RESUMO
Cytomegalovirus (CMV) infection and reactivation in solid organ transplant (SOT) recipients increases the risk of viremia, graft failure and death. Clinical studies of CMV serostatus indicate that donor positive recipient negative (D+/R-) patients have greater viremia risk than D-/R-. The majority of patients are R+ having intermediate serologic risk. To characterize the long-term impact of CMV infection and assess viremia risk, we sought to measure the effects of CMV on the recipient immune epigenome. Specifically, we profiled DNA methylation in 156 individuals before lung or kidney transplant. We found that the methylome of CMV positive SOT recipients is hyper-methylated at loci associated with neural development and Polycomb group (PcG) protein binding, and hypo-methylated at regions critical for the maturation of lymphocytes. In addition, we developed a machine learning-based model to predict the recipient CMV serostatus after correcting for cell type composition and ancestry. This CMV episcore measured at baseline in R+ individual stratifies viremia risk accurately in the lung transplant cohort, and along with serostatus the CMV episcore could be a potential biomarker for identifying R+ patients at high viremia risk.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Metilação de DNA , Epigênese Genética , Transplante de Pulmão , Viremia , Humanos , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/sangue , Transplante de Pulmão/efeitos adversos , Masculino , Feminino , Citomegalovirus/genética , Pessoa de Meia-Idade , Adulto , TransplantadosRESUMO
Dengue viruses are the causative agents of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, which are mainly transmitted by Aedes aegypti and Aedes albopictus mosquitoes, and cost billions of dollars annually in patient treatment and mosquito control. Progress in understanding DENV pathogenesis and developing effective treatments has been hampered by the lack of a suitable small pathological animal model. Until now, the candidate vaccine, antibody, and drug for DENV have not been effectively evaluated. Here, we analyzed the pathogenicity of DENV-1 in type â and type â ¡ interferon receptor-deficient mice (AGB6) by intraperitoneal inoculation. Infected mice showed such neurological symptoms as opisthotonus, hunching, ataxia, and paralysis of one or both hind limbs. Viremia can be detected 3 days after infection. It was found that 6.98 × 103 PFU or higher dose induce 100% mortality. To determine the cause of lethality in mice, heart, liver, spleen, lung, kidney, intestinal, and brain tissues were collected from AGB6 mice (at an attack dose of 6.98 × 103 PFU) for RNA quantification, and it was found that the viral load in brain tissues peaked at moribund states (14 dpi) and that the viral loads in the other tissues and organs decreased over time. Significant histopathologic changes were observed in brain tissue (hippocampal region and cerebral cortex). Hematological analysis showed hemorrhage and hemoconcentration in infected mice. DENV-1 can be isolated from the brain tissue of infected mice. Subsequently, brain tissue transcriptome sequencing was performed to assess host response characteristics in infected AGB6 mice. Transcriptional patterns in brain tissue suggest that aberrant expression of pro-inflammatory cytokines induces antiviral responses and tissue damage. Screening of hub genes and their characterization by qPCR and ELISA, it was hypothesized that IL-6 and IFN-γ might be the key factors in dengue virus-induced inflammatory response. Therefore, this study provides an opportunity to decipher certain aspects of dengue pathogenesis further and provides a new platform for drug, antibody, and vaccine testing.
Assuntos
Vírus da Dengue , Dengue , Modelos Animais de Doenças , Transcriptoma , Carga Viral , Animais , Vírus da Dengue/patogenicidade , Vírus da Dengue/genética , Dengue/virologia , Dengue/imunologia , Camundongos , Sorogrupo , Perfilação da Expressão Gênica , Encéfalo/virologia , Encéfalo/patologia , Virulência , Viremia , Camundongos KnockoutRESUMO
AIMS: This study aims to evaluate the presence of EBV, HCMV, and BKV genomic sequences in the plasma samples (active infection/viremia) of kidney transplant recipients suspected of rejection and to investigate host and risk factors related to the activation of these viruses in these patients. METHODS: In this cross-sectional single-center study, plasma samples were collected from 98 suspected kidney transplant rejection patients at Labafinejad Hospital, Tehran, Iran, between December 2022 and June 2023. Quantitative real-time PCR assays for HCMV, EBV, and BK were performed using GeneProof Real-time PCR kits. ROC curve analysis was used to determine the viral load cutoff point for each virus. FINDINGS: HCMV active viremia was detected in 18 (18.36%) recipients, EBV active viremia in 7 (7.14%), and BKV active viremia in 5 (5.10%). ROC results indicated viral load cutoff points of 778, 661, and 457 points for HCMV, EBV, and BKV, respectively. The duration of time after transplantation significantly differed between active viremia and no viremia groups (120.5 vs. 46 months, P = 0.014). In the BKV active viremia group, the increase in creatinine compared to baseline creatinine was significantly higher than in the no viremia group (2.7 vs. 0.8, P = 0.017). The odds ratio of HCMV active viremia in patients taking tacrolimus was 2.84 times higher, and the odds of HCMV active viremia in patients taking antithymocyte globulin was 3.01 times higher than in patients not taking these drugs. CONCLUSION: Rapid and timely diagnosis of viral active infections in kidney transplant patients is crucial for effective disease management and implementation of appropriate treatment strategies. Identifying potential risk factors, including host and treatment-related factors that influence transplantation, can facilitate the development of suitable preventive strategies.
Assuntos
Vírus BK , Infecções por Citomegalovirus , Citomegalovirus , Infecções por Vírus Epstein-Barr , Rejeição de Enxerto , Herpesvirus Humano 4 , Transplante de Rim , Infecções por Polyomavirus , Carga Viral , Viremia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Vírus BK/isolamento & purificação , Vírus BK/genética , Adulto , Estudos Transversais , Infecções por Polyomavirus/virologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Citomegalovirus/virologia , Citomegalovirus/isolamento & purificação , Citomegalovirus/genética , Rejeição de Enxerto/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Irã (Geográfico)/epidemiologia , Fatores de Risco , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/sangue , Idoso , Adulto Jovem , Transplantados/estatística & dados numéricosRESUMO
African swine fever (ASF) is an acute infectious disease with a high mortality rate in both domestic and wild boars. Commercial vaccines or antiviral drugs for ASF were not available due to the complex diversity of the structure and genome of its pathogen African swine fever virus (ASFV). In recent years, there have been many reports on candidate strains of attenuated vaccines for ASFV. In this study, we obtained a recombinant virus named SY18ΔL60LΔCD2v by simultaneously deleting the L60L gene and CD2v gene from highly virulent strain SY18. In vitro, SY18ΔL60LΔCD2v displayed a decreased growth kinetic compared to that of parental SY18. In vivo, high doses (105 TCID50) of SY18ΔL60LΔCD2v can protect pigs (5/5) from attacks by the parental SY18 strain (102 TCID50). Low doses (102 TCID50) of SY18ΔL60LΔCD2v only protected 20% of pigs (1/5) from attacks by the parental SY18 strain (102 TCID50). The results indicated that the absence of these two genes in SY18 could induce protection against the homologous parental strain, and there were no obvious clinical symptoms or viremia. These results indicate that the SY18ΔL60LΔCD2v strain can serve as a new live attenuated vaccine candidate for the prevention and control of ASFV infection.
Assuntos
Vírus da Febre Suína Africana , Febre Suína Africana , Deleção de Genes , Vacinas Atenuadas , Vacinas Virais , Vírus da Febre Suína Africana/genética , Vírus da Febre Suína Africana/imunologia , Vírus da Febre Suína Africana/patogenicidade , Animais , Suínos , Febre Suína Africana/prevenção & controle , Febre Suína Africana/virologia , Febre Suína Africana/imunologia , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/administração & dosagem , Vacinas Virais/imunologia , Vacinas Virais/genética , Proteínas Virais/genética , Proteínas Virais/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Viremia/prevenção & controleRESUMO
INTRODUCTION: This study investigated variables associated with mortality in kidney transplant recipients (KTRs) diagnosed with post-transplant lymphoproliferative disease (PTLD) and a simultaneous Epstein-Barr virus (EBV) viremia. METHODS: This was a retrospective cohort study enrolling KTRs diagnosed with PTLD between 2018 and 2020. Outcome: death within two years after diagnosis. RESULTS: Among 1,625 KTRs who collected EBV viremia (by PCR, 2018-2020) for any reason, 238 (14.6%) had a positive viral load and 41 (17.2%) simultaneous PTLD. These 41 patients were 40.1 years old at diagnosis and 8.6 years after transplantation; 26.8% were induced with rATG and 92.7% were maintained on tacrolimus and azathioprine (TAC/AZA) as immunosuppressive regimen. Lymph nodes (75.6%) was the most common site of PTLD, followed by the gastrointestinal tract (48.8%), with 61.0% at Lugano stage IV and 80.5% monomorphic PTLD. The mean EBV viral load was 12,198 IU/mL. One- and two-year patient survival post-diagnosis was 60.4% and 46.8%, respectively. In the Cox regression analysis, age at PTLD diagnosis (HR for each year = 1.039; p < 0.001) and EBV viral load (HR for each log = 1.695; p = 0.026) were associated with risk of death. CONCLUSION: This study suggests that in patients predominantly on TAC/AZA, PTLD with simultaneous EBV positive viral load is a late event, and worse survival is associated with older age and EBV viral load at diagnosis.
Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Transplante de Rim , Transtornos Linfoproliferativos , Complicações Pós-Operatórias , Carga Viral , Humanos , Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/virologia , Transtornos Linfoproliferativos/etiologia , Estudos Retrospectivos , Masculino , Feminino , Adulto , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/complicações , Pessoa de Meia-Idade , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/genética , Fatores Etários , Complicações Pós-Operatórias/virologia , Complicações Pós-Operatórias/diagnóstico , Viremia/diagnóstico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêuticoRESUMO
ABSTRACTThe severity of the dengue epidemic is on the rise, with its geographic range had expanded to southern Europe by 2024. In this August, the WHO updated the pathogens that could spark the next pandemic, dengue virus was on the list. Vaccines and drugs serve as powerful tools for both preventing dengue infections and treating patients. Animal models play a pivotal role in vaccine development and drug screening. Available potential susceptible animals, including non-human primates, rodents, pigs, and tree shrews, have been extensively explored to establish animal models of dengue disease. Despite significant advancements, there are still notable limitations. Different animal models exhibit distinct constraining factors such as viraemia, host susceptibility, immune function of the host, clinical symptoms, ADE (antibody-dependent enhancement) phenomena, cytokine storm response to various serotypes and strain variations. Furthermore, despite extensive research on the dengue virus receptor in recent years, genetically modified animal models immunocompetent harbouring dengue virus susceptibility receptors have not yet been available. This work reviewed the research progress of dengue virus receptors and dengue animal models, suggesting that the development of genetically modified murine models expressing dengue virus functional receptors may hold a promise for future dengue disease research, especially for its vaccine development.
Assuntos
Vacinas contra Dengue , Vírus da Dengue , Dengue , Modelos Animais de Doenças , Animais , Dengue/imunologia , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/genética , Humanos , Vacinas contra Dengue/imunologia , Camundongos , Desenvolvimento de Vacinas , Suínos , ViremiaRESUMO
Purpose: People living with HIV are twice as likely to develop cardiovascular diseases (CVDs) and myocardial infarction related to atherosclerosis than the uninfected population. This study aimed to evaluate the prevalence of subclinical atherosclerosis in a young, mid-eastern European population of PLWH receiving ART for undetectable viremia. Patients and Methods: This was a single-centre study. We included 34 patients below 50 years old, treated in Szczecin, Poland, with confirmed HIV-1 infection, treated with antiretroviral therapy (ART), and undetectable viremia. All patients underwent coronary artery computed tomography (CACT), carotid artery intima-media thickness (IMT) evaluation, and echocardiography. Results: In the primary assessment, only two (5.8%) patients had an increased CVD risk calculated using the Framingham Risk Score (FRS), but we identified coronary or carotid plaques in 26.5% of the patients. Neither traditional risk factors nor those associated with HIV significantly influenced the presence of the plaque. IMT was significantly positively correlated with age and the FRS (R=0.38, p=0.04). Relative wall thickness assessed in echocardiography was higher in those with plaque (0.49 vs 0.44, p=0.04) and significantly correlated with IMT (R=0.38, p=0.04). Conclusion: In our population, more than a quarter of PLWH with undetectable viremia had subclinical atherosclerosis in either the coronary or carotid arteries. The FRS underpredicted atherosclerosis in this population. The role of RWT as a possible early marker of atherosclerosis needs further studies.
Assuntos
Fármacos Anti-HIV , Espessura Intima-Media Carotídea , Infecções por HIV , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/diagnóstico , Infecções por HIV/complicações , Feminino , Pessoa de Meia-Idade , Adulto , Polônia/epidemiologia , Prevalência , Medição de Risco , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Dados Preliminares , Viremia/epidemiologia , Viremia/tratamento farmacológico , Doenças das Artérias Carótidas/epidemiologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico , Resultado do Tratamento , Placa Aterosclerótica , Angiografia por Tomografia Computadorizada , Doenças Assintomáticas , Angiografia Coronária , Fatores Etários , Resposta Viral Sustentada , Carga Viral , Fatores de Risco , Estudos TransversaisRESUMO
Bile acids are microbial metabolites that can impact infection of enteric and hepatitis viruses, but their functions during systemic viral infection remain unclear. Here we show that elevated levels of the secondary bile acid taurolithocholic acid (TLCA) are associated with reduced fatality rates and suppressed viraemia in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne haemorrhagic fever virus. TLCA inhibits viral replication and mitigates host inflammation during SFTSV infection in vitro, and indirectly suppresses SFTSV-mediated induction of ferroptosis by upregulating fatty acid desaturase 2 via the TGR5-PI3K/AKT-SREBP2 axis. High iron and ferritin serum levels during early infection were correlated with decreased TLCA levels and fatal outcomes in SFTSV-infected patients, indicating potential biomarkers. Furthermore, treatment with either ferroptosis inhibitors or TLCA protected mice from lethal SFTSV infection. Our findings highlight the therapeutic potential of bile acids to treat haemorrhagic fever viral infection.
Assuntos
Ferroptose , Ácido Taurolitocólico , Ferroptose/efeitos dos fármacos , Animais , Camundongos , Humanos , Ácido Taurolitocólico/farmacologia , Ácido Taurolitocólico/análogos & derivados , Replicação Viral/efeitos dos fármacos , Ferro/metabolismo , Masculino , Feminino , Camundongos Endogâmicos C57BL , Viremia/tratamento farmacológico , Ácidos e Sais Biliares/metabolismoRESUMO
BACKGROUND: High HIV viral loads (VL) are associated with increased morbidity, mortality, and on-going transmission. HIV controllers maintain low VLs in the absence of antiretroviral therapy (ART). We previously used a massively multiplexed antibody profiling assay (VirScan) to compare antibody profiles in HIV controllers and persons living with HIV (PWH) who were virally suppressed on ART. In this report, we used VirScan to evaluate whether antibody reactivity to specific HIV targets and broad reactivity across the HIV genome was associated with VL and controller status 1-2 years after infection. METHODS: Samples were obtained from participants who acquired HIV infection in a community-randomized trial in Africa that evaluated an integrated strategy for HIV prevention (HPTN 071 PopART). Controller status was determined using VL and antiretroviral (ARV) drug data obtained at the seroconversion visit and 1 year later. Viremic controllers had VLs <2,000 copies/mL at both visits; non-controllers had VLs >2,000 copies/mL at both visits. Both groups had no ARV drugs detected at either visit. VirScan testing was performed at the second HIV-positive visit (1-2 years after HIV infection). RESULTS: The study cohort included 13 viremic controllers and 64 non-controllers. We identified ten clusters of homologous peptides that had high levels of antibody reactivity (three in gag, three in env, two in integrase, one in protease, and one in vpu). Reactivity to 43 peptides (eight unique epitopes) in six of these clusters was associated with lower VL; reactivity to six of the eight epitopes was associated with HIV controller status. Higher aggregate antibody reactivity across the eight epitopes (more epitopes targeted, higher mean reactivity across all epitopes) and across the HIV genome was also associated with lower VL and controller status. CONCLUSIONS: We identified HIV antibody targets associated with lower VL and HIV controller status 1-2 years after infection. Robust aggregate responses to these targets and broad antibody reactivity across the HIV genome were also associated with lower VL and controller status. These findings provide novel insights into the relationship between humoral immunity and viral containment that could help inform the design of antibody-based approaches for reducing HIV VL.
Assuntos
Anticorpos Anti-HIV , Infecções por HIV , Carga Viral , Viremia , Humanos , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/sangue , Feminino , Viremia/imunologia , Viremia/virologia , Adulto , HIV-1/imunologiaRESUMO
OBJECTIVE: In the hepatitis C virus (HCV) diagnostic algorithm, an anti-HCV screening test is recommended first. In countries with low HCV prevalence, anti-HCV testing can often give false-positive results. This may lead to unnecessary retesting, increased costs, and psychological stress for patients. METHODS: In this study, the most appropriate S/Co (signal-cutoff) value to predict HCV viremia in anti-HCV test(+) individuals was determined, and the effect of genotype differences was evaluated. Of the 96,515 anti-HCV tests performed between 2020 and 2023, 934 were reactive. A total of 332 retests and 65 patients without HCV-ribonucleic acid (RNA) analysis were excluded. Demographic data were calculated for 537 patients, and 130 patients were included in the study. RESULTS: The average age of 537 patients was 55±18 years, and 57.1% were women. The anti-HCV positivity rate was 0.62% (602/96,515), and the actual anti-HCV positivity rate was 0.13% (130/96,515). Anti-HCV levels were higher in HCV-RNA(+) patients than in HCV-RNA-negative individuals (p<0.0001) (Table 1). Receiver operating characteristic curve analysis identified the optimal S/Co value to be 10.86 to identify true positive cases. Sensitivity was 96.1%, specificity was 61.2%, positive predictive value (PPV) was 44.2%, and negative predictive value (NPV) was 98% (Figure 2). A total of 107 (82.3%) of the patients were identified as GT1, and the most common subtype was GT1b (n=100). CONCLUSION: If anti-HCV S/Co is ≥10.86, direct HCV RNA testing may be recommended; However, the possibility of false positivity should be considered in patients with a S/Co value below 10.86.
Assuntos
Genótipo , Hepacivirus , Anticorpos Anti-Hepatite C , Hepatite C , Valor Preditivo dos Testes , RNA Viral , Viremia , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Hepacivirus/genética , RNA Viral/sangue , RNA Viral/análise , Anticorpos Anti-Hepatite C/sangue , Hepatite C/genética , Hepatite C/sangue , Adulto , Idoso , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Reticuloendotheliosis virus (REV), a member of the family Retroviridae, is a hot area of research, and a previous study showed that exosomes purified from REV-positive semen were not blocked by REV-specific neutralizing antibodies and established productive infections. METHODS: To further verify the infectivity of exosomes from REV-infected cells, we isolated and purified exosomes from REV-infected DF-1 cells and identified them using Western blot and a transmission electron microscope. We then inoculated 7-day-old embryonated eggs, 1-day-old chicks and 23-week-old hens with and without antibody treatment. REV was administered simultaneously as a control. RESULTS: In the absence of antibodies, the results indicated that REV-exosomes and REV could infect chicks, resulting in viremia and viral shedding, compared with the infection caused by REV, REV-exosomes reduced the hatching rate and increased mortality after hatching, causing severe growth inhibition and immune organ damage in 1-day-old chicks; both REV and REV-exosomes also could infect hens, however, lead to transient infection. In the presence of antibodies, REV-exosomes were not blocked by REV-specific neutralizing antibodies and infected 7-day-old embryonated eggs. However, REV could not infect 1-day-old chicks and 23-week-old hens. CONCLUSION: In this study, we compared the infectious ability of REV-exosomes and REV, REV-exosomes could escape from REV-specific neutralizing antibodies in embryonated eggs, providing new insights into the immune escape mechanism of REV.
Assuntos
Anticorpos Antivirais , Galinhas , Exossomos , Doenças das Aves Domésticas , Vírus da Reticuloendoteliose , Infecções por Retroviridae , Eliminação de Partículas Virais , Animais , Exossomos/virologia , Exossomos/imunologia , Anticorpos Antivirais/imunologia , Galinhas/virologia , Vírus da Reticuloendoteliose/imunologia , Doenças das Aves Domésticas/virologia , Doenças das Aves Domésticas/transmissão , Doenças das Aves Domésticas/imunologia , Infecções por Retroviridae/virologia , Infecções por Retroviridae/transmissão , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/veterinária , Anticorpos Neutralizantes/imunologia , Linhagem Celular , Viremia/virologia , FemininoRESUMO
In the absence of antiretroviral therapy (ART), a subset of individuals, termed HIV controllers, have levels of plasma viremia that are orders of magnitude lower than non-controllers (NC) who are at higher risk for HIV disease progression. In addition to having fewer infected cells resulting in fewer cells with HIV RNA, it is possible that lower levels of plasma viremia in controllers are due to a lower fraction of the infected cells having HIV-1 unspliced RNA (HIV usRNA) compared with NC. To directly test this possibility, we used sensitive and quantitative single-cell sequencing methods to compare the fraction of infected cells that contain one or more copies of HIV usRNA in peripheral blood mononuclear cells (PBMC) obtained from controllers and NC. The fraction of infected cells containing HIV usRNA did not differ between the two groups. Rather, the levels of viremia were strongly associated with the total number of infected cells that had HIV usRNA, as reported by others, with controllers having 34-fold fewer infected cells per million PBMC. These results reveal that viremic control is not associated with a lower fraction of proviruses expressing HIV usRNA, unlike what is reported for elite controllers, but is only related to having fewer infected cells overall, maybe reflecting greater immune clearance of infected cells. Our findings show that proviral silencing is not a key mechanism for viremic control and will help to refine strategies toward achieving HIV remission without ART.
Assuntos
Infecções por HIV , HIV-1 , Leucócitos Mononucleares , RNA Viral , Viremia , Humanos , HIV-1/genética , HIV-1/fisiologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , RNA Viral/genética , Viremia/virologia , Leucócitos Mononucleares/virologia , Masculino , Carga Viral , Feminino , Adulto , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Investigate the outcomes of women with HIV (WWH) with low-level viremia (LLV). DESIGN: The prevalence of LLV and potential clinical sequelae, such as virologic failure and non-AIDS comorbidity (NACM) development, are poorly characterized among WWH. METHODS: We analyzed data from the Women's Interagency HIV Study among WWH enrolled from 2003 to 2020 who reported antiretroviral therapy use at least 1âyear followed by an HIV-1 viral load less than 200âcopies/ml. Consecutive viral load measurements from four semi-annual visits were used to categorize women at baseline as having: virologic suppression (all viral load undetectable), intermittent LLV (iLLV; nonconsecutive detectable viral load up to 199âcopies/ml), persistent LLV (pLLV; at least two consecutive detectable viral load up to 199âcopies/ml), or virologic failure (any viral load ≥200âcopies/ml). Adjusted hazard ratios quantified the association of virologic category with time to incident virologic failure and multimorbidity (≥2 of 5 NACM) over 5-year follow-up. RESULTS: Of 1598 WWH, baseline median age was 47âyears, 64% were Black, 21% Hispanic, and median CD4 + cell count was 621âcells/µl. After excluding 275 women (17%) who had virologic failure at baseline, 58, 19, and 6% were categorized as having virologic suppression, iLLV, and pLLV, respectively. Compared with WWH with virologic suppression, the adjusted hazard ratio [aHR; 95% confidence interval (CI)] for incident virologic failure was 1.88 (1.44-2.46) and 2.51 (1.66-3.79) for iLLV and pLLV, respectively; and the aHR for incident multimorbidity was 0.81 (0.54-1.21) and 1.54 (0.88-2.71) for iLLV and pLLV, respectively. CONCLUSION: Women with iLLV and pLLV had an increased risk of virologic failure. Women with pLLV had a trend towards increased multimorbidity risk.
Assuntos
Infecções por HIV , Carga Viral , Viremia , Humanos , Feminino , Viremia/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Adulto , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , HIV-1/isolamento & purificação , Contagem de Linfócito CD4 , PrevalênciaRESUMO
BACKGROUND: Cytomegalovirus retinitis (CMVR) is a well-described complication of CMV disease in immunocompromised hosts. While robust data exists for CMVR in patients with acquired immunodeficiency syndrome (AIDS), the incidence and risk factors for CMVR in solid organ transplant recipients (SOTR) with CMV viremia are less defined. METHODS: We performed a retrospective cohort study of SOTR who had CMV viremia and underwent routine ophthalmologic examination between 1/1/2018 and 3/16/2022. Univariate statistics were performed to evaluate risk factors for development of CMVR. RESULTS: Overall, 38 patients were included, primarily kidney (78.9%), heart (7.9%), and liver (7.9%) transplant recipients. Five patients (13.2%) developed CMVR during the study period. CMVR was diagnosed an average 281 days after index transplantation, 84 days from the most recent rejection episode, and 69 days from onset of viremia. Only 1 patient (20%) had symptoms at the time of CMVR diagnosis. CMVR was associated with preceding allograft rejection as well as transplanted organ type. CONCLUSION: While CMV tissue disease more commonly manifests in other organs, CMVR occurred relatively frequently in this group of high-risk SOTR with CMV viremia. As most of the patients in our study did not have ocular symptoms at the time of diagnosis, routine ophthalmologic screening should be considered in SOTR with CMV viremia.
Assuntos
Retinite por Citomegalovirus , Transplante de Órgãos , Humanos , Retinite por Citomegalovirus/epidemiologia , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Feminino , Transplante de Órgãos/efeitos adversos , Fatores de Risco , Adulto , Hospedeiro Imunocomprometido , Incidência , Idoso , Viremia/epidemiologia , TransplantadosRESUMO
Atypical porcine pestivirus (APPV) is a novel member of the Pestivirus genus detected in association with congenital tremor (CT) type A-II outbreaks and from apparently healthy pigs, both as singular infection and as part of multi-pathogen infections. 'Classical' pestiviruses are known to cause immunosuppression of their host, which can increase susceptibility to secondary infections, severely impacting health, welfare, and production. To investigate APPV's effect on the host's immune system and characterise disease outcomes, 12 piglets from a natural APPV CT type A-II outbreak were experimentally infected with porcine reproductive and respiratory syndrome virus (PRRSV), a significant porcine pathogen. Rectal temperatures indicating febrile responses, viremia and viral-specific humoral and cellular responses were assessed throughout the study. Pathological assessment of the lungs and APPV-PRRSV co-localisation within the lungs was performed at necropsy. Viral co-localisation and pathological assessment of the lungs (Immunohistochemistry, BaseScope in situ hybridisation) were performed post-mortem. APPV status did not impact virological or immunological differences in PRRSV-infected groups. However, significantly higher rectal temperatures were observed in the APPV+ve/PRRSV+ve group over four days, indicating APPV increased the febrile response. Significant differences in the lung consolidation of the apical and intermediate lobes were also present, suggesting that APPV co-infection may augment lung pathology.
Assuntos
Coinfecção , Pulmão , Infecções por Pestivirus , Pestivirus , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Animais , Suínos , Infecções por Pestivirus/veterinária , Infecções por Pestivirus/virologia , Infecções por Pestivirus/patologia , Pestivirus/patogenicidade , Pestivirus/genética , Coinfecção/virologia , Coinfecção/veterinária , Síndrome Respiratória e Reprodutiva Suína/virologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Pulmão/virologia , Pulmão/patologia , Viremia , Doenças dos Suínos/virologia , Doenças dos Suínos/patologia , Doenças dos Suínos/imunologia , Anticorpos Antivirais/sangueRESUMO
Porcine circovirus type 2 (PCV2) causes postweaning multisystemic wasting syndrome in piglets. Differences in the infectivity and horizontal transmissibility of different isolates of PCV2a, PCV2b, and PCV2d in pigs were evaluated by HE and IHC staining, PCR, virus titration, and IPMA to determine their clinical symptoms, pathological changes, levels of virus and antibody, and cohabitation infectivity. In the cohabitation infection experiment, weak viremia and low levels of antibodies were detected in the pigs challenged with PCV2a-CL, whereas no viremia or antibodies were detected in the corresponding cohabiting pigs. Furthermore, no PCV2 was isolated from any organ of pigs that were challenged with PCV2a-CL, as well as from those of their cohabiting pigs. In contrast, persistent viremia and pathological changes, including swollen inguinal lymph nodes, were detected in both the challenged and cohabiting pigs after PCV2b-BY or PCV2d-LNHC infection. Alive PCV2 was detected in the tonsils, inguinal lymph nodes, spleen, and kidneys of the experimental pigs by virus titration, and the highest viral titer was detected in the tonsils, followed by the inguinal lymph nodes. In a comparative analysis of the challenged and cohabiting pigs, a 1-week delay in viremia and specific antibodies was observed in the cohabiting pigs. Moreover, the number of viruses isolated from the tonsils and inguinal lymph nodes of the pigs cohabiting with PCV2d-LNHC-challenged pigs was significantly greater than those in the pigs that were directly challenged with PCV2d-LNHC in cohabitation infection experiment (P<0.05). Together, these results indicated that the infectivity and horizontal transmissibility of the strains PCV2b-BY and PCV2d-LNHC were much greater than those of the strain PCV2a-CL and provided some insights into PCV2 pathogenicity.
Assuntos
Anticorpos Antivirais , Infecções por Circoviridae , Circovirus , Animais , Circovirus/patogenicidade , Circovirus/classificação , Circovirus/isolamento & purificação , Suínos , Infecções por Circoviridae/virologia , Infecções por Circoviridae/veterinária , Infecções por Circoviridae/transmissão , Anticorpos Antivirais/sangue , Viremia/transmissão , Viremia/virologia , Viremia/veterinária , Doenças dos Suínos/virologia , Doenças dos Suínos/transmissão , Síndrome Definhante Multissistêmico de Suínos Desmamados/virologia , Síndrome Definhante Multissistêmico de Suínos Desmamados/transmissão , Carga ViralRESUMO
CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.
Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Células Matadoras Naturais , Transplante de Fígado , Humanos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Antivirais/uso terapêutico , Masculino , Citomegalovirus/imunologia , Pessoa de Meia-Idade , Feminino , Células Matadoras Naturais/imunologia , Adulto , Transplantados , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Viremia/imunologiaRESUMO
In vitro studies have shown that deletion of nef and deleterious mutation in the Nef dimerization interface attenuates HIV replication and associated pathogenesis. Humanized rodents with human immune cells and lymphoid tissues are robust in vivo models for investigating the interactions between HIV and the human immune system. Here, we demonstrate that nef deletion impairs HIV replication and HIV-induced immune dysregulation in the blood and human secondary lymphoid tissue (human spleen) in bone marrow-liver-thymus-spleen (BLTS) humanized mice. Furthermore, we also show that nef defects (via deleterious mutations in the dimerization interface) impair HIV replication and HIV-induced immune dysregulation in the blood and human spleen in BLTS-humanized mice. We demonstrate that the reduced replication of nef-deleted and nef-defective HIV is associated with robust antiviral innate immune response, and T helper 1 response. Our results support the proposition that Nef may be a therapeutic target for adjuvants in HIV cure strategies.
Assuntos
Modelos Animais de Doenças , Infecções por HIV , HIV-1 , Fígado , Baço , Viremia , Replicação Viral , Produtos do Gene nef do Vírus da Imunodeficiência Humana , Animais , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Camundongos , Humanos , Viremia/imunologia , Baço/imunologia , Baço/virologia , HIV-1/imunologia , HIV-1/genética , HIV-1/fisiologia , Fígado/virologia , Fígado/imunologia , Fígado/patologia , Medula Óssea/virologia , Medula Óssea/imunologia , Timo/imunologia , Timo/virologia , Imunidade InataRESUMO
Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.
Assuntos
COVID-19 , Neuropilina-1 , SARS-CoV-2 , Animais , SARS-CoV-2/fisiologia , SARS-CoV-2/patogenicidade , COVID-19/virologia , COVID-19/patologia , COVID-19/metabolismo , Camundongos , Neuropilina-1/metabolismo , Neuropilina-1/genética , Viremia/virologia , Sistema Nervoso Central/virologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/metabolismo , Células Receptoras Sensoriais/virologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Mesocricetus , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Camundongos Endogâmicos C57BL , Internalização do Vírus , MasculinoRESUMO
Background: About 20% of on-treatment patients with chronic hepatitis B (CHB) experienced low-level viraemia (LLV), which is associated with persistent low-grade inflammation, fibrosis progression, and increased risk of hepatocellular carcinoma. We aimed to investigate the high-risk factors related to LLV. Methods: In this retrospective study, patients receiving entecavir (ETV) treatment from January 2018 to January 2023 were enrolled, and were divided into a LLV (HBV DNA 20-2000 IU/mL) cohort and a complete virological response (CVR) (HBV DNA < 20 IU/mL) cohort according to the virological response at week 48 posttreatment. Treatment baseline characteristics were retrieved from electronic medical records. Multivariate logistic regression was performed. Results: Totally, 1653 patients were enrolled, male patients accounted for 73.0%; the median age was 44 years; the mean HBV DNA level was 5.9 Log10 IU/ml. Among them, 472 (28.6%) experienced LLV. Multivariate analysis showed that HBeAg positivity (OR = 2.650, 95% CI: 2.000-3.511, p < 0.001), HBV DNA ≥ 6.0 Log10 IU/mL (OR = 1.370, 95% CI: 1.054-1.780, p = 0.019), qHBsAg ≥ 9000 IU/mL (OR = 4.472, 95% CI: 3.410-5.866, p < 0.001), cirrhosis (OR = 1.650, 95% CI: 1.234-2.207, P = 0.001), LSM ≥ 13.0 kPa (OR = 1.644, 95% CI: 1.203-2.246, p = 0.002), and PLT < 100×109/L (OR = 1.450, 95% CI: 1.094-1.922, p = 0.010) at baseline were related to the development of LLV. Conclusions: High HBV DNA/HBsAg quantification/LSM, low PLT, HBeAg positivity, and liver cirrhosis were high-risk factors associated with LLV in patients receiving entecavir treatment.