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1.
Neurobiol Dis ; 199: 106594, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39025270

RESUMO

AIMS: Cytoplasmic dynein heavy chain (DYNC1H1) is a multi-subunit protein complex that provides motor force for movement of cargo on microtubules and traffics them back to the soma. In humans, mutations along the DYNC1H1 gene result in intellectual disabilities, cognitive delays, and neurologic and motor deficits. The aim of the study was to generate a mouse model to a newly identified de novo heterozygous DYNC1H1 mutation, within a functional ATPase domain (c9052C > T(P3018S)), identified in a child with motor deficits, and intellectual disabilities. RESULTS: P3018S heterozygous (HET) knockin mice are viable; homozygotes are lethal. Metabolic and EchoMRI™ testing show that HET mice have a higher metabolic rate, are more active, and have less body fat compared to wildtype mice. Neurobehavioral studies show that HET mice perform worse when traversing elevated balance beams, and on the negative geotaxis test. Immunofluorescent staining shows neuronal migration abnormalities in the dorsal and lateral neocortex with heterotopia in layer I. Neuron-subtype specific transcription factors CUX1 and CTGF identified neurons from layers II/III and VI respectively in cortical layer I, and abnormal pyramidal neurons with MAP2+ dendrites projecting downward from the pial surface. CONCLUSION: The HET mice are a good model for the motor deficits seen in the child, and highlights the importance of cytoplasmic dynein in the maintenance of cortical function and dendritic orientation relative to the pial surface. Our results are discussed in the context of other dynein mutant mice and in relation to clinical presentation in humans with DYNC1H1 mutations.

2.
Cells ; 12(13)2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37443768

RESUMO

During inflammatory, demyelinating diseases such as multiple sclerosis (MS), inflammation and axonal damage are prevalent early in the course. Axonal damage includes swelling, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise neuronal integrity. The clearance of damaged cell components is important to maintain normal turnover and restore homeostasis. In this study, we used mass spectrometry to identify insoluble proteins within high-speed/mercaptoethanol/sarcosyl-insoluble pellets from purified white matter plaques isolated from the brains of individuals with relapsing-remitting MS (RRMS). We determined that the transmembrane protein 106B (TMEM106B), normally lysosome-associated, is insoluble in RRMS plaques relative to normal-appearing white matter from individuals with Alzheimer's disease and non-neurologic controls. Relative to wild-type mice, hypomorphic mice with a reduction in TMEM106B have increased axonal damage and lipid droplet accumulation in the spinal cord following myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis. Additionally, the corpora callosa from cuprizone-challenged hypomorphic mice fail to clear lipid droplets efficiently during remyelination, suggesting that when TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, further exploration of these sites is warranted.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Medula Espinal/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Lipídeos/efeitos adversos
3.
Nature ; 589(7841): 293-298, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33299182

RESUMO

H1 linker histones are the most abundant chromatin-binding proteins1. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood2. Here we show that the local density of H1 controls the balance of repressive and active chromatin domains by promoting genomic compaction. We generated a conditional triple-H1-knockout mouse strain and depleted H1 in haematopoietic cells. H1 depletion in T cells leads to de-repression of T cell activation genes, a process that mimics normal T cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T cells reveals that H1-mediated chromatin compaction occurs primarily in regions of the genome containing higher than average levels of H1: the chromosome conformation capture (Hi-C) B compartment and regions of the Hi-C A compartment marked by PRC2. Reduction of H1 stoichiometry leads to decreased H3K27 methylation, increased H3K36 methylation, B-to-A-compartment shifting and an increase in interaction frequency between compartments. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. Our results establish H1 as a critical regulator of gene silencing through localized control of chromatin compaction, 3D genome organization and the epigenetic landscape.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/genética , Epigênese Genética , Histonas/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Cromatina/química , Cromatina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Inativação Gênica , Histonas/química , Ativação Linfocitária/genética , Masculino , Metilação , Camundongos , Camundongos Knockout
4.
Cell Rep ; 24(5): 1136-1150, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30067971

RESUMO

In response to activation, CD4+ T cells upregulate autophagy. However, the functional consequences of that upregulation have not been fully elucidated. In this study, we identify autophagy as a tolerance-avoidance mechanism. Our data show that inhibition of autophagy during CD4+ T cell activation induces a long-lasting state of hypo-responsiveness that is accompanied by the expression of an anergic gene signature. Cells unable to induce autophagy after T cell receptor (TCR) engagement show inefficient mitochondrial respiration and decreased turnover of the protein tyrosine phosphatase PTPN1, which translates into defective TCR-mediated signaling. In vivo, inhibition of autophagy during antigen priming induces T cell anergy and decreases the severity of disease in an experimental autoimmune encephalomyelitis mouse model. Interestingly, CD4+ T cells isolated from the synovial fluid of juvenile idiopathic arthritis patients, while resistant to suboptimal stimulation-induced anergy, can be tolerized with autophagy inhibitors. We propose that autophagy constitutes a tolerance-avoidance mechanism, which determines CD4+ T cell fate.


Assuntos
Autofagia , Linfócitos T CD4-Positivos/imunologia , Anergia Clonal , Encefalomielite Autoimune Experimental/imunologia , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo
5.
Cell Metab ; 25(3): 673-685, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28215843

RESUMO

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα+) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα+ cells with high CD9 expression (CD9high) originates pro-fibrotic cells whereas their CD9low counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRα+CD9high fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9high progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα+ cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.


Assuntos
Adipócitos/patologia , Tecido Adiposo/patologia , Obesidade/metabolismo , Obesidade/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Células-Tronco/metabolismo , Tetraspanina 29/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Adulto , Animais , Peso Corporal , Epididimo/metabolismo , Fibrose , Homeostase , Humanos , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Obesidade/fisiopatologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais
6.
Eur J Immunol ; 46(6): 1326-34, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27151577

RESUMO

In the past 10 years, autophagy has emerged as a crucial regulator of T-cell homeostasis, activation, and differentiation. Through the ability to adjust the cell's proteome in response to different stimuli, different forms of autophagy have been shown to control T-cell homeostasis and survival. Autophagic processes can also determine the magnitude of the T-cell response to TCR engagement, by regulating the cellular levels of specific signaling intermediates and modulating the metabolic output in activated T cells. In this review we will examine the mechanisms that control autophagy activity in T cells, such as ROS signaling and signaling through common gamma-chain cytokine receptors, and the different aspect of T-cell biology, including T-cell survival, effector cell function, and generation of memory, which can be regulated by autophagy.


Assuntos
Autofagia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Autoimunidade , Autofagia/genética , Autofagia/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Metabolismo Energético , Homeostase , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Imunossenescência , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Chaperonas Moleculares/metabolismo , Organelas/imunologia , Organelas/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais
7.
J Leukoc Biol ; 99(2): 387-98, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26497246

RESUMO

Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative L-asparaginase exhibits L-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that L-asparagine is a nutrient important for T cell activation and that L-asparagine deprivation, such as that mediated by the Salmonella Typhimurium L-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and L-lactate secretion. We also show that L-asparagine deprivation mediated by the Salmonella Typhimurium L-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which l-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming.


Assuntos
Asparaginase/fisiologia , Asparagina/fisiologia , Proteínas de Bactérias/fisiologia , Evasão da Resposta Imune/fisiologia , Salmonella typhimurium/enzimologia , Subpopulações de Linfócitos T/metabolismo , Sequência de Aminoácidos , Animais , Asparaginase/genética , Asparaginase/farmacologia , Asparagina/deficiência , Asparagina/farmacologia , Autofagia/efeitos dos fármacos , Proteínas de Bactérias/genética , Células Cultivadas , Feminino , Genes myc , Evasão da Resposta Imune/genética , Interleucina-2/biossíntese , Interleucina-2/genética , Ácido Láctico/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-myc/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Serina-Treonina Quinases TOR/metabolismo , Virulência
8.
Methods Mol Biol ; 1343: 143-53, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26420715

RESUMO

Autophagy is an essential catabolic process that regulates a diverse array of functions by targeting cellular components for degradation by lysosomes. Studies in mammalian cells have shown that the regulation of autophagy is highly complex and optimization of experimental approaches to analyze this process needs to be developed for each model studied. This chapter provides an overview of two of the most commonly used ways to monitor autophagy activity in T cell. It involves description of common techniques, namely Western blot and cell immunostaining, giving specific recommendations for working with T cells and monitoring macroautophagy. We also discuss the analysis required for correct interpretation of the results and quantification of macroautophagy activity.


Assuntos
Linfócitos T/metabolismo , Animais , Autofagia/fisiologia , Separação Celular/métodos , Imunofluorescência , Ativação Linfocitária/imunologia , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Subpopulações de Linfócitos T/metabolismo
9.
Autophagy ; 11(10): 1864-77, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26391567

RESUMO

Macroautophagy is a cellular process that mediates degradation in the lysosome of cytoplasmic components including proteins and organelles. Previous studies have shown that macroautophagy is induced in activated T cells to regulate organelle homeostasis and the cell's energy metabolism. However, the signaling pathways that initiate and regulate activation-induced macroautophagy in T cells have not been identified. Here, we show that activation-induced macroautophagy in T cells depends on signaling from common γ-chain cytokines. Consequently, inhibition of signaling through JAK3, induced downstream of cytokine receptors containing the common γ-chain, prevents full induction of macroautophagy in activated T cells. Moreover, we found that common γ-chain cytokines are not only required for macroautophagy upregulation during T cell activation but can themselves induce macroautophagy. Our data also show that macroautophagy induction in T cells is associated with an increase of LC3 expression that is mediated by a post-transcriptional mechanism. Overall, our findings unveiled a new role for common γ-chain cytokines as a molecular link between autophagy induction and T-cell activation.


Assuntos
Autofagia/imunologia , Linfócitos T CD4-Positivos/imunologia , Comunicação Celular/imunologia , Citocinas/metabolismo , Ativação Linfocitária/imunologia , Transdução de Sinais , Animais , Feminino , Camundongos Endogâmicos C57BL , Fosforilação
10.
Nat Immunol ; 15(11): 1046-54, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25263126

RESUMO

Chaperone-mediated autophagy (CMA) targets soluble proteins for lysosomal degradation. Here we found that CMA was activated in T cells in response to engagement of the T cell antigen receptor (TCR), which induced expression of the CMA-related lysosomal receptor LAMP-2A. In activated T cells, CMA targeted the ubiquitin ligase Itch and the calcineurin inhibitor RCAN1 for degradation to maintain activation-induced responses. Consequently, deletion of the gene encoding LAMP-2A in T cells caused deficient in vivo responses to immunization or infection with Listeria monocytogenes. Impaired CMA activity also occurred in T cells with age, which negatively affected their function. Restoration of LAMP-2A in T cells from old mice resulted in enhancement of activation-induced responses. Our findings define a role for CMA in regulating T cell activation through the targeted degradation of negative regulators of T cell activation.


Assuntos
Autofagia/imunologia , Ativação Linfocitária/imunologia , Proteína 2 de Membrana Associada ao Lisossomo/imunologia , Chaperonas Moleculares/imunologia , Células Th1/imunologia , Envelhecimento/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/biossíntese , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Inibidores de Calcineurina/metabolismo , Proteínas de Ligação ao Cálcio , Células Cultivadas , Oxidases Duais , Feminino , Humanos , Imunização , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Proteína 2 de Membrana Associada ao Lisossomo/biossíntese , Proteína 2 de Membrana Associada ao Lisossomo/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/metabolismo , NADPH Oxidases/genética , Estresse Oxidativo/imunologia , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/metabolismo
11.
J Pathol ; 226(2): 255-73, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21990109

RESUMO

Autophagy is a process traditionally known to contribute to cellular cleaning through the removal of intracellular components in lysosomes. In recent years, intensive scrutiny at the molecular level to which autophagy has been subjected has also contributed to expanding our understanding of the physiological role of this pathway. Added to the well-characterized role in quality control, autophagy has proved to be important in the maintenance of cellular homeostasis and of the energetic balance, in cellular and tissue remodelling, and cellular defence against extracellular insults and pathogens. It is not a surprise that, in light of this growing number of physiological functions, connections between autophagic malfunction and human pathologies have also been strengthened. In this review, we focus on several pathological conditions associated with primary or secondary defects in autophagy and comment on a recurring theme for many of them, ie the fact that autophagy can often exert both beneficial and aggravating effects on the progression of disease. Elucidating the factors that determine the switch between these dual functions of autophagy in disease has become a priority when considering the potential therapeutic implications of the pharmacological modulation of autophagy in many of these pathological conditions.


Assuntos
Doenças Autoimunes/patologia , Autofagia/fisiologia , Infecções/patologia , Neoplasias/patologia , Doenças Neurodegenerativas/patologia , Diferenciação Celular , Sobrevivência Celular , Progressão da Doença , Metabolismo Energético , Insuficiência Cardíaca/patologia , Humanos , Lisossomos/fisiologia , Chaperonas Moleculares/fisiologia
12.
PLoS Pathog ; 7(2): e1001280, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21347347

RESUMO

Establishment of stable HIV-1 infection requires the efficient integration of the retroviral genome into the host DNA. The molecular mechanism underlying the control of this process by the chromatin structure has not yet been elucidated. We show here that stably associated nucleosomes strongly inhibit in vitro two viral-end integration by decreasing the accessibility of DNA to integrase. Remodeling of the chromatinized template by the SWI/SNF complex, whose INI1 major component interacts with IN, restores and redirects the full-site integration into the stable nucleosome region. These effects are not observed after remodeling by other human remodeling factors such as SNF2H or BRG1 lacking the integrase binding protein INI1. This suggests that the restoration process depends on the direct interaction between IN and the whole SWI/SNF complex, supporting a functional coupling between the remodeling and integration complexes. Furthermore, in silico comparison between more than 40,000 non-redundant cellular integration sites selected from literature and nucleosome occupancy predictions also supports that HIV-1 integration is promoted in the genomic region of weaker intrinsic nucleosome density in the infected cell. Our data indicate that some chromatin structures can be refractory for integration and that coupling between nucleosome remodeling and HIV-1 integration is required to overcome this natural barrier.


Assuntos
Proteínas Cromossômicas não Histona/fisiologia , Integrase de HIV/fisiologia , Nucleossomos/metabolismo , Nucleossomos/virologia , Fatores de Transcrição/fisiologia , Integração Viral/fisiologia , Animais , Transformação Celular Viral/genética , Células Cultivadas , Montagem e Desmontagem da Cromatina/fisiologia , Proteínas Cromossômicas não Histona/metabolismo , Eficiência , Regulação Viral da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Células HeLa , Humanos , Modelos Biológicos , Estabilidade Proteica , Spodoptera , Fatores de Transcrição/metabolismo , Transcrição Gênica
13.
J Virol ; 82(23): 11555-67, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18799576

RESUMO

Lens epithelium-derived growth factor (LEDGF)/p75 functions as a bimodal tether during lentiviral DNA integration: its C-terminal integrase-binding domain interacts with the viral preintegration complex, whereas the N-terminal PWWP domain can bind to cellular chromatin. The molecular basis for the integrase-LEDGF/p75 interaction is understood, while the mechanism of chromatin binding is unknown. The PWWP domain is homologous to other protein interaction modules that together comprise the Tudor clan. Based on primary amino acid sequence and three-dimensional structural similarities, 24 residues of the LEDGF/p75 PWWP domain were mutagenized to garner essential details of its function during human immunodeficiency virus type 1 (HIV-1) infection. Mutating either Trp-21 or Ala-51, which line the inner wall of a hydrophobic cavity that is common to Tudor clan members, disrupts chromatin binding and virus infectivity. Consistent with a role for chromatin-associated LEDGF/p75 in stimulating integrase activity during infection, recombinant W21A protein is preferentially defective for enhancing integration into chromatinized target DNA in vitro. The A51P mutation corresponds to the S270P change in DNA methyltransferase 3B that causes human immunodeficiency, centromeric instability, and facial anomaly syndrome, revealing a critical role for this amino acid position in the chromatin binding functions of varied PWWP domains. Our results furthermore highlight the requirement for a conserved Glu in the hydrophobic core that mediates interactions between other Tudor clan members and their substrates. This initial systematic mutagenesis of a PWWP domain identifies amino acid residues critical for chromatin binding function and the consequences of their changes on HIV-1 integration and infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Cromatina/metabolismo , HIV-1/patogenicidade , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Linhagem Celular , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Camundongos , Estrutura Terciária de Proteína , Fatores de Transcrição/química , Integração Viral
14.
Nucleic Acids Res ; 36(4): 1237-46, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18174227

RESUMO

Integration is an essential step in the retroviral lifecycle, and the lentiviral integrase binding protein lens epithelium-derived growth factor (LEDGF)/p75 plays a crucial role during human immunodeficiency virus type 1 (HIV-1) cDNA integration. In vitro, LEDGF/p75 stimulates HIV-1 integrase activity into naked target DNAs. Here, we demonstrate that this chromatin-associated protein also stimulates HIV-1 integration into reconstituted polynucleosome templates. Activation of integration depended on the LEDGF/p75-integrase interaction with either type of template. A differential requirement for the dominant DNA and chromatin-binding elements of LEDGF/p75 was however observed when using naked DNA versus polynucleosomes. With naked DNA, the complete removal of these N-terminal elements was required to abate cofactor function. With polynucleosomes, activation mainly depended on the PWWP domain, and to a lesser extent on nearby AT-hook DNA-binding motifs. GST pull-down assays furthermore revealed a role for the PWWP domain in binding to nucleosomes. These results are completely consistent with recent ex vivo studies that characterized the PWWP and integrase-binding domains of LEDGF/p75 as crucial for restoring HIV-1 infection to LEDGF-depleted cells. Our studies therefore establish novel in vitro conditions, highlighting chromatinized DNA as target acceptor templates, for physiologically relevant studies of LEDGF/p75 in lentiviral cDNA integration.


Assuntos
Integrase de HIV/metabolismo , HIV-1/genética , Peptídeos e Proteínas de Sinalização Intercelular/química , Nucleossomos/metabolismo , Integração Viral , DNA/metabolismo , HIV-1/enzimologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Estrutura Terciária de Proteína , Moldes Genéticos
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