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1.
Nature ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599977

RESUMO

Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4+ T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1.

2.
Cell Host Microbe ; 31(1): 83-96.e5, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36596305

RESUMO

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions.


Assuntos
Infecções por HIV , HIV-1 , Humanos , HIV-1/genética , Heterocromatina , Provírus/genética , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos , Latência Viral , Carga Viral , Antirretrovirais/uso terapêutico
3.
Comput Struct Biotechnol J ; 21: 105-119, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36544475

RESUMO

Obesity affects the function of multiple organs/tissues including the exocrine organ salivary glands. However, the effects of obesity on transcriptomes and cell compositions in the salivary glands have yet been studied by bulk RNA-sequencing and single-cell RNA-sequencing. Besides, the cell types in the sublingual gland, one of the three major salivary glands, have yet been characterized by the approach of single-cell RNA-sequencing. In this report, we find that the histological structure of the three major salivary glands are not obviously affected in the obese mice. Bulk RNA-sequencing analysis shows that the most prominent changes observed in the three major salivary glands of the obese mice are the mobilization of transcriptomes related to the immune response and down-regulation of genes related to the secretory function of the salivary glands. Based on single-cell RNA-sequencing analysis, we identify and annotate 17 cell clusters in the sublingual gland for the first time, and find that obesity alters the relative compositions of immune cells and secretory cells in the major glands of obese mice. Integrative analysis of the bulk RNA-sequencing and single-cell RNA-sequencing data confirms the activation of immune response genes and compromise of secretory function in the three major salivary glands of obese mice. Consequently, the secretion of extracellular matrix proteins is significantly reduced in the three major salivary glands of obese mice. These results provide new molecular insights into understanding the effect of obesity on salivary glands.

4.
J Med Virol ; 95(1): e28425, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36562411

RESUMO

Development of biomarkers for predicting the occurrence of hepatitis E virus related-acute liver failure (HEV-ALF) is conducive to prevention and early intervention. Serum samples from 250 HEV-ALF patients, 250 patients with acute hepatitis E (AHE) and 250 health controls (HCs) were collected. We assessed the predictive ability of extracellular vesicle (EV)-derived argininosuccinate synthase 1 (ASS1) levels for HEV-ALF occurrence. Serum EVs were successfully isolated. EV-derived ASS1 levels in the HEV-ALF patients were significantly higher than those in the AHE patients and HCs. In HEV-ALF patients, EV-derived ASS1 levels were positively correlated with the number of failed organs and disease progression. The logistical regression showed that EV-derived ASS1 level is an independent risk factor for HEV-ALF, and orthogonal partial least squares discriminant analysis (OPLS-DA) also suggested that EV-derived ASS1 level has high predictive capability. Besides, the area under the curve (AUC) of EV-derived ASS1 level to predict HEV-ALF occurrence was 0.728 (0.684-0.772) with the sensitivity and specificity being 72.80% and 64.80%, which had a high decision-making ability. Furthermore, there existed no significant difference between the age ≥60 and age <60 groups in EV-derived ASS1 levels. Serum EV-derived ASS1 level is a promising predictor for the occurrence of HEV-ALF.


Assuntos
Vesículas Extracelulares , Vírus da Hepatite E , Hepatite E , Falência Hepática Aguda , Humanos , Argininossuccinato Sintase , Hepatite E/diagnóstico , Hepatite E/epidemiologia
5.
J Genet Genomics ; 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36460297

RESUMO

In mammals, the expression of the homeobox family member Cdx2/CDX2 is restricted within the intestine. Conditional ablation of the mouse Cdx2 in the endodermal cells causes a homeotic transformation of the intestine towards the esophagus or gastric fate. In this report, we show that null mutants of zebrafish cdx1b, encoding the counterpart of mammalian CDX2, could survive more than 10 days post fertilization, a stage when the zebrafish digestive system has been well developed. Through RNA sequencing (RNA-seq) and single cell sequencing (scRNA-seq) of the dissected intestine from the mutant embryos we demonstrated that the loss-of-function of the zebrafish cdx1b yields hepatocyte-like intestinal cells, a phenotype never observed in the mouse model. Further RNA-seq data analysis, genetic and signaling inhibitor studies reveal that Cdx1b functions to guard the intestinal fate by repressing, directly or indirectly, a range of transcriptional factors and signaling pathways for liver specification. Finally, we demonstrated that heatshock-induced overexpression of cdx1b in a transgenic fish abolishes the liver formation. Therefore, we demonstrate that Cdx1b is a key repressor of hepatic fate during the intestine specification in zebrafish.

6.
Front Genet ; 13: 1059682, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452154

RESUMO

Numerous missense mutations have been reported in autosomal dominant polycystic kidney disease which is one of the most common renal genetic disorders. The underlying mechanism for cystogenesis is still elusive, partly due to the lack of suitable animal models. Currently, we tried to establish a porcine transgenic model overexpressing human PKD2-D511V (hPKD2-D511V), which is a dominant-negative mutation in the vertebrate in vitro models. A total of six cloned pigs were finally obtained using somatic cell nuclear transfer. However, five with functional hPKD2-D511V died shortly after birth, leaving only one with the dysfunctional transgenic event to survive. Compared with the WT pigs, the demised transgenic pigs had elevated levels of hPKD2 expression at the mRNA and protein levels. Additionally, no renal malformation was observed, indicating that hPKD2-D511V did not alter normal kidney development. RNA-seq analysis also revealed that several ADPKD-related pathways were disturbed when overexpressing hPKD2-D511V. Therefore, our study implies that hPKD2-D511V may be lethal due to the dominant-negative effect. Hence, to dissect how PKD2-D511V drives renal cystogenesis, it is better to choose in vitro or invertebrate models.

7.
Front Immunol ; 13: 1017164, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569826

RESUMO

Introduction: Spontaneous control of HIV-1 replication in the absence of anti-retroviral therapy (ART) naturally occurs in a small proportion of HIV-1-infected individuals known as elite controllers (EC), likely as a result of improved innate and adaptive immune mechanisms. Previous studies suggest that enhanced cytosolic immune recognition of HIV-1 reverse transcripts in conventional dendritic cells (mDC) from EC enables effective induction of antiviral effector T cell responses. However, the specific molecular circuits responsible for such improved innate recognition of HIV-1 in mDC from these individuals remain unknown. Results and methods: Here, we identified a subpopulation of EC whose mDC displayed higher baseline abilities to respond to intracellular HIV-1 dsDNA stimulation. A computational analysis of transcriptional signatures from such high responder EC, combined with functional studies, suggested cytosolic recognition of HIV-1 dsDNA by cGAS, combined with sensing of viral mRNA by RIG-I after polymerase III-mediated HIV-1 DNA transcription. Discussion: Together, our work identifies collaborative networks of innate sensing pathways that enhance cell-intrinsic abilities of mDC to induce antiviral innate responses against HIV-1; these observations might be useful for the therapeutic induction of effective antiviral immune responses.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Células Dendríticas , Nucleotidiltransferases/metabolismo , Antivirais
8.
Int J Infect Dis ; 127: 129-136, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36476348

RESUMO

BACKGROUND: The persistence of HIV-1-infected cells during antiretroviral therapy is well documented but may be modulated by early initiation of antiretroviral therapy in infants. METHODS: Here, we longitudinally analyzed the proviral landscape in nine infants with vertical HIV-1 infection from Mozambique over a median period of 24 months, using single-genome, near full-length, next-generation proviral sequencing. RESULTS: We observed a rapid decline in the frequency of intact proviruses, leading to a disproportional under-representation of intact HIV-1 sequences within the total number of HIV-1 DNA sequences after 12-24 months of therapy. In addition, proviral integration site profiling in one infant demonstrated clonal expansion of infected cells harboring intact proviruses and indicated that viral rebound was associated with an integration site profile dominated by intact proviruses integrated into genic and accessible chromatin locations. CONCLUSION: Together, these results permit rare insight into the evolution of the HIV-1 reservoir in infants infected with HIV-1 and suggest that the rapid decline of intact proviruses, relative to defective proviruses, may be attributed to a higher vulnerability of genome-intact proviruses to antiviral immunity. Technologies to analyze combinations of intact proviral sequences and corresponding integration sites permit a high-resolution analysis of HIV-1 reservoir cells after early antiretroviral treatment initiation in infants.

9.
ACS Chem Neurosci ; 13(22): 3198-3209, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36331871

RESUMO

Memory impairment and emotional disorder are two common clinical comorbidities in patients with epilepsy. It is imperative to develop a novel therapeutic agent or a strategy. 6-Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a dopamine-1 receptor agonist and sigma-1 receptor allosteric modulator, which displays the neuron-protective and anti-neuroinflammation activity. We examined the effect of SKF83959 on the memory impairment and emotional disorder in the latent period of epilepsy using the mice post-status epilepticus model. We found that SKF83959 ameliorated memory impairment and depressive-like mood, alleviated the neuron damage and the formation of gliosis in hippocampus, suppressed the rise of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3ß. All of these protective actions were reversed by BD1047 (a sigma-1 receptor antagonist). In addition, the intra-hippocampus injection of ketoconazole (a dehydroepiandrosterone synthesis inhibitor) also reversed the protective activity of SKF83959. Thus, we concluded that SKF83959 ameliorated the memory impairment and depressive-like mood in epilepsy via allosterically activating the sigma-1 receptor and subsequently inhibiting the calcineurin/glycogen synthase kinase-3ß pathway.


Assuntos
Calcineurina , Epilepsia , Ratos , Animais , Camundongos , Regulação Alostérica , Ratos Sprague-Dawley , Agonistas de Dopamina/farmacologia , Epilepsia/tratamento farmacológico , Quinases da Glicogênio Sintase
10.
Front Immunol ; 13: 984553, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439166

RESUMO

SARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19. However, the effects of viremia on immune responses in blood cells remain unclear. The current study comprehensively examined transcriptional signatures of PBMCs involving T cells, B cells, NK cells, monocytes, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs) respectively, from three different groups including individuals with moderate (nM), or severe disease with (vS) or without (nS) detectable plasma viral load. Whole transcriptome analysis demonstrated that all seven immune cell subsets were associated with disease severity regardless of cell type. Supervised clustering analysis demonstrated that mDCs and pDCs gene signatures could distinguish disease severity. Notably, transcriptional signatures of the vS group were enriched in pathways related to DNA repair, E2F targets, and G2M checkpoints; in contrast, transcriptional signatures of the nM group were enriched in interferon responses. Moreover, we observed an impaired induction of interferon responses accompanied by imbalanced cell-intrinsic immune sensing and an excessive inflammatory response in patients with severe disease (nS and vS). In sum, our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in seven major immune cells in COVID-19 patients.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Viremia , Imunidade Inata , Interferons/metabolismo
11.
Front Immunol ; 13: 1022190, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275766

RESUMO

As a common malignant tumor of gastrointestinal tract, the incidence of colorectal cancer (CRC) has gradually increased in recent years. In western developed countries, it has even become the second largest malignant tumor next to lung cancer. Immunotherapy is a hot topic in the field of cancer therapy, including immune checkpoint blockade (ICB), adoptive cell therapy (ACT), cancer vaccines and cytokines, aiming to improve the ability of the immune system to recognize, target and eliminate cancer cells. However, cold CRC, which accounts for a high proportion of CRC, is not so reactive to it. The development of immunotherapy to prevent cancer cells from forming "immune escape" pathways to the immune system in cold CRC, has been under increasing study attention. There is proof that an organic combination of radiotherapy, chemotherapy, and several immunotherapies can considerably boost the immune system's capacity to eradicate tumor cells. In this review, we summarized the role of immunotherapy in colorectal cancer. In addition, we propose a breakthrough and strategy to improve the role of immunotherapy in cold CRC based on its characteristics.


Assuntos
Vacinas Anticâncer , Neoplasias Colorretais , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Fatores Imunológicos/uso terapêutico , Citocinas
12.
Cells ; 11(20)2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36291156

RESUMO

The zebrafish intestine and liver, as in other vertebrates, are derived from the endoderm. Great effort has been devoted to deciphering the molecular mechanisms controlling the specification and development of the zebrafish intestine and liver; however, genome-wide comparison of the transcriptomes between these two organs at the larval stage remains unexplored. There is a lack of extensive identification of feature genes marking specific cell types in the zebrafish intestine and liver at 5 days post-fertilization, when the larval fish starts food intake. In this report, through RNA sequencing and single-cell RNA sequencing of intestines and livers separately dissected from wild-type zebrafish larvae at 5 days post-fertilization, together with the experimental validation of 47 genes through RNA whole-mount in situ hybridization, we identified not only distinctive transcriptomes for the larval intestine and liver, but also a considerable number of feature genes for marking the intestinal bulb, mid-intestine and hindgut, and for marking hepatocytes and cholangiocytes. Meanwhile, we identified 135 intestine- and 97 liver-enriched transcription factor genes in zebrafish larvae at 5 days post-fertilization. Our findings provide rich molecular and cellular resources for studying cell patterning and specification during the early development of the zebrafish intestine and liver.


Assuntos
Transcriptoma , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Larva/genética , Larva/metabolismo , Transcriptoma/genética , Intestinos , Fígado/metabolismo , RNA/metabolismo , Fatores de Transcrição/metabolismo
13.
World J Gastroenterol ; 28(38): 5648-5657, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36304089

RESUMO

BACKGROUND: Accurate assessment of the quality of academic journals is of great significance. While Journal Impact Factor (JIF), calculated by Clarivate and based upon the Web of Science literature database, and CiteScore (CS), developed by Elseiver and based upon the Scopus database, have enjoyed high uptake worldwide, efforts continue towards creation of other scientometric indexes that will provide ever-greater qualitative insights into journal impact. Such efforts have yielded the newly-launched Journal Article Influence Index (JAII), which is based on the Reference Citation Analysis (RCA) database, an open multidisciplinary citation analysis database based on artificial intelligence technology. AIM: To evaluate and summarize the similarities and differences between JAII and JIF/CS as journal evaluation indicators, and provide an intuitive method for visual representation of the related data. METHODS: We searched the Journal Citation Reports to obtain the 2021 JIF list, downloaded the CS list updated in July on the Scopus website, and collected the comprehensive list of 2022 JAIIs from the RCA database (www.referencecitationanalysis.com). RESULTS: Our research results revealed that by breaking through the time limit of mainstream journal evaluation methods, the JAII is able to perform well in data reliability, establishing its benefit as a complementary scientometric index to JIF and CS. CONCLUSION: JAII provides comprehensive assessment of the quality and performance of journals.


Assuntos
Gastroenterologia , Publicações Periódicas como Assunto , Humanos , Inteligência Artificial , Reprodutibilidade dos Testes , Fator de Impacto de Revistas
14.
Cell Rep ; 40(3): 111126, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858580

RESUMO

Initiation of antiretroviral therapy (ART) in infected neonates within hours after birth limits viral reservoir seeding but does not prevent long-term HIV-1 persistence. Here, we report parallel assessments of HIV-1 reservoir cells and innate antiviral immune responses in a unique cohort of 37 infected neonates from Botswana who started ART extremely early, frequently within hours after birth. Decline of genome-intact HIV-1 proviruses occurs rapidly after initiation of ART and is associated with an increase in natural killer (NK) cell populations expressing the cytotoxicity marker CD57 and with a decrease in NK cell subsets expressing the inhibitory marker NKG2A. Immune perturbations in innate lymphoid cells, myeloid dendritic cells, and monocytes detected at birth normalize after rapid institution of antiretroviral therapy but do not notably influence HIV-1 reservoir cell dynamics. These results suggest that HIV-1 reservoir cell seeding and evolution in early-treated neonates is markedly influenced by antiviral NK cell immune responses.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos , Humanos , Imunidade Inata , Recém-Nascido , Células Matadoras Naturais
15.
Trends Immunol ; 43(8): 608-616, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35905706

RESUMO

With more than 38 million people living with HIV-1 (PLWH) worldwide, developing a cure for HIV-1 remains a major global health priority. Lifelong persistence of HIV-1 is frequently attributed to a pool of stable, transcriptionally silent HIV-1 proviruses, which are unaffected by currently available antiretroviral therapy (ART) or host immune activity. In this opinion article, we propose a more dynamic interpretation of HIV-1 reservoir cell biology and argue that HIV-1 proviruses frequently display residual viral transcriptional activity, making them vulnerable to longitudinal immune-mediated selection processes. Such mechanisms may, over extended periods of ART, induce an attenuated viral reservoir profile characterized by intact proviruses preferentially integrated into heterochromatin locations. We suggest that intensifying and accelerating naturally occurring selection mechanisms might represent a promising strategy for finding a potential cure for HIV-1 infection.


Assuntos
Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , Infecções por HIV/tratamento farmacológico , Humanos , Provírus , Latência Viral
16.
Cell ; 185(2): 266-282.e15, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35026153

RESUMO

HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered "transcriptionally silent," but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.


Assuntos
HIV-1/genética , Provírus/genética , Transcrição Genética , Idoso , Sequência de Bases , Evolução Biológica , Cromatina/metabolismo , Células Clonais , DNA Viral/genética , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Ionomicina/farmacologia , Masculino , Pessoa de Meia-Idade , Filogenia , Provírus/efeitos dos fármacos , RNA Viral/genética , Acetato de Tetradecanoilforbol/farmacologia , Transcrição Genética/efeitos dos fármacos , Integração Viral/genética , Latência Viral/efeitos dos fármacos , Latência Viral/genética
17.
Neurochem Res ; 47(2): 264-278, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34468932

RESUMO

Further understanding the mechanism for microglia activation is necessary for developing novel anti-inflammatory strategies. Our previous study found that the activation of sigma-1 receptor can effectively inhibit the neuroinflammation, independent of the canonical mechanisms, such as NF-κB, JNK and ERK inflammatory pathways. Thus, it is reasonable that an un-identified, non-canonical pathway contributes to the activation of microglia. In the present study, we found that a sigma-1 receptor agonist of 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084) suppressed lipopolysaccharide (LPS) elevated nitric oxide (NO) content in BV-2 microglia culture supernatant and LPS-raised mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS) in BV-2 microglia. Moreover, PRE-084 alleviated LPS-increased Ser 9 de-phosphorylation of glycogen synthase kinase-3 beta (GSK-3ß), LPS-elevated catalytic activity of calcineurin, and LPS-raised percent and frequency of Ca2+ oscillatory BV-2 cells. We further found that the inhibitory effect of PRE-084 was reversed by a calcineurin activator of chlorogenic acid and a GSK-3ß activator of pyrvinium. Moreover, an IP3 receptor inhibitor of 2-aminoethoxydiphenyl borate mimicked the anti-inflammatory activity of PRE-084. Thus, we identified a noncanonical pro-neuroinflammary pathway of Ca2+ oscillation/Calcineurin/GSK-3ß and the inhibition of this pathway is necessary for the anti-inflammatory activity of sigma-1 receptor activation.


Assuntos
Calcineurina , Microglia , Anti-Inflamatórios/farmacologia , Calcineurina/metabolismo , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores sigma , Fator de Necrose Tumoral alfa/metabolismo
18.
Ann Intern Med ; 175(1): 95-100, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34781719

RESUMO

BACKGROUND: A sterilizing cure of HIV-1 infection has been reported in 2 persons living with HIV-1 who underwent allogeneic hematopoietic stem cell transplantations from donors who were homozygous for the CCR5Δ32 gene polymorphism. However, this has been considered elusive during natural infection. OBJECTIVE: To evaluate persistent HIV-1 reservoir cells in an elite controller with undetectable HIV-1 viremia for more than 8 years in the absence of antiretroviral therapy. DESIGN: Detailed investigation of virologic and immunologic characteristics. SETTING: Tertiary care centers in Buenos Aires, Argentina, and Boston, Massachusetts. PATIENT: A patient with HIV-1 infection and durable drug-free suppression of HIV-1 replication. MEASUREMENTS: Analysis of genome-intact and replication-competent HIV-1 using near-full-length individual proviral sequencing and viral outgrowth assays, respectively; analysis of HIV-1 plasma RNA by ultrasensitive HIV-1 viral load testing. RESULTS: No genome-intact HIV-1 proviruses were detected in analysis of a total of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissues. Seven defective proviruses, some of them derived from clonally expanded cells, were detected. A viral outgrowth assay failed to retrieve replication-competent HIV-1 from 150 million resting CD4+ T cells. No HIV-1 RNA was detected in 4.5 mL of plasma. LIMITATIONS: Absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses. A sterilizing cure of HIV-1 can never be empirically proved. CONCLUSION: Genome-intact and replication-competent HIV-1 were not detected in an elite controller despite analysis of massive numbers of cells from blood and tissues, suggesting that this patient may have naturally achieved a sterilizing cure of HIV-1 infection. These observations raise the possibility that a sterilizing cure may be an extremely rare but possible outcome of HIV-1 infection. PRIMARY FUNDING SOURCE: National Institutes of Health and Bill & Melinda Gates Foundation.


Assuntos
Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/genética , Receptores CCR5/genética , Adulto , Argentina , Linfócitos T CD4-Positivos/imunologia , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno , Humanos , Massachusetts , Gravidez , Resultado da Gravidez , Provírus/genética , Provírus/imunologia , Carga Viral , Viremia/virologia , Replicação Viral/imunologia
19.
Sci Rep ; 11(1): 23938, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34907282

RESUMO

Colorectal carcinoma (CRC) is one of the most prevalent malignant tumors worldwide. Meanwhile, the majority of CRC related deaths results from liver metastasis. Gene expression profile of CRC patients with liver Metastasis was identified using 4 datasets. The data was analyzed using GEO2R tool. GO and KEGG pathway analysis were performed. PPI network of the DEGs between 1 and 2 gene sets was also constructed. The set 1 is named between primary CRC tissues and metastatic CRC tissues. The set 2 is named between primary CRC tissues and normal tissues. Finally, the prognostic value of hub genes was also analyzed. 35 DEGs (set 1) and 142 DEGs (set 2) were identified between CRC liver metastatic cancer patients. The PPI network was constructed using the top 10 set 1 hub genes which included AHSG, SERPINC1, FGA, F2, CP, ITIH2, APOA2, HPX, PLG, HRG and set 2 hub genes which included TIMP1, CXCL1, COL1A2, MMP1, AURKA, UBE2C, CXCL12, TOP2A, ALDH1A1 and PRKACB. Therefore, ITIH2 might represent the potential core gene for colon cancer liver metastasis. COL1A2 behaves as a key gene in colorectal carcinoma.


Assuntos
Neoplasias Colorretais , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Genes Neoplásicos , Neoplasias Hepáticas , Proteínas de Neoplasias , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética
20.
Sci Transl Med ; 13(624): eabl4097, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34910552

RESUMO

Increasing evidence suggests that durable drug-free control of HIV-1 replication is enabled by effective cellular immune responses that may induce an attenuated viral reservoir configuration with a weaker ability to drive viral rebound. Here, we comprehensively tracked effects of antiviral immune responses on intact and defective proviral sequences from elite controllers (ECs), analyzing both classical escape mutations and HIV-1 chromosomal integration sites as biomarkers of antiviral immune selection pressure. We observed that, within ECs, defective proviruses were commonly located in permissive genic euchromatin positions, which represented an apparent contrast to autologous intact proviruses that were frequently located in heterochromatin regions; this suggests differential immune selection pressure on intact versus defective proviruses in ECs. In comparison to individuals receiving antiretroviral therapy, intact and defective proviruses from ECs showed reduced frequencies of escape mutations in cytotoxic T cell epitopes and antibody contact regions, possibly due to the small and poorly inducible reservoir that may be insufficient to drive effective viral escape in ECs. About 15% of ECs harbored nef deletions in intact proviruses, consistent with increased viral vulnerability to host immunity in the setting of nef dysfunction. Together, these results suggest a distinct signature of immune footprints in proviral sequences from ECs.


Assuntos
Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , Controladores de Elite , Epitopos de Linfócito T , HIV-1/genética , Humanos , Provírus/genética , Carga Viral
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