de Aminoácidos , Afinidade de Anticorpos/imunologia , Sequência de Bases , DNA Complementar/genética , Mapeamento de Epitopos , Feminino , Infecções por HIV/imunologia , Antígenos HLA-B/imunologia , Humanos , Análise de Sequência de DNA , Carga Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
13.
Retrovirology ; 12: 20, 2015 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-25808313

RESUMO

BACKGROUND: Presentation of identical HIV-1 peptides by closely related Human Leukocyte Antigen class I (HLAI) molecules can select distinct patterns of escape mutation that have a significant impact on viral fitness and disease progression. The molecular mechanisms by which HLAI micropolymorphisms can induce differential HIV-1 escape patterns within identical peptide epitopes remain unknown. RESULTS: Here, we undertook genetic and structural analyses of two immunodominant HIV-1 peptides, Gag180-188 (TPQDLNTML, TL9-p24) and Nef71-79 (RPQVPLRPM, RM9-Nef) that are among the most highly targeted epitopes in the global HIV-1 epidemic. We show that single polymorphisms between different alleles of the HLA-B7 superfamily can induce a conformational switch in peptide conformation that is associated with differential HLAI-specific escape mutation and immune control. A dominant R71K mutation in the Nef71-79 occurred in those with HLA-B*07:02 but not B*42:01/02 or B*81:01. No structural difference in the HLA-epitope complexes was detected to explain this observation. CONCLUSIONS: These data suggest that identical peptides presented through very similar HLAI landscapes are recognized as distinct epitopes and provide a novel structural mechanism for previously observed differential HIV-1 escape and disease progression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Evasão da Resposta Imune , Adulto , Epitopos de Linfócito T/genética , Antígenos HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos
14.
J Virol ; 87(19): 10889-94, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23864640

RESUMO

HLA-B*57 is strongly associated with immune control of HIV and delayed AIDS progression. The closely related, but less protective, HLA-B*58:01 presents similar epitopes, but HLA-B*58:01(+) individuals do not generate CD8(+) T cells targeting the KF11-Gag epitope, which has been linked to low viremia. Here we show that HLA-B*58:01 binds and presents KF11 peptide, but HIV-infected HLA-B*58:01(+) cells fail to process KF11. This unexpected finding demonstrates that immunodominance patterns can be influenced by intracellular events independent of HLA binding motifs.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-B/imunologia , Viremia/imunologia , Linfócitos T CD8-Positivos/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Antígenos HLA-B/metabolismo , Humanos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Carga Viral , Viremia/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
15.
J Virol ; 87(5): 2628-38, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23255798

RESUMO

CD8(+) T cells are major players in antiviral immunity against human immunodeficiency virus type 1 (HIV-1) through recognition of viral epitopes presented on the surface of infected cells. However, the early events involving HIV-1 epitope presentation to CD8(+) T cells remain poorly understood but are nonetheless crucial for the rapid clearance of virus-infected cells. Here, we comprehensively studied the kinetics of antigen presentation of two protective epitopes, KF11Gag and KK10Gag, restricted by HLA alleles B*57:01 and B*27:05, respectively, and compared these to KY9Pol and VL9Vpr epitopes in a single cycle of HIV-1 replication. We consistently demonstrate differences in epitope presentation kinetics, with very early presentation, within 3 h postinfection, for the protective KF11Gag, KK10Gag epitopes, and KY9Pol but only late presentation for VL9Vpr. We show that this early presentation relies on the antigen being presented from incoming viral particles and is correlated with rapid CD8(+) T cell activation and clearance of virus-infected cells. Additionally, our data indicate a dose-response dependency between the levels of CD8(+) T cell activation and the amount of virus inoculum. These data reflect a proof of principle emphasizing the importance of identifying early-presented viral epitopes for rapid elimination of HIV-1-infected cells.


Assuntos
Apresentação de Antígeno , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Epitopos/imunologia , HIV-1/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Linhagem Celular , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Ativação Linfocitária , Replicação Viral
16.
Front Immunol ; 15: 1360412, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745652

RESUMO

A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.


Assuntos
Mycobacterium tuberculosis , Células Mieloides , Tuberculose Pulmonar , Humanos , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores de Orexina/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Adulto , Feminino , Masculino , Antígenos CD/metabolismo , Antígenos CD/genética , Pessoa de Meia-Idade , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Pulmão/metabolismo , Biomimética , Monócitos/imunologia , Monócitos/metabolismo
17.
J Virol ; 86(2): 919-29, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22090105

RESUMO

The genetic polymorphism that has the greatest impact on immune control of human immunodeficiency virus (HIV) infection is expression of HLA-B*57. Understanding of the mechanism for this strong effect remains incomplete. HLA-B*57 alleles and the closely related HLA-B*5801 are often grouped together because of their similar peptide-binding motifs and HIV disease outcome associations. However, we show here that the apparently small differences between HLA-B*57 alleles, termed HLA-B*57 micropolymorphisms, have a significant impact on immune control of HIV. In a study cohort of >2,000 HIV C-clade-infected subjects from southern Africa, HLA-B*5703 is associated with a lower viral-load set point than HLA-B*5702 and HLA-B*5801 (medians, 5,980, 15,190, and 19,000 HIV copies/ml plasma; P = 0.24 and P = 0.0005). In order to better understand these observed differences in HLA-B*57/5801-mediated immune control of HIV, we undertook, in a study of >1,000 C-clade-infected subjects, a comprehensive analysis of the epitopes presented by these 3 alleles and of the selection pressure imposed on HIV by each response. In contrast to previous studies, we show that each of these three HLA alleles is characterized both by unique CD8(+) T-cell specificities and by clear-cut differences in selection pressure imposed on the virus by those responses. These studies comprehensively define for the first time the CD8(+) T-cell responses and immune selection pressures for which these protective alleles are responsible. These findings are consistent with HLA class I alleles mediating effective immune control of HIV through the number of p24 Gag-specific CD8(+) T-cell responses generated that can drive significant selection pressure on the virus.


Assuntos
Epitopos de Linfócito T/imunologia , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-B/genética , Polimorfismo Genético , Seleção Genética , África Austral , Alelos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Estudos de Coortes , Epitopos de Linfócito T/genética , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , HIV-1/fisiologia , Antígenos HLA-B/imunologia , Humanos , Carga Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
18.
J Virol ; 86(21): 11493-500, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22896606

RESUMO

Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here, we exploit an experiment of nature involving two recently diverged HLA alleles, HLA-B*42:01 and HLA-B*42:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay (P = 2 × 10(-10)) and functionally through CTL escape mutation (P = 2 × 10(-8)). HLA-B*42:01, which presents multiple Gag epitopes, is associated with a 0.52 log(10) lower viral-load set point than HLA-B*42:02 (P = 0.02), which presents no p24 Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A*30:01/B*42/Cw*17:01 haplotype is equivalent to 75% of that of HLA-B*57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of a particular HIV-specific CTL on disease control.


Assuntos
Resistência à Doença , Infecções por HIV/imunologia , Antígeno HLA-B27/genética , Antígeno HLA-B27/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Carga Viral
19.
J Virol ; 86(23): 12643-54, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22973023

RESUMO

The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8(+) T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P = 2 × 10(-5)). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ∼90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8(+) T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8(+) T-cell response in all individuals, irrespective of HLA type.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Produtos do Gene gag/genética , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1 , Antígeno HLA-B35/genética , África Austral , Progressão da Doença , ELISPOT , Epitopos de Linfócito T/imunologia , Citometria de Fluxo , Produtos do Gene gag/imunologia , Antígeno HLA-B35/classificação , Antígeno HLA-B35/imunologia , Humanos , Japão , México , Filogenia , Reino Unido , Carga Viral
20.
J Immunol ; 186(10): 5675-86, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21498667

RESUMO

The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Viremia/imunologia , África , Alelos , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Citometria de Fluxo , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Análise de Sequência de Proteína , Carga Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene pol do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene rev do Vírus da Imunodeficiência Humana/imunologia
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