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1.
Lancet Respir Med ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33556319

RESUMO

BACKGROUND: To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. METHODS: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 µg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. FINDINGS: Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15-16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49-31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. INTERPRETATION: Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. FUNDING: The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

3.
Nature ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33238290

RESUMO

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate investigation of pathologies including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. We generated long-term feeder-free, chemically defined culture of distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids exhibited AT1 transdifferentiation potential while basal cell organoids developed lumens lined by differentiated club and ciliated cells. Single cell analysis of basal organoid KRT5+ cells revealed a distinct ITGA6+ITGB4+ mitotic population whose proliferation further segregated to a TNFRSF12Ahi subfraction comprising ~10% of KRT5+ basal cells, residing in clusters within terminal bronchioles and exhibiting enriched clonogenic organoid growth activity. Distal lung organoids were created with apical-out polarity to display ACE2 on the exposed external surface, facilitating SARS-CoV-2 infection of AT2 and basal cultures and identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and establishes a facile in vitro organoid model for human distal lung infections including COVID-19-associated pneumonia.

4.
bioRxiv ; 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32743583

RESUMO

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange and is affected by disorders including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. Investigations of these localized pathologies have been hindered by a lack of 3D in vitro human distal lung culture systems. Further, human distal lung stem cell identification has been impaired by quiescence, anatomic divergence from mouse and lack of lineage tracing and clonogenic culture. Here, we developed robust feeder-free, chemically-defined culture of distal human lung progenitors as organoids derived clonally from single adult human alveolar epithelial type II (AT2) or KRT5 + basal cells. AT2 organoids exhibited AT1 transdifferentiation potential, while basal cell organoids progressively developed lumens lined by differentiated club and ciliated cells. Organoids consisting solely of club cells were not observed. Upon single cell RNA-sequencing (scRNA-seq), alveolar organoids were composed of proliferative AT2 cells; however, basal organoid KRT5 + cells contained a distinct ITGA6 + ITGB4 + mitotic population whose proliferation segregated to a TNFRSF12A hi subfraction. Clonogenic organoid growth was markedly enriched within the TNFRSF12A hi subset of FACS-purified ITGA6 + ITGB4 + basal cells from human lung or derivative organoids. In vivo, TNFRSF12A + cells comprised ~10% of KRT5 + basal cells and resided in clusters within terminal bronchioles. To model COVID-19 distal lung disease, we everted the polarity of basal and alveolar organoids to rapidly relocate differentiated club and ciliated cells from the organoid lumen to the exterior surface, thus displaying the SARS-CoV-2 receptor ACE2 on the outwardly-facing apical aspect. Accordingly, basal and AT2 apical-out organoids were infected by SARS-CoV-2, identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung alveolar and basal stem cells, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and exemplifies progenitor identification within a slowly proliferating human tissue. Further, our studies establish a facile in vitro organoid model for human distal lung infectious diseases including COVID-19-associated pneumonia.

5.
bioRxiv ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32743589

RESUMO

Drug discovery campaigns against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are beginning to target the viral RNA genome 1, 2 . The frameshift stimulation element (FSE) of the SARS-CoV-2 genome is required for balanced expression of essential viral proteins and is highly conserved, making it a potential candidate for antiviral targeting by small molecules and oligonucleotides 3-6 . To aid global efforts focusing on SARS-CoV-2 frameshifting, we report exploratory results from frameshifting and cellular replication experiments with locked nucleic acid (LNA) antisense oligonucleotides (ASOs), which support the FSE as a therapeutic target but highlight difficulties in achieving strong inactivation. To understand current limitations, we applied cryogenic electron microscopy (cryo-EM) and the Ribosolve 7 pipeline to determine a three-dimensional structure of the SARS-CoV-2 FSE, validated through an RNA nanostructure tagging method. This is the smallest macromolecule (88 nt; 28 kDa) resolved by single-particle cryo-EM at subnanometer resolution to date. The tertiary structure model, defined to an estimated accuracy of 5.9 Å, presents a topologically complex fold in which the 5' end threads through a ring formed inside a three-stem pseudoknot. Our results suggest an updated model for SARS-CoV-2 frameshifting as well as binding sites that may be targeted by next generation ASOs and small molecules.

6.
Nature ; 586(7830): 560-566, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32854108

RESUMO

Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic1. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures2,3. SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2)4. Here we used reverse genetics5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro-both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-196.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Modelos Animais de Doenças , Interferons/farmacologia , Interferons/uso terapêutico , Interleucinas/farmacologia , Interleucinas/uso terapêutico , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Envelhecimento/imunologia , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Interferons/administração & dosagem , Interleucinas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Modelos Moleculares , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Receptores Virais/genética , Receptores Virais/metabolismo
7.
Dig Dis Sci ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770488

RESUMO

BACKGROUND: Mongolia is a highly endemic region for chronic hepatitis B (HBV), hepatitis delta (HDV), and hepatitis C (HCV) infections. Aim of this study was to comprehensively characterize chronic viral hepatitis among Mongols living in Southern California. METHODS: Three screening events were conducted between August and November 2018, with 528 adult Mongols tested for HBV and HCV. HBsAg (+) individuals (CHB) underwent additional testing for HDV RNA and anti-HDV. Liver tests, platelet count, and FibroScan™ were performed on CHB and chronic HCV (CHC) individuals. RESULTS: Fifty-one out of 534 were HBsAg reactive (9.7%), and all were foreign-born. Mean age of CHB individuals was 37.8 (range 18-69) years. Forty-six out of 51 were HBeAg (-). HBV genotypes were exclusively D2 or A1. Twenty-one out of 51 (41.2%) were anti-HDV (+) and 17/51 (33.3%) were HDV RNA (+). HDV RNA (+) individuals had significantly higher ALT, fibrosis-4 score, and liver stiffness compared to HDV RNA (-) individuals. Incidence of advanced fibrosis was higher in HDV RNA (+) individuals (57% vs. 13%, p = 0.013). Forty-eight (9.1%) individuals were anti-HCV (+) and 19 (3.6%) were HCV RNA (+). Mean age of CHC individuals was 40.2 (range 28-71) years. Prevalence of anti-HCV (+) was higher among those born between 1945 and 1965 versus those born after 1965 (18.8% vs. 7.9%, p = 0.025). Genotype 1b was predominant. Incidence of cirrhosis was 7% among all participants. CONCLUSIONS: Mongols living in the USA are at high risk for CHB and CHC infections. One-third of CHB individuals had CHD superinfection with advanced fibrosis. Universal screening for viral hepatitis in Mongols in the USA is mandatory.

8.
bioRxiv ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32511406

RESUMO

Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2. We used reverse genetics to remodel the S and mACE2 binding interface resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro , and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of IFN lambda-1a treatment in human COVID-19 infections.

9.
mBio ; 11(3)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576678

RESUMO

It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.


Assuntos
Betacoronavirus/imunologia , Antígeno CD47/metabolismo , Imunomodulação/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Células A549 , Imunidade Adaptativa/imunologia , Animais , Antígeno CD47/genética , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Humanos , Imunidade Inata/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Regulação para Cima/imunologia
11.
RNA ; 26(8): 937-959, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32398273

RESUMO

As the COVID-19 outbreak spreads, there is a growing need for a compilation of conserved RNA genome regions in the SARS-CoV-2 virus along with their structural propensities to guide development of antivirals and diagnostics. Here we present a first look at RNA sequence conservation and structural propensities in the SARS-CoV-2 genome. Using sequence alignments spanning a range of betacoronaviruses, we rank genomic regions by RNA sequence conservation, identifying 79 regions of length at least 15 nt as exactly conserved over SARS-related complete genome sequences available near the beginning of the COVID-19 outbreak. We then confirm the conservation of the majority of these genome regions across 739 SARS-CoV-2 sequences subsequently reported from the COVID-19 outbreak, and we present a curated list of 30 "SARS-related-conserved" regions. We find that known RNA structured elements curated as Rfam families and in prior literature are enriched in these conserved genome regions, and we predict additional conserved, stable secondary structures across the viral genome. We provide 106 "SARS-CoV-2-conserved-structured" regions as potential targets for antivirals that bind to structured RNA. We further provide detailed secondary structure models for the extended 5' UTR, frameshifting stimulation element, and 3' UTR. Lastly, we predict regions of the SARS-CoV-2 viral genome that have low propensity for RNA secondary structure and are conserved within SARS-CoV-2 strains. These 59 "SARS-CoV-2-conserved-unstructured" genomic regions may be most easily accessible by hybridization in primer-based diagnostic strategies.


Assuntos
Betacoronavirus/genética , RNA Viral/química , RNA Viral/genética , Sequência de Bases , Betacoronavirus/classificação , Evolução Molecular , Genoma Viral , Conformação de Ácido Nucleico , Alinhamento de Sequência , Termodinâmica
12.
J Exp Med ; 217(5)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32289152

RESUMO

With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Interferons/metabolismo , Pneumonia Viral/metabolismo , Humanos , Pandemias , Internalização do Vírus
13.
Nature ; 579(7798): 303-308, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31945771

RESUMO

Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways1,2. Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human ß-arrestin 1 (ßarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with ßarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin-arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin-receptor interactions.


Assuntos
Modelos Moleculares , Receptores de Neurotensina/química , beta-Arrestina 1/química , Microscopia Crioeletrônica , Humanos , Fosforilação , Estabilidade Proteica , Estrutura Quaternária de Proteína , Receptores de Neurotensina/metabolismo , beta-Arrestina 1/metabolismo
14.
Sci Transl Med ; 12(527)2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969487

RESUMO

Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIß (PI4KIIIß). Molecular, biochemical, and cell biological studies show that PI4KIIIß-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIß-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIß antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIß-dependent secretion for cancer cell survival and tumor progression.

15.
Sci Rep ; 9(1): 18719, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822697

RESUMO

Fuzhenghuayu (FZHY) is a compound extracted from natural plants. Its anti-fibrotic effect has been confirmed in experimental and clinical studies. However, precise effects and underlying mechanisms of FZHY in liver angiogenesis largely remain understood. In this study, we investigated the effects of FZHY on sinusoidal capillarization and angiogenesis with mice challenged for Carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN), in vitro human hepatic sinusoidal endothelial cells (HHSEC) and Human Umbilical Vein Endothelial Cell (HUVEC) 3D fibrin gel model. Besides its anti-fibrotic effect, FZHY ameliorated CCl4 and DMN-induced sinusoidal capillarization, angiogenesis and expression of angiogenesis-associated factors, i.e. CD31, VEGF, VEGF receptor II, phosphor-ERK and HIF-1α. Consistent with the findings based on animal models, inhibitory effects of FZHY on capillarization and angiogenesis were further confirmed in HHSEC and the HUVEC 3D fibrin gel model, respectively. These data suggest that FZHY ameliorates not only liver fibrosis but also vessel remodeling in experimental models. Therefore, FZHY might be a potentially useful drug to treat liver cirrhosis in clinical practice.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Animais , Capilares/efeitos dos fármacos , Tetracloreto de Carbono/efeitos adversos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Fígado/patologia , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Neovascularização Patológica/metabolismo , Transdução de Sinais
16.
Clin Liver Dis ; 23(3): 557-572, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31266627

RESUMO

Chronic hepatitis D (CHD) results from an infection with the hepatitis B virus and hepatitis D virus (HDV). CHD is the most severe form of human viral hepatitis. Current treatment options consist of interferon alfa, which is effective only in a minority of patients. Study of HDV molecular virology has resulted in new approaches entering clinical trials, with phase-3 studies the most advanced. These include the entry inhibitor bulevirtide, the nucleic acid polymer REP 2139-Ca, the farnesyltransferase inhibitor lonafarnib, and pegylated interferon lambda. This article summarizes the available data on these emerging therapeutics.


Assuntos
Coinfecção/tratamento farmacológico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite D Crônica/tratamento farmacológico , Vírus Delta da Hepatite/efeitos dos fármacos , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Antivirais/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Feminino , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Hepatite D Crônica/diagnóstico , Hepatite D Crônica/epidemiologia , Humanos , Masculino , Piperidinas/uso terapêutico , Prognóstico , Piridinas/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Resultado do Tratamento
17.
Gastroenterology ; 157(4): 1055-1066.e11, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31251928

RESUMO

BACKGROUND & AIMS: Trends of mortality associated with extrahepatic complications of chronic liver disease might be changing. We studied trends in mortality from extrahepatic complications of viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease in the United States. METHODS: We performed a population-based study using US Census and the National Center for Health Statistics mortality records from 2007 through 2017. We identified trends in age-standardized mortality using Joinpoint trend analysis with estimates of annual percent change. RESULTS: The liver-related mortality among patients with hepatitis C virus (HCV) infection increased from 2007 through 2013 and then decreased once patients began receiving treatment with direct-acting antiviral (DAA) agents, from 2014 through 2017. Among patients with HCV infection, the age-standardized mortality for extrahepatic cancers was 2.6%, for cardiovascular disease was 1.9%, and for diabetes was 3.3%. Among individuals with hepatitis B virus infection, liver-related mortality decreased steadily from 2007 through 2017. During the study, age-standardized mortality from hepatitis B virus-related extrahepatic complications increased by an average of 2.0% each year. Although liver-related mortality from ALD continued to increase, mortality from extrahepatic complications of ALD did not change significantly during the 11-year study. Among patients with nonalcoholic fatty liver disease, the cause of death was most frequently cardiovascular disease, which increased gradually over the study period, whereas liver-related mortality increased rapidly. CONCLUSIONS: In an analysis of US Census and the National Center for Health Statistics mortality records, we found that after widespread use of DAA agents for treatment of viral hepatitis, cause-specific mortality from extrahepatic cancers increased, whereas mortality from cardiovascular disease or diabetes increased only among patients with HCV infection. These findings indicate the need to reassess risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals successfully treated for HCV infection with DAA agents.


Assuntos
Causas de Morte/tendências , Hepatite B Crônica/mortalidade , Hepatite C Crônica/mortalidade , Hepatopatias Alcoólicas/mortalidade , Hepatopatia Gordurosa não Alcoólica/mortalidade , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Censos , Bases de Dados Factuais , Atestado de Óbito , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Humanos , Hepatopatias Alcoólicas/diagnóstico , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Prevalência , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia , Adulto Jovem
18.
J Hepatol ; 70(5): 1008-1015, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30982526

RESUMO

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.


Assuntos
Hepatite D Crônica/tratamento farmacológico , Biomarcadores , Ensaios Clínicos como Assunto , Antígenos de Superfície da Hepatite B/análise , Hepatite D Crônica/patologia , Humanos , Lipopeptídeos/uso terapêutico , Fígado/patologia , Ácidos Nucleicos/uso terapêutico , Piperidinas/uso terapêutico , Polímeros/uso terapêutico , Piridinas/uso terapêutico , RNA Viral/análise , Resultado do Tratamento
19.
Viruses ; 11(3)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875937

RESUMO

Backgrounds and Aims: We previously demonstrated that serum hepatitis B virus (HBV) DNA in HBV infected humanized mice exhibited a highly dynamic multiphasic kinetic pattern from infection initiation to steady-state. Here, we investigated whether this pattern is consistent across different HBV clones or in the presence of hepatitis D virus (HDV) co-infection. Methods: We analyzed early serum viral kinetics using 26 HBV genotype C (GtC) mono-infected mice [clones: PXB, Hiroshima GtC CL4 (CL4) and Hiroshima GtC CL5 (CL5)] and four HBV CL4/HDV genotype one co-infected mice. Results: The HBV kinetics observed with clones CL4 and CL5 were similar to that previously defined in HBV PXB infected mice. Additionally, no significant differences in HBV DNA levels were observed between HBV mono-infected and HBV/HDV co-infected mice through 4 weeks post-inoculation (p.i.). However, HBV DNA levels at 6 weeks p.i. in HBV/HDV co-infected mice were significantly lower than those in HBV mono-infected mice (P = 0.002), consistent with HDV suppression of chronic HBV. Conclusions: HBV infection initiation is multiphasic across multiple viral clones and is not altered by HDV co-infection. The latter suggests that higher HDV titers (>8 log IU/mL) and/or longer duration of HDV infection might be needed to trigger HDV-induced suppression on HBV.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B/sangue , Hepatite D/sangue , Vírus Delta da Hepatite/fisiologia , Animais , Animais Geneticamente Modificados , Células Cultivadas , Coinfecção/sangue , Coinfecção/virologia , DNA Viral/sangue , Genótipo , Hepatite B/virologia , Vírus da Hepatite B/genética , Hepatite D/virologia , Vírus Delta da Hepatite/genética , Humanos , Cinética , Camundongos , Carga Viral
20.
Nat Commun ; 10(1): 794, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770827

RESUMO

Prolonged exposure of CD8+ T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8+ T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα+ CD8+ T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα+ cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8+ T cell-killing in vivo. SIRPα+ CD8+ T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8+ T cells during chronic infection expands the cytotoxic subset of SIRPα+ CD8+ T cells.


Assuntos
Infecções por Arenaviridae/imunologia , Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Receptores Imunológicos/imunologia , Animais , Infecções por Arenaviridae/genética , Infecções por Arenaviridae/virologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Feminino , Expressão Gênica/imunologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/virologia
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