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2.
Nature ; 561(7723): E29, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30232426
4.
Nature ; 543(7646): 564-567, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28297712

RESUMO

The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+ lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Provírus/crescimento & desenvolvimento , Receptores de IgG/metabolismo , Replicação Viral , Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Divisão Celular , Separação Celular , Células Cultivadas , DNA Viral/análise , Perfilação da Expressão Gênica , Células HEK293 , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Provírus/genética , Provírus/isolamento & purificação , Regulação para Cima/genética , Latência Viral/efeitos dos fármacos , Latência Viral/genética , Latência Viral/imunologia
5.
AIDS ; 30(15): 2299-302, 2016 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-27428742

RESUMO

To further understand the exceptional HIV-1 control observed in Post-Treatment Controllers (PTCs) from the Virological and Immunological Sustained CONtrol after Treatment Interruption study we investigated their HIV-specific T-cell responses. Polyfunctionality of HIV-specific CD4 and CD8 T cells and the ratios of HIV-specific CD4 T cells per infected cells were similar in post-treatment controllers, continuously early-treated patients and long-term non-progressors Overall early treatment appears to preserve robust HIV-specific CD4 T cells, which might contribute to the posttreatment control of HIV.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Prevenção Secundária
6.
Cell Rep ; 14(9): 2100-2107, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26923586

RESUMO

HIV-1 post-integration latency in CD4+ lymphocytes is responsible for viral persistence despite treatment, but mechanisms involved in the establishment of latent viral reservoirs are not fully understood. We determined that both interleukin 2 (IL-2) and IL-7 induced SAMHD1 phosphorylation in T592, abrogating its antiviral activity. However, IL-7 caused a much more profound stimulatory effect on HIV-1 reverse transcription and integration than IL-2 that required chemokine co-stimulation. Both cytokines barely induced transcription due to low NF-κB induction, favoring the establishment of latent reservoirs. Effect of IL-7 on SAMHD1 phosphorylation was confirmed in IL-7-treated patients (ACTG 5214 study). Dasatinib--a tyrosine-kinase inhibitor--blocked SAMHD1 phosphorylation induced by IL-2 and IL-7 and restored HIV-1 restriction. We propose that γc-cytokines play a major role in the reservoir establishment not only by driving homeostatic proliferation but also by increasing susceptibility of CD4+ lymphocytes to HIV-1 infection through SAMHD1 inactivation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , HIV-1/fisiologia , Interleucina-7/fisiologia , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Integração Viral , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Humanos , Interleucina-2/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Transcrição Reversa , Proteína 1 com Domínio SAM e Domínio HD
7.
Biochem Pharmacol ; 106: 30-45, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26851491

RESUMO

Massive activation of infected CD4+ T cells during acute HIV-1 infection leads to reservoir seeding and T-cell destruction. During T-cell activation, the antiviral effect of the innate factor SAMHD1 is neutralized through phosphorylation at T592, allowing HIV-1 infection. Dasatinib, a tyrosine kinase inhibitor currently used for treating chronic myeloid leukemia, has been described to control HIV-1 replication through its negative effect on T-cell proliferation and viral entry. We demonstrate that Dasatinib can actually interfere with SAMHD1 phosphorylation in human peripheral blood lymphocytes, preserving its antiviral activity against HIV-1. Dasatinib prevented SAMHD1 phosphorylation in vitro and ex vivo, impairing HIV-1 reverse transcription and proviral integration. This was the major mechanism of action because the presence of Vpx, which degrades SAMHD1, in HIV-1 virions impeded the inhibitory effect of Dasatinib on HIV-1 replication. In fact, infection with VSV-pseudotyped HIV-1 virions and fusion of BlaM-Vpr-containing HIV-1 viruses with activated PBMCs in the presence of Dasatinib suggested that Dasatinib was not acting at fusion level. Finally, PBMCs from patients on chronic treatment with Dasatinib showed a lower level of SAMHD1 phosphorylation in response to activating stimuli and low susceptibility to HIV-1 infection ex vivo. Consequently, Dasatinib is a compound currently used in clinic that preserves the antiviral function of SAMHD1. Using Dasatinib as adjuvant of antiretroviral therapy during early primary HIV-1 infection would contribute to reduce viral replication and spread, prevent reservoir seeding, and preserve CD4 counts and CTL responses. These events would create a more favorable virologic and immunologic environment for future interventional studies aiming at HIV-1 eradication.


Assuntos
Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Dasatinibe/farmacologia , Infecções por HIV/tratamento farmacológico , Proteínas Monoméricas de Ligação ao GTP/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Replicação Viral/efeitos dos fármacos , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/virologia , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Infecções por HIV/enzimologia , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/crescimento & desenvolvimento , Interações Hospedeiro-Patógeno , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Ativação Linfocitária , Masculino , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Fosforilação/efeitos dos fármacos , Proteína 1 com Domínio SAM e Domínio HD , Transdução de Sinais , Vesiculovirus/genética , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/metabolismo , Internalização do Vírus/efeitos dos fármacos
8.
AIDS ; 28(11): 1567-77, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-24804861

RESUMO

OBJECTIVES: The aim of the study was to determine the molecular mechanisms underlying the quasi-equilibrium between HIV and its host in the model of functional cure represented by elite controllers who spontaneously maintain exceptionally low levels of HIV reservoirs. DESIGN: Whole-genome transcriptional study and quantification of the cell-associated HIV DNA and HIV RNA levels of the four major resting CD4 T-cell subsets in HIV-1-infected elite controllers, viremic long-term nonprogressors (vir-LTNPs), and uninfected individuals. METHODS: We compared the whole-genome transcriptional profiles (ArrayExpress accession number E-MTAB-1480) of the four major resting CD4 T-cell subsets [naive (TN), central-memory (TCM), transitional-memory (TTM), and effector-memory (TEM)] from 14 HIV-1-infected individuals including seven elite controllers (E-LTNPs) and seven vir-LTNPs, and from seven uninfected individuals. The HIV-1 cellular DNA and mRNA levels were quantified in parallel in each sorted subset. RESULTS: Host gene transcriptomes followed subset differentiation and viremia except in E-LTNPs wherein TCM, the main CD4 cell compartment, showed the highest activity with three specific signatures involving overexpression of T-cell receptor and costimulation signaling pathways, overexpression of the PRDM-1/Blimp-1 transcriptional repressor, and downmodulation of type-I IFN-related genes. Among subsets, the PRDM1/Blimp-1 upregulation was associated with lower levels of both cellular HIV-DNA and HIV mRNA levels. CONCLUSION: This unique Blimp-1 transcriptional repressor signature and the contrast between host and virus transcriptional activities in TCM from elite controllers suggest Blimp-1 might be involved in controlling the HIV reservoirs in the key TCM subset.


Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas Repressoras/metabolismo , Transcrição Gênica , Latência Viral , Adulto , Idoso , Animais , Linfócitos T CD4-Positivos/imunologia , DNA Viral/análise , DNA Viral/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , Humanos , Masculino , Pessoa de Meia-Idade , Fator 1 de Ligação ao Domínio I Regulador Positivo , RNA Viral/análise , RNA Viral/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia
9.
Cell Rep ; 3(4): 1036-43, 2013 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-23602554

RESUMO

SAMHD1 restricts HIV-1 replication in myeloid and quiescent CD4(+) T cells. Here, we show that SAMHD1 restriction activity is regulated by phosphorylation. SAMHD1 interacts with cyclin A2/cdk1 only in cycling cells. Cyclin A2/CDK1 phosphorylates SAMHD1 at the Threonine 592 residue both in vitro and in vivo. Phosphorylation of SAMHD1 Thr592 correlates with loss of its ability to restrict HIV-1. Indeed, while PMA treatment of proliferating THP1 cells results in reduced Thr592 phosphorylation, activation of resting peripheral blood mononuclear cells (PBMCs) and purified quiescent CD4(+) T cells results in increased phosphorylation of SAMHD1 Thr592. Interestingly, we found that treatment of cells by type 1 interferon reduced Thr592 phosphorylation, reinforcing the link between the phosphorylation of SAMHD1 and its antiviral activity. Unlike wild-type SAMHD1, a phosphorylation-defective mutant was able to restrict HIV-1 replication in both PMA-treated and untreated cells. Our results uncover the phosphorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 as a key regulatory mechanism of its antiviral activity.


Assuntos
Proteína Quinase CDC2/metabolismo , Ciclina A2/metabolismo , HIV-1/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Animais , Antivirais/farmacologia , Sequência de Bases , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Humanos , Interferon Tipo I/farmacologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Dados de Sequência Molecular , Proteínas Monoméricas de Ligação ao GTP/genética , Fosforilação , Proteína 1 com Domínio SAM e Domínio HD , Alinhamento de Sequência , Replicação Viral/efeitos dos fármacos
10.
PLoS Pathog ; 9(3): e1003211, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23516360

RESUMO

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Alelos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Soropositividade para HIV , HIV-1/fisiologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Carga Viral , Viremia/prevenção & controle , Replicação Viral
11.
Curr Opin HIV AIDS ; 8(3): 204-10, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23493099

RESUMO

PURPOSE OF REVIEW: To discuss the recent major advances in the understanding of how host immune defenses contribute to HIV reservoir control. RECENT FINDINGS: Immune control of HIV-1 reservoirs is a two-step process: viral replication activation from latent reservoirs followed by elimination of virus-expressing cells by the host. Environmental factors, such as pro-inflammatory type-I interferon, chemokines or cytokines, can facilitate HIV-1 replication, confer dormancy in CD4 cells or confer resistance to cytopathogenic effects of cytotoxic CD8 T cells. Therefore, they constitute a double-edged sword for immune control of HIV reservoirs. Concomitantly, adaptive immunity takes advantage of CD4 T-cell homeostatic mechanisms and can expose HIV-1 antigen-expressing cells to HIV-specific cytotoxic CD8 T cells, and limit virus spreading. These highly interconnected phenomena can lead to quasi-equilibrium between the HIV-1 reservoirs and host immune control that can serve as a model for the 'shock and kill' immune-based therapeutic strategies in play in the course of finding an HIV cure. SUMMARY: Immune control of HIV reservoirs in CD4 T cells involves modulation of both HIV-1 latency and the continuous reseeding of the reservoir offering conceptual models that may advance HIV cure strategies.


Assuntos
Reservatórios de Doenças/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Infecções por HIV/prevenção & controle , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Replicação Viral/imunologia
12.
J Acquir Immune Defic Syndr ; 62(3): 255-9, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23274932

RESUMO

To evaluate the contribution of CD4 T cells from blood and gut compartments to the HIV-1 reservoir, we directly quantified cell-associated HIV DNA in isolated rectal (R-) and peripheral blood (PB-) memory CD4 T cells from 11 successfully long-term treated patients. Proportion of activated (CD25(+); CD69(+); and HLA-DR(+)) and CCR5 expressing CD4 T cells were markedly higher in rectal tissue compared with blood. However, HIV-1 infection levels of R- and PB-memory CD4 T cells did not significantly differ (medians: 4000 and 2100 copies per million cells) after effective long-term viral control, suggesting that each of these 2 compartments does not contribute in a similar fashion to the total HIV reservoir.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Reservatórios de Doenças/virologia , Infecções por HIV/imunologia , HIV-1/genética , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/virologia , DNA Viral/análise , Infecções por HIV/virologia , Antígenos HLA-DR/análise , Humanos , Memória Imunológica/imunologia , Receptores CCR5/metabolismo , Carga Viral
13.
Immunity ; 37(5): 917-29, 2012 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-23142782

RESUMO

The bone marrow (BM) has been identified as a possible organ for T cell priming, yet the fundamental mechanisms of a polyclonal immune response in the BM remain unknown. We found that after intradermal injection of modified vaccinia Ankara virus, unexpected sources of newly primed polyclonal virus-specific CD8(+), but not CD4(+), T cells were localized in the BM and the draining lymph nodes (dLNs) prior to blood circulation. We identified neutrophils as the virus-carrier cells from the dermis to the BM. In both neutrophil-depleted and Ccr1(-/-) mice, virus-specific BM CD8(+) responses were lost. Myeloid antigen-presenting cells were required for BM CD8(+) T cell priming. A systems biology analysis of dLN and BM virus-specific CD8(+) T cells revealed distinct transcriptional and multifunctional profiles for cells primed in each organ. We provide direct evidence for how antigen is transported to the BM, providing a source of virus-specific memory CD8(+) T cells.


Assuntos
Antígenos/imunologia , Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Derme/imunologia , Memória Imunológica/imunologia , Neutrófilos/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Receptores CCR1/imunologia
14.
Retrovirology ; 9: 87, 2012 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-23092122

RESUMO

BACKGROUND: Quiescent CD4+ T lymphocytes are highly refractory to HIV-1 infection due to a block at reverse transcription. RESULTS: Examination of SAMHD1 expression in peripheral blood lymphocytes shows that SAMHD1 is expressed in both CD4+ and CD8+ T cells at levels comparable to those found in myeloid cells. Treatment of CD4+ T cells with Virus-Like Particles (VLP) containing Vpx results in the loss of SAMHD1 expression that correlates with an increased permissiveness to HIV-1 infection and accumulation of reverse transcribed viral DNA without promoting transcription from the viral LTR. Importantly, CD4+ T-cells from patients with Aicardi-Goutières Syndrome harboring mutation in the SAMHD1 gene display an increased susceptibility to HIV-1 infection that is not further enhanced by VLP-Vpx-treatment. CONCLUSION: Here, we identified SAMHD1 as the restriction factor preventing efficient viral DNA synthesis in non-cycling resting CD4+ T-cells. These results highlight the crucial role of SAMHD1 in mediating restriction of HIV-1 infection in quiescent CD4+ T-cells and could impact our understanding of HIV-1 mediated CD4+ T-cell depletion and establishment of the viral reservoir, two of the HIV/AIDS hallmarks.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Transcrição Reversa , DNA Viral/metabolismo , Humanos , Proteínas Monoméricas de Ligação ao GTP/imunologia , Proteína 1 com Domínio SAM e Domínio HD , Proteínas Virais Reguladoras e Acessórias/imunologia , Proteínas Virais Reguladoras e Acessórias/metabolismo
15.
J Antimicrob Chemother ; 67(10): 2323-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22687892

RESUMO

OBJECTIVES: Precise characterization of viruses present in reservoirs in long-term pretreated patients will be a major issue to consider in the context of viral eradication. We assessed the frequency of defective viruses present in cellular reservoirs. METHODS: Peripheral blood mononuclear cells (PBMCs) and rectal biopsy samples were compared between five patients on successful long-term highly active antiretroviral therapy (HAART) (>7 years without blips) and five untreated patients. Molecular cloning and sequencing of the reverse transcriptase region were used to detect the presence of and quantify in-frame stop codons in HIV quasi-species. The relationship between the size of the reservoir and the frequency of defective genomes was assessed. RESULTS: Defective genomes were systematically detected in all patients on long-term HAART in both compartments (PBMCs and rectal tissues), with a higher level of defective genomes per sample compared with PBMCs of untreated patients. A high level of defective genomes was correlated with a small size of HIV proviral DNA. Regarding the nucleotide context, guanine (G) to adenine (A) substitution at tryptophan positions was responsible for the appearance of 89% of all in-frame stop codons in the context of G-to-A hypermutation, likely reflecting APOBEC3 footprints on the viral genome. CONCLUSIONS: We propose a scenario whereby defective genomes accumulate during HAART treatment, eventually reaching a viral extinction threshold. In the context of viral eradication, measurement of the relative amounts of defective and non-defective viruses (by molecular cloning and ultradeep sequencing) should be used as a new criterion for eradicating HIV.


Assuntos
Terapia Antirretroviral de Alta Atividade , Citosina Desaminase/metabolismo , Vírus Defeituosos/genética , Infecções por HIV/virologia , HIV-1/genética , Mucosa Intestinal/virologia , Leucócitos Mononucleares/virologia , Desaminases APOBEC , Adolescente , Antirretrovirais/administração & dosagem , Criança , Clonagem Molecular , Citidina Desaminase , Vírus Defeituosos/isolamento & purificação , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Humanos , Masculino , Reto/virologia , Análise de Sequência de DNA , Resultado do Tratamento
16.
Clin Infect Dis ; 54(10): 1495-503, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22441653

RESUMO

BACKGROUND: The stable immune control of human immunodeficiency virus (HIV) in long-term nonprogressors (LTNPs) with protective human leukocyte antigen (HLA) alleles raises the question of whether and how these alleles influence the immune distribution of the HIV reservoirs. METHODS: Cell-associated HIV-DNA levels were quantified in blood sorted resting CD4 T-cell subsets from 8 LTNPs with and 10 without HLA-B*27 or HLA-B*57 alleles (HLA-B27/B57). RESULTS: A remarkably lower infection level of central memory CD4 T cells (T(CM)) was an exclusive feature that distinguished the HLA-B27/B57 HIV reservoirs from the other ones. In LTNPs, T(CM) protection was correlated with preservation of T(CM) counts, which correlated positively with the magnitude of HIV Gag-specific CD8 T cells. In HLA-B27/B57 LTNPs, a lower activation level of their memory CD4 T cells was associated with lower amounts of cell HIV-DNA in each resting memory CD4 subset and were also associated with higher ratios of HIV Gag-specific CD8 T cells per infected resting CD4 T cell (effector/target [E/T]). As a result, HLA-B27/B57 E/T ratios were negatively correlated with the contribution of memory CD4 T-cell subsets to the total HIV reservoirs. CONCLUSIONS: The potent antiviral immunity governed by the protective HLA-B27/B57 alleles, by limiting T(CM) infection and pool exhaustion, are associated with a reduced T(CM) contribution to the HIV reservoir.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , Antígenos HLA-B/genética , DNA Viral/isolamento & purificação , Antígenos HLA-B/imunologia , Humanos , Provírus/isolamento & purificação , Carga Viral
17.
Curr Opin HIV AIDS ; 6(3): 181-7, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21460722

RESUMO

PURPOSE OF REVIEW: The limitations of life-long antiretroviral therapies for the HIV infection lead to a novel concept of a functional cure developing innovative therapeutic strategies to generate a long-term remission of HIV replication without treatment. This concept requires an understanding of the mechanisms by which HIV is controlled in conditions of undetectable virus replication, before developing ambitious therapies blocking durably viral replication - and ultimately eradicating HIV. RECENT FINDINGS: Recent literature shows that the exceptional elite controller status is usually not driven by virus gross genetic defects, despite some virus attenuation resulting from immune selective pressure, but is frequently determined by host's genetic factors permitting robust cell-mediated immunity to control the virus replication and reservoirs. Lack of immunity and immune deficiency can however limit this model in some cases and only a subgroup in whom both the virus and the immune deficiency are controlled, that is the elite long-term controllers, might represent the best current model for a functional cure. SUMMARY: This review examines whether the exceptional HIV-infected elite controllers, who spontaneously and durably maintain extremely low virus replication, might be considered as a model for a functional cure and whether the mechanisms identified in these exceptional individuals might serve to identify therapeutic or vaccine strategies.


Assuntos
Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , HIV-1/imunologia , Viremia/imunologia , Viremia/prevenção & controle , Vacinas contra a AIDS/imunologia , Fármacos Anti-HIV/uso terapêutico , Humanos , Resultado do Tratamento
18.
PLoS One ; 5(8): e11966, 2010 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-20700504

RESUMO

BACKGROUND: Terminal differentiation of NK cells is crucial in maintaining broad responsiveness to pathogens and discriminating normal cells from cells in distress. Although it is well established that KIRs, in conjunction with NKG2A, play a major role in the NK cell education that determines whether cells will end up competent or hyporesponsive, the events underlying the differentiation are still debated. METHODOLOGY/PRINCIPAL FINDINGS: A combination of complementary approaches to assess the kinetics of the appearance of each subset during development allowed us to obtain new insights into these terminal stages of differentiation, characterising their gene expression profiles at a pan-genomic level, their distinct surface receptor patterns and their prototypic effector functions. The present study supports the hypothesis that CD56dim cells derive from the CD56bright subset and suggests that NK cell responsiveness is determined by persistent inhibitory signals received during their education. We report here the inverse correlation of NKG2A expression with KIR expression and explore whether this correlation bestows functional competence on NK cells. We show that CD56dimNKG2A-KIR+ cells display the most differentiated phenotype associated to their unique ability to respond against HLA-E+ target cells. Importantly, after IL-12+IL-18 stimulation, reacquisition of NKG2A strongly correlates with IFN-gamma production in CD56dimNKG2A- NK cells. CONCLUSIONS/SIGNIFICANCE: Together, these findings call for the reclassification of mature human NK cells into distinct subsets and support a new model, in which the NK cell differentiation and functional fate are based on a stepwise decrease of NKG2A and acquisition of KIRs.


Assuntos
Diferenciação Celular , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores KIR/metabolismo , Antígeno CD56/metabolismo , Linhagem Celular , Perfilação da Expressão Gênica , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Interferon gama/biossíntese , Interleucina-12/farmacologia , Interleucina-18/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Cinética , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Fenótipo , Receptores KIR/genética , Antígenos HLA-E
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