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1.
World J Gastroenterol ; 27(31): 5181-5188, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34497443

RESUMO

Hepatitis C virus (HCV) reactivation occurs in 23% of HCV-infected cancer patients receiving chemotherapy. Forty-three percent of the patients with reactivation of HCV during chemotherapy develop a hepatitis flare. Most of the cancer patients with HCV reactivation have an unremarkable clinical course following an HCV-related hepatitis flare during chemotherapy. However, 26%-57% of the cancer patients developing an acute flare of chronic hepatitis C during chemotherapy require unanticipated discontinuation or dose reduction of chemotherapy, which results in deleterious changes in the cancer treatment plan. Although an optimal strategy for HCV screening in cancer patients receiving chemotherapy has not been established, universal pre-chemotherapy HCV testing for patients with hematological malignancies is recommended by current guidelines. All the currently approved direct-acting antivirals (DAAs) can be used in cancer patients, but the use of DAAs during chemotherapy should avoid drug-drug interactions between chemotherapy and antiviral agents. If there are no contraindications or anticipated drug-drug interactions, DAAs treatment can be administered before, during, or after chemotherapy. In conclusion, HCV reactivation occurs in approximately one-fourth of HCV-infected cancer patients receiving chemotherapy. An HCV-related hepatitis flare during chemotherapy may lead to the discontinuation of potentially life-saving chemotherapy. Currently, universal HCV screening is recommended in hematological malignancy patients before chemotherapy, but there is no evidence-based guideline for other cancer patients. DAAs treatment can cure HCV infection and prevent HCV reactivation during chemotherapy.


Assuntos
Hepatite B Crônica , Hepatite C Crônica , Hepatite C , Antivirais/efeitos adversos , Hepacivirus , Hepatite B Crônica/tratamento farmacológico , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Exacerbação dos Sintomas , Ativação Viral
2.
Eur J Med Res ; 26(1): 92, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384499

RESUMO

PURPOSE: Herpes zoster (HZ), or shingles, is a clinical syndrome resulting from the reactivation of latent varicella zoster virus (VZV) within the sensory ganglia. We evaluated the safety and tolerability of ES16001 (ethanol extract of Elaeocarpus sylvestris var. ellipticus), a novel inhibitor of varicella zoster virus reactivation in healthy adults. METHOD: Single-center, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) studies were conducted in 20- to 45-year-old healthy adults without chronic disease. In the SAD study (n = 32), subjects randomly received a single oral dose of 240, 480, 960, or 1440 mg ES16001 or a placebo. In the MAD study (n = 16), subjects randomly received once daily doses of 480 or 960 mg ES16001 or a placebo for 5 days. The safety and tolerability of the drug were evaluated by monitoring participants' treatment emergent adverse events (TEAEs) and vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory tests. RESULTS: In the SAD study, 11 adverse reactions were seen in 5 subjects, and in the MAD study, 8 adverse reactions were seen in 6 subjects. All adverse reactions were mild, and no serious adverse reactions occurred. The most common adverse reaction was an increase in alanine aminotransferase (ALT), but all test values were in the clinically non-significant range, and their clinical significance was judged to be small considering the fact that most of the test values returned to normal immediately after the end of drug administration. CONCLUSION: ES16001 has good safety and tolerability when administered both once and repeatedly to healthy subjects. Further research is needed to identify any possible drug-induced hepatotoxicity, which appears infrequently. Our findings provide a rationale for further clinical investigations of ES16001 for the prevention of HZ. TRIAL REGISTRATION: CRIS, KCT0006066. Registered 7 April 2021-Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/19071 ).


Assuntos
Antivirais/efeitos adversos , Elaeocarpaceae/química , Herpes Zoster/tratamento farmacológico , Extratos Vegetais/efeitos adversos , Adulto , Alanina Transaminase/sangue , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Tolerância a Medicamentos , Feminino , Herpes Zoster/prevenção & controle , Humanos , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ativação Viral/efeitos dos fármacos
3.
Nat Commun ; 12(1): 5000, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404805

RESUMO

The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.


Assuntos
Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Neutralizantes/administração & dosagem , COVID-19/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/virologia , Chlorocebus aethiops , Modelos Animais de Doenças , Epitopos , Feminino , Células HEK293 , Haplorrinos , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Células Vero , Ativação Viral
4.
Zhonghua Gan Zang Bing Za Zhi ; 29(7): 659-665, 2021 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-34371536

RESUMO

Objective: To investigate the effect of programmed death receptor (PD)-1 antibody therapy in patients with hepatitis B-associated liver cancer. Methods: Data of 29 chronically infected HBV patients with liver cancer who received PD-1 antibody combined with tyrosine kinase inhibitor in the Department of Infectious Diseases of the Fifth Medical Center of PLA General Hospital from March 2020 to January 2021 were selected. At the same time, all of the above-mentioned hepatitis B virus (HBV) patients were treated with nucleos(t)ide analogues. Patients clinical diagnostic data, laboratory test results, tumor response and the incidence of adverse reactions were collected retrospectively to understand the overall safety, therapeutic anti-tumor effect, HBV changes condition and the correlation between HBV changes and anti-tumor PD-1 antibody efficacy, high viral load treatment condition, and HBV reactivation safety issues. Statistical analysis was performed by non-parametric rank sum test. Results: Therapeutic anti-tumor effect and safety profile were good in patients. The complete remission rate was reached 27.6%. Adverse reactions were mostly mild, and the incidence of serious adverse reactions was low. After 12 weeks of follow-up, HBV DNA and hepatitis B surface antigen (HBsAg) was quantitatively decreased (P < 0.05). HBV DNA and HBsAg were decreased more significantly in patients with progressive disease (PD), stable disease (SD) and partial response (PR) (P < 0.05). Five patients with HBV DNA ≥ 10(4) IU/ml had responded well to the tumor treatment without serious adverse reactions. One patient had a slight increase in HBV DNA and alanine aminotransferase, while there was no HBV reactivation and correlated liver damage. Conclusion: Patients with HBV-associated liver cancer who received combined therapy have good anti-tumor efficacy and safety profile. PD-1 treatment has a certain effect on HBV. Compared with non-responders, patients with tumor response have better antiviral treatment efficacy. The safety of treatment in patients with high viral load is manageable, and there are no safety issues related to HBV reactivation.


Assuntos
Hepatite B , Neoplasias Hepáticas , Antivirais/uso terapêutico , DNA Viral , Hepatite B/complicações , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Morte Celular , Estudos Retrospectivos , Ativação Viral
6.
Front Cell Infect Microbiol ; 11: 686035, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350133

RESUMO

The failure of highly active antiretroviral therapy (HAART) has been largely responsible for the existence of latent human immunodeficiency virus type 1 (HIV-1) reservoirs. The "shock and kill" strategy was confirmed to reactivate HIV-1 latent reservoirs by latency-reversing agents (LRAs) for accelerated HIV-1 clearance. However, a single LRA might be insufficient to induce HIV-1 reactivation from latency due to the complexity of the multiple signaling regulatory pathways that establish the HIV-1 latent reservoir. Therefore, combinations of LRAs or dual-mechanism LRAs are urgently needed to purge the latent reservoirs. We demonstrate here for the first time that a dual-target inhibitor with a specific suppressive effect on both BRD4 and TIP60, CPI-637, could reactivate latent HIV-1 in vitro by permitting Tat to bind positive transcription elongation factor b (P-TEFb) and assembling Tat-super-elongation complex (SEC) formation. In addition, CPI-637-mediated TIP60 downregulation further stimulated BRD4 dissociation from the HIV-1 long terminal repeat (LTR) promoter, allowing Tat to more effectively bind P-TEFb compared to BRD4 inhibition alone. Much more importantly, CPI-637 exerted a potent synergistic effect but alleviated global T cell activation and blocked viral spread to uninfected bystander CD4+ T cells with minimal cytotoxicity. Our results indicate that CPI-637 opens up the prospect of novel dual-target inhibitors for antagonizing HIV-1 latency and deserves further investigation for development as a promising LRA with a "shock and kill" strategy.


Assuntos
Benzodiazepinonas/farmacologia , Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , Proteínas de Ciclo Celular/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , Humanos , Lisina Acetiltransferase 5/antagonistas & inibidores , Proteínas Nucleares , Fatores de Transcrição/antagonistas & inibidores , Ativação Viral , Latência Viral
8.
World J Gastroenterol ; 27(25): 3762-3779, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34321842

RESUMO

Hepatitis B remains a significant global clinical problem, despite the implementation of safe and effective vaccination programs. The prevalence of hepatitis B virus (HBV) in patients with inflammatory bowel disease (IBD) largely follows the regional epidemiologic status. Serological screening with hepatitis B surface antigen (HBsAg), and antibodies to hepatitis B surface (anti-HBs) and core (anti-HBc) proteins is a key element in the management of IBD patients and, ideally, should be performed at IBD diagnosis. Stratification of individual cases should be done according to the serologic profile and the IBD-specific treatment, with particular emphasis in patients receiving immunosuppressive regimens. In patients who have not contracted HBV, vaccination is indicated to accomplish protective immunity. Vaccination in immunosuppressed patients, however, is a challenging issue and several strategies for primary and revaccination have been proposed. The risk of HBV reactivation in patients with IBD should be considered in both HBsAg-positive and HBsAg-negative/anti-HBc-positive patients, when immunosuppressive therapies are administered. HBV reactivation is preventable via the administration of prophylactic nucleot(s)ide analogues and should be the standard approach in HBsAg-positive patients. HBsAg-negative/anti-HBc-positive patients represent a non-homogeneous group and bear a significantly lower risk of HBV reactivation. Biochemical, serological and molecular monitoring is currently the recommended approach for anti-HBc patients. Acute HBV infection is rarely reported in IBD patients. In the present review, we outline the problems associated with HBV infection in patients with IBD and present updated evidence for their management.


Assuntos
Hepatite B , Doenças Inflamatórias Intestinais , DNA Viral , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Anticorpos Anti-Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Ativação Viral
9.
PLoS One ; 16(7): e0254129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34197543

RESUMO

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome with the need of invasive ventilation. Pulmonary herpes simplex-1 (HSV-1) reactivation in invasively ventilated patients is a known phenomenon. To date very little is known about the frequency and the predisposing factors of HSV-1 reactivation in COVID-19. Therefore, we evaluated our cohort of invasively ventilated COVID-19 patients with severe pneumonia for HSV-1 in respiratory specimens and combined these results with functional immunomonitoring of the peripheral blood. Tracheal secretions and bronchial lavages were screened by PCR for HSV-1 positivity. Comprehensive immunophenotyping and quantitative gene expression analysis of Interferon-stimulated genes (IFI44L, MX1, RSAD2, ISIG15 and IFIT1) and IL-1 beta were performed in whole blood. Time course of infection beginning at symptom onset was grouped into three phases ("early" phase 1: day 1-10, "middle" phase 2: day 11-30 and "late" phase 3: day 31-40). Pulmonary HSV-1 reactivation was exclusively observed in the later phases 2 and 3 in 15 of 18 analyzed patients. By FACS analysis a significant increase in activated CD8 T cells (CD38+HLADR+) in phase 2 was found when compared with phase 1 (p<0.05). Expression of Interferon-stimulated genes (IFI44L, RSAD2 ISIG15, MX1, IFIT1) was significantly lower after HSV-1 detection than before. Taken together, reactivation of HSV-1 in the later phase of SARS-CoV-2- infection occurs in parallel with a drop of antiviral innate responsiveness as shown by decreased expression of Interferon-stimulated genes and a concurrent increase of highly activated CD38+HLADR+ CD8 T cells.


Assuntos
COVID-19/terapia , Herpes Simples/etiologia , Herpesvirus Humano 1/fisiologia , Respiração Artificial , Ativação Viral , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/imunologia , Feminino , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/isolamento & purificação , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Respiração Artificial/efeitos adversos , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação
10.
Nat Commun ; 12(1): 4503, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301927

RESUMO

Promoter-proximal pausing of RNA polymerase II is a key process regulating gene expression. In latent HIV-1 cells, it prevents viral transcription and is essential for latency maintenance, while in acutely infected cells the viral factor Tat releases paused polymerase to induce viral expression. Pausing is fundamental for HIV-1, but how it contributes to bursting and stochastic viral reactivation is unclear. Here, we performed single molecule imaging of HIV-1 transcription. We developed a quantitative analysis method that manages multiple time scales from seconds to days and that rapidly fits many models of promoter dynamics. We found that RNA polymerases enter a long-lived pause at latent HIV-1 promoters (>20 minutes), thereby effectively limiting viral transcription. Surprisingly and in contrast to current models, pausing appears stochastic and not obligatory, with only a small fraction of the polymerases undergoing long-lived pausing in absence of Tat. One consequence of stochastic pausing is that HIV-1 transcription occurs in bursts in latent cells, thereby facilitating latency exit and providing a rationale for the stochasticity of viral rebounds.


Assuntos
Regulação Viral da Expressão Gênica , Infecções por HIV/genética , HIV-1/genética , Regiões Promotoras Genéticas/genética , Latência Viral/genética , Algoritmos , RNA Polimerases Dirigidas por DNA/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Células HeLa , Humanos , Modelos Genéticos , Processos Estocásticos , Fatores de Tempo , Ativação Viral/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
11.
Nat Commun ; 12(1): 4436, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290252

RESUMO

Latent human cytomegalovirus (HCMV) infection is characterized by limited gene expression, making latent HCMV infections refractory to current treatments targeting viral replication. However, reactivation of latent HCMV in immunosuppressed solid organ and stem cell transplant patients often results in morbidity. Here, we report the killing of latently infected cells via a virus-specific nanobody (VUN100bv) that partially inhibits signaling of the viral receptor US28. VUN100bv reactivates immediate early gene expression in latently infected cells without inducing virus production. This allows recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals, which could serve as a therapy to reduce the HCMV latent reservoir of transplant patients.


Assuntos
Citomegalovirus/efeitos dos fármacos , Anticorpos de Domínio Único/farmacologia , Linfócitos T Citotóxicos/imunologia , Latência Viral/efeitos dos fármacos , Células Cultivadas , Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Expressão Gênica/efeitos dos fármacos , Genes Precoces/genética , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/virologia , Receptores de Quimiocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anticorpos de Domínio Único/metabolismo , Proteínas Virais/metabolismo , Ativação Viral/efeitos dos fármacos
12.
BMJ Case Rep ; 14(7)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244190

RESUMO

A 93-year-old man was admitted with 1 week of frank jaundice and abdominal pain. His medical history included diffuse large B-cell lymphoma treated with rituximab and cyclophosphamide, hydroxydaunomycin, oncovin and prednisolone (R-CHOP) chemotherapy 10 months prior. His investigations revealed marked hyperbilirubinemia with a total bilirubin of 355 µmol/L, along with a 17-fold elevation in alanine transaminase and impaired hepatic synthetic function. He tested hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) negative, hepatitis B core antibody (HBcAb) positive and had elevated hepatitis B virus DNA level at 13 691 IU/L. This was in the setting of radiological evidence of suspected cirrhosis. He was later found to have tested positive for HBcAb and negative for HBsAg and HBsAb prior to chemotherapy, but had not received antiviral prophylaxis. He was diagnosed with fulminant hepatitis secondary to delayed hepatitis B reactivation in the setting of rituximab. Hepatitis B reactivation and the role of screening and antiviral prophylaxis in isolated HBcAb-positive patients is reviewed.


Assuntos
Hepatite B , Falência Hepática , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B/uso terapêutico , Vírus da Hepatite B , Humanos , Masculino , Rituximab/efeitos adversos , Ativação Viral
13.
Nat Commun ; 12(1): 4642, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330907

RESUMO

The continental subsurface houses a major portion of life's abundance and diversity, yet little is known about viruses infecting microbes that reside there. Here, we use a combination of metagenomics and virus-targeted direct-geneFISH (virusFISH) to show that highly abundant carbon-fixing organisms of the uncultivated genus Candidatus Altiarchaeum are frequent targets of previously unrecognized viruses in the deep subsurface. Analysis of CRISPR spacer matches display resistances of Ca. Altiarchaea against eight predicted viral clades, which show genomic relatedness across continents but little similarity to previously identified viruses. Based on metagenomic information, we tag and image a putatively viral genome rich in protospacers using fluorescence microscopy. VirusFISH reveals a lytic lifestyle of the respective virus and challenges previous predictions that lysogeny prevails as the dominant viral lifestyle in the subsurface. CRISPR development over time and imaging of 18 samples from one subsurface ecosystem suggest a sophisticated interplay of viral diversification and adapting CRISPR-mediated resistances of Ca. Altiarchaeum. We conclude that infections of primary producers with lytic viruses followed by cell lysis potentially jump-start heterotrophic carbon cycling in these subsurface ecosystems.


Assuntos
Archaea/genética , Vírus de Archaea/genética , Genoma Viral/genética , Metagenoma/genética , Metagenômica/métodos , Archaea/classificação , Archaea/virologia , Vírus de Archaea/metabolismo , Vírus de Archaea/fisiologia , Biofilmes/crescimento & desenvolvimento , Ecossistema , Genômica/métodos , Interações Hospedeiro-Patógeno/genética , Lisogenia/genética , Microscopia de Fluorescência , Filogenia , RNA Ribossômico 16S/genética , Especificidade da Espécie , Ativação Viral/genética
14.
Epidemiol Infect ; 149: e145, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34130765

RESUMO

The appearance on the skin of herpes virus lesions, concomitantly with the coronavirus disease 2019 (COVID-19) pandemic, leads us to suspect an underlying infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Diagnostic reverse transcriptase polymerase chain reaction tests and immunoglobulin M (IgM) and IgG seroconversion studies have therefore been carried out. We present three cases of herpes virus infections in immunocompetent patients: one of the infections was herpes simplex 1 in a 40-year-old woman, and the other two were herpes varicella-zoster infections in a 62-year-old man and a 25-year-old woman. The patients were in the care of the southern health district of Seville of the SAS (Andalusian Health Service) during the Spanish state of alarm over the COVID-19 pandemic. The SARS-CoV-2 infection was confirmed in only one of the three cases. In this study, we briefly review the etiopathogenic role of the COVID-19 pandemic situation, whereby immunodeficiencies are generated that favour the appearance of other viral infections, such as herpes virus infections.


Assuntos
COVID-19/complicações , Herpes Simples/etiologia , Herpes Zoster/etiologia , Herpesvirus Humano 3/fisiologia , Simplexvirus/fisiologia , Ativação Viral , Adulto , COVID-19/epidemiologia , COVID-19/virologia , Feminino , Herpes Simples/diagnóstico , Herpes Simples/virologia , Herpes Zoster/diagnóstico , Herpes Zoster/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espanha/epidemiologia
15.
Nat Commun ; 12(1): 3922, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188039

RESUMO

Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the host pathways involved in post-ART HIV control. Here we report plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-remission using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. These signatures remain significant after adjusting for key demographic and clinical confounders. We also report mechanistic links between some of these biomarkers and HIV latency reactivation and/or myeloid inflammation in vitro. Finally, machine learning algorithms, based on selected sets of these biomarkers, predict time-to-viral-rebound with 74% capacity and probability-of-viral-remission with 97.5% capacity. In summary, we report non-invasive plasma biomarkers, with potential functional significance, that predict both the duration and probability of HIV remission after treatment interruption.


Assuntos
Biomarcadores/sangue , Infecções por HIV/sangue , Suspensão de Tratamento , Adulto , Antirretrovirais/administração & dosagem , Estudos de Coortes , DNA Viral/sangue , Feminino , Glicômica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Inflamação , Macrófagos/imunologia , Masculino , Metabolômica , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , RNA Viral/sangue , Ativação Viral
16.
J Infect Chemother ; 27(10): 1454-1458, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34176717

RESUMO

INTRODUCTION: In quantitative assays for hepatitis B virus (HBV) DNA, although the amplification reaction signal is detected for low-positive cases, quantification remains challenging. HBV reactivation has been reported in many studies, but only a few have focused on HBV low-positive cases. This study aimed to determine the reactivation rate and risk factors for HBV reactivation in low-positive cases. METHODS: In this retrospective cohort study, we analyzed 7498 patients who had their HBV DNA measured at Sapporo Medical University Hospital between April 2008 and November 2020. Patient selection criteria were defined as follows: hepatitis B surface antigen was negative; HBV DNA was detectable but not quantifiable at least once. HBV DNA was monitored according to the guidelines for HBV reactivation. RESULTS: In total, 49,086 HBV DNA quantitative tests were performed. HBV DNA levels of 2578 tests were detectable but not quantifiable. Eighty patients met the criteria in this study. The median observation period was 497 days, and the 2-year reactivation rate was 15%. Ten patients had low HBV DNA positivity at baseline. Malignant lymphoma was observed in 15 patients; chemotherapy was used to treat other solid tumors in 35 patients, and immunosuppressive therapy was used in 30 patients. Multivariate analysis revealed that HBV DNA detected below the quantification level at baseline was an independent risk factor for HBV reactivation (adjusted hazard ratio 5.82; P = 0.010). CONCLUSIONS: Patients with low HBV DNA positivity, especially at baseline, are at high risk for HBV reactivation and therefore require closer monitoring.


Assuntos
Vírus da Hepatite B , Hepatite B , DNA Viral/genética , Hepatite B/epidemiologia , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Humanos , Estudos Retrospectivos , Fatores de Risco , Ativação Viral
17.
Commun Biol ; 4(1): 682, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083759

RESUMO

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.


Assuntos
Antivirais/farmacologia , COVID-19/complicações , Herpesvirus Humano 8/fisiologia , SARS-CoV-2/fisiologia , Sarcoma de Kaposi/etiologia , Ativação Viral , Azitromicina/farmacologia , Benzamidinas/farmacologia , COVID-19/tratamento farmacológico , Linhagem Celular , Guanidinas/farmacologia , Infecções por Herpesviridae/induzido quimicamente , Infecções por Herpesviridae/etiologia , Herpesvirus Humano 8/efeitos dos fármacos , Humanos , Vírus Oncogênicos/efeitos dos fármacos , Vírus Oncogênicos/fisiologia , SARS-CoV-2/efeitos dos fármacos , Sarcoma de Kaposi/induzido quimicamente , Proteínas Virais/metabolismo , Ativação Viral/efeitos dos fármacos
18.
Viruses ; 13(5)2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062863

RESUMO

Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus. In healthy people, primary infection is generally asymptomatic, and the virus can go on to establish lifelong latency in cells of the myeloid lineage. However, HCMV often causes severe disease in the immunosuppressed: transplant recipients and people living with AIDS, and also in the immunonaive foetus. At present, there are several antiviral drugs licensed to control HCMV disease. However, these are all faced with problems of poor bioavailability, toxicity and rapidly emerging viral resistance. Furthermore, none of them are capable of fully clearing the virus from the host, as they do not target latent infection. Consequently, reactivation from latency is a significant source of disease, and there remains an unmet need for treatments that also target latent infection. This review briefly summarises the most common HCMV antivirals used in clinic at present and discusses current research into targeting the latent HCMV reservoir.


Assuntos
Antivirais/farmacologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Latência Viral/efeitos dos fármacos , Infecções por Citomegalovirus/etiologia , Reservatórios de Doenças , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , Humanos , Transplante de Órgãos/efeitos adversos , Ativação Viral/efeitos dos fármacos
19.
World J Gastroenterol ; 27(19): 2312-2324, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34040324

RESUMO

Hepatitis B virus reactivation (HBVr) can occur in patients treated with immunosuppressive medications. Risk stratification for HBVr based on hepatitis B virus (HBV) serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use. Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies. Tumor necrosis factor (TNF)-α inhibitors have been widely used for patients with inflammatory bowel disease, psoriasis, and rheumatic diseases. Further, the clinical benefits of interleukin (IL)-12/23, IL-17, or Janus kinases inhibitors have been demonstrated in these patients. It is well known that TNF-α inhibitor use can lead to HBVr, however, the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood. In this review, we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics, and immunological mechanisms of these medications causing HBVr.


Assuntos
Doenças Autoimunes , Produtos Biológicos , Hepatite B , Antivirais/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Produtos Biológicos/efeitos adversos , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Humanos , Fator de Necrose Tumoral alfa/farmacologia , Ativação Viral
20.
Front Cell Infect Microbiol ; 11: 642500, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34041042

RESUMO

Background: The aim of this study was to explore potential risk factors for cytomegalovirus (CMV) reactivation and their impact on liver failure patient outcomes. Methods: A 10-year retrospective case-control study was conducted in adult participants, who were diagnosed with liver failure and had undergone CMV DNA tests. CMV reactivation cases were matched with controls at a 2:1 ratio based on age, sex, and year of admission. Univariate and multivariate analyses were used to explore risk factors for CMV reactivation. Results: Between January 2011 and April 2020, 198 adult patients with liver failure and available CMV DNA test results were enrolled into the study. Among them, 33 patients had detectable CMV DNA in their plasma (16.7%). Clinical manifestations and liver function were comparable between the CMV reactivation and non-reactivation groups. However, CMV reactivation may triple mortality in patients with liver failure. We found that nearly 50% of patients in the CMV-positive group received glucocorticoids, compared to 13.6% in the CMV-negative group (P=0.000). The median total glucocorticoid dose included 836.5 mg of methylprednisolone (IQR 308.7-1259.0 mg) in the CMV-positive group, which was significantly higher than that in the CMV-negative group. A multivariate analysis revealed that glucocorticoid use significantly increased the risk of CMV reactivation (adjusted OR, 4.84; 95% CI, 1.61-14.49; P=0.005). Patients with CMV reactivation tended to be associated with higher white cell counts (adjusted OR, 1.21; 95% CI, 1.08-1.36; P=0.002). Conclusions: High intravenous glucocorticoid doses may be the most important risk factor for CMV reactivation in liver failure.


Assuntos
Infecções por Citomegalovirus , Falência Hepática , Adulto , Estudos de Casos e Controles , Citomegalovirus , Humanos , Estudos Retrospectivos , Ativação Viral
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