ABSTRACT
Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N6 -methyladenosine (m6 A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m6 A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m6 A levels and upregulation of the m6 A reader YTH N6 -methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m6 A-dependence, along with upregulation of TNF-α and IL1-ß. Overall, we characterized the m6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.
Subject(s)
Coinfection , HIV Infections , Mycoses , Humans , Toll-Like Receptor 2/genetics , RNA HelicasesABSTRACT
BACKGROUND: N6-methyladenosine (m6A) methylation has become an active research area in viral infection, while little bibliometric analysis has been performed. In this study, we aim to visualize hotspots and trends using bibliometric analysis to provide a comprehensive and objective overview of the current research dynamics in this field. METHODS: The data related to m6A methylation in viral infection were obtained through the Web of Science Core Collection form 2000 to 2022. To reduce bias, the literature search was conducted on December 1, 2022. Bibliometric and visual analyzes were performed using CiteSpace and Bibliometrix package. After screening, 319 qualified records were retrieved. RESULTS: These publications mainly came from 28 countries led by China and the United States (the US), with the US ranking highest in terms of total link strength.The most common keywords were m6A, COVID-19, epitranscriptomics, METTL3, hepatitis B virus, innate immunity and human immunodeficiency virus 1. The thematic map showed that METTL3, plant viruses, cancer progression and type I interferon (IFN-I) reflected a good development trend and might become a research hotspot in the future, while post-transcriptional modification, as an emerging or declining theme, might not develop well. CONCLUSIONS: In conclusion, m6A methylation in viral infection is an increasingly important topic in articles. METTL3, plant viruses, cancer progression and IFN-I may still be research hotspots and trends in the future.
Subject(s)
Adenine/analogs & derivatives , Interferon Type I , Neoplasms , Virus Diseases , Humans , Bibliometrics , Methylation , MethyltransferasesABSTRACT
BACKGROUND: Fungal skin diseases are common skin diseases with a heterogeneous distribution worldwide. OBJECTIVES: This study aimed to analyse the spatiotemporal trends in the burden of fungal skin diseases at global, regional, and national levels from 1990 to 2021. METHODS: Based on the data obtained from the Global Burden of Disease Study (GBD) 2021, we described the incident cases, prevalent cases, number of disability-adjusted life years (DALYs), and corresponding age-standardised rates (ASRs) for fungal skin diseases in 1990 and 2021 by sex, age, socio-demographic index (SDI), 21 GBD regions, and 204 countries and territories. We used Joinpoint regression analysis to assess the temporal trends in burden of fungal skin diseases during 1990 to 2021. Spearman's rank test was used to analyse the relationship between disease burden and potential factors. RESULTS: From 1990 to 2021, the incident cases, prevalent cases, and DALYs for fungal skin diseases worldwide increased by 67.93%, 67.73%, and 66.77%, respectively. Globally, the age-standardised incidence rate (ASIR), age-standardised prevalence rate (ASPR), and age-standardised DALYs rate (ASDR) for fungal skin diseases in 2021 were 21668.40 per 100,000 population (95% UI: 19601.19-23729.17), 7789.55 per 100,000 population (95% UI: 7059.28-8583.54), and 43.39 per 100,000 population (95% UI: 17.79-89.10), respectively. Between 1990 and 2021, the ASIR, ASPR, and ASDR for fungal skin diseases have modestly increased, with AAPC of 11.71% (95% confidence interval [CI]: 11.03%-12.39%), 19.24% (95% CI: 18.12%-20.36%), and 20.25% (95% CI: 19.33%-21.18%), respectively. Males experienced a higher burden of fungal skin diseases than females. The incident cases, prevalent cases, and DALYs for fungal skin diseases were highest at the age of 5-9, while the ASRs were highest among the elderly. At national level, the highest ASRs were observed in Nigeria, Ethiopia, and Mali. Overall, SDI was negatively correlated with the ASRs, whereas Global Land-Ocean Temperature Index (GLOTI) was remarkably positively correlated with the burden of fungal skin diseases. CONCLUSIONS: Between 1990 and 2021, the global burden of fungal skin diseases has increased, causing a high disease burden worldwide, particularly in underdeveloped regions and among vulnerable population such as children and the elderly. With global warming and aging of the population, the burden of fungal skin diseases may continue to increase in the future. Targeted and specific measures should be taken to address these disparities and the ongoing burden of fungal skin diseases.
Subject(s)
Dermatomycoses , Global Burden of Disease , Global Health , Humans , Male , Female , Adult , Dermatomycoses/epidemiology , Middle Aged , Prevalence , Incidence , Young Adult , Global Health/statistics & numerical data , Adolescent , Aged , Disability-Adjusted Life Years , Child, Preschool , Child , Infant , Infant, Newborn , Aged, 80 and over , Cost of IllnessABSTRACT
BACKGROUND: As a key process in transcriptional regulatory mechanisms, alternative splicing (AS) plays a crucial role in maintaining the diversity of RNA and protein expression, and mediates the immune response in infectious diseases, especially for the COVID-19. Therefore, urgent data gathering and more research of AS profiles in microbe-infected human cells are needed to improve understanding of COVID-19 and related infectious diseases. Herein, we have created CASA, the COVID-19 Alternative Splicing Atlas to provide a convenient computing platform for studies of AS in COVID-19 and COVID-19-related infectious diseases. METHODS: In CASA, we reanalyzed thousands of RNA-seq datasets generated from 65 different tissues, organoids and cell lines to systematically obtain quantitative data on AS events under different conditions. A total of 262,994 AS events from various infectious diseases with differing severity were detected and visualized in this database. In order to explore the potential function of dynamics AS events, we performed analysis of functional annotations and drug-target interactions affected by AS in each dataset. RNA-binding proteins (RBPs), which may regulate these dynamic AS events are also provided for users in this database. RESULTS: CASA displays microbe-induced alterations of the host cell splicing landscape across different virus families and helps users identify condition-specific splicing patterns, as well as their potential regulators. CASA may greatly facilitate the exploration of AS profiles and novel mechanisms of host cell splicing by viral manipulation. CASA is freely available at http://www.splicedb.net/casa/ .
Subject(s)
Alternative Splicing , COVID-19 , Humans , Alternative Splicing/genetics , COVID-19/genetics , RNA Splicing , RNA-Binding Proteins/genetics , RNA/metabolismABSTRACT
BACKGROUND: Vaccination has been proven to be an effective approach against the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to determine the acceptance rate and factors influencing acceptance of COVID-19 vaccination among people living with HIV (PLWH) in Guangxi, China. METHODS: A cross-sectional survey was carried out in five cities in Guangxi, China from May 7 to June 1, 2021. Questionnaires on the acceptance of COVID-19 vaccination and the related factors were conducted among PLWH recruited by simple random sampling. Univariate and multivariate logistic regression analyses were performed to identify factors associated with acceptance of COVID-19 vaccination. RESULTS: Of all valid respondents (n = 903), 72.9% (n = 658) were willing to receive COVID-19 vaccination. Fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the main reason for being willing to receive vaccination (76.0%), while the main reasons for not willing were the concerns about vaccine safety (54.7%) and the vaccination's effect on antiretroviral therapy (ART) (50.6%). The most important factors influencing acceptance were the perception that vaccination is unsafe for HIV-infected people (aOR = 0.082, 95% CI = 0.024-0.282) and the poor efficacy in preventing SARS-CoV-2 infection in HIV-infected people (aOR = 0.093, 95% CI = 0.030-0.287). Other factors associated with acceptance included Zhuang ethnicity (aOR = 1.653, 95% CI = 1.109-2.465), highest education level of middle school, high school or above (aOR = 1.747, 95% CI = 1.170-2.608; aOR = 2.492, 95% CI = 1.326-4.682), and the vaccination having little effect on ART efficacy (aOR = 2.889, 95% CI = 1.378-6.059). CONCLUSIONS: Acceptance rate of the COVID-19 vaccination is relatively low among PLWH compared to the general population in China, although some patients refused vaccination due to concerns about vaccine safety and vaccination affecting ART efficacy. More research is needed to investigate the impact of the COVID-19 vaccines on ART efficacy and the effectiveness in preventing SARS-CoV-2 infection among PLWH.
Subject(s)
COVID-19 , HIV Infections , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , China/epidemiology , Cross-Sectional Studies , Humans , SARS-CoV-2 , Surveys and Questionnaires , VaccinationABSTRACT
BACKGROUND: The first-generation integrase inhibitors (INIs) raltegravir (RAL) and elvitegravir (EVG) have shown efficacy against HIV infection, but they have the limitations of once-more daily dosing and extensive cross-resistance. Dolutegravir (DTG, S/GSK1349572), a second-generation drug that overcomes such shortcomings, is under spotlight. The purpose of this study is to review the evidence for DTG use in clinical settings, including its efficacy and safety. METHODS: PubMed, EMbase, Ovid, Web of Science, Science Direct, and related websites were screened from establishment until July 2013, and scientific meeting proceedings were manually searched. Two reviewers independently screened 118 citations repeatedly to identify randomized controlled trials comparing the efficacy and safety of DTG-based regimen with those of RAL- or elvitegravir-based regimens. Using the selected studies with comparable outcome measures and indications, we performed a meta-analysis based on modified intention-to-treat (mITT), on-treatment (OT), and as-treated (AT) virological outcome data. Independent data extraction and quality assessment were conducted. RESULTS: Four unique studies were included with the use of DTG in antiretroviral therapy-naive patients. In therapy-naive patients, DTG combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) resulted in a significantly better virological outcome with a mITT relative risk (RR)of 1.07 (95 % confidence interval (95 % CI 1.03-1.12). Evidence further supported use of DTG had a better virological suppression in the 50 mg once daily group (mITT RR 1.07; 95 % CI 1.03-1.12) as well as in the sub-analysis in dolutegravir/efavirenz(DTG/EFV) and dolutegravir/raltegravir (DTG/RAL) groups (RR 1.09, 95 % CI 1.03-1.15; RR 1.06, 95 % CI 0.98-1.15, respectively). In the matter of safety of DTG-based regimen, the risk of any event was RR 0.98 (95 % CI 0.94-1.01), the risk of serious adverse events (AEs) was RR 0.84 (95 % CI 0.62-1.15), and the risk of drug-related serious AEs was RR 0.33 (95 % CI 0.13-0.79). CONCLUSION: In general, DTG 50 mg given once daily combined with an active background drug is a better choice in terms of both efficacy and safety.
Subject(s)
Anti-HIV Agents/administration & dosage , Benzoxazines/administration & dosage , HIV Infections/drug therapy , HIV-1/isolation & purification , Heterocyclic Compounds, 3-Ring/administration & dosage , Raltegravir Potassium/administration & dosage , Alkynes , Cyclopropanes , Deoxycytidine/administration & dosage , Dideoxynucleosides/administration & dosage , Drug Combinations , HIV Infections/virology , Humans , Lamivudine/administration & dosage , Oxazines , Piperazines , Pyridones , Randomized Controlled Trials as Topic , Tenofovir/administration & dosage , Treatment OutcomeABSTRACT
OBJECTIVE: To explore the effects of different types of interferon (IFN) on the expression of hepatitis C virus(HCV) replication-related miRNAs in human hepatocytes. METHODS: The levels of miRNAs in Huh7 cells treated with types I (IFN-α, IFN-ß), II (IFN-γ) and III (IFN-λ1) interferons (IFNs) were determined by real-time quantitative polymerase chain reaction (PCR). The levels of various miRNAs were compared among different IFN treatment groups. RESULTS: The expression of miRNA-196, miRNA-296, miRNA-351, miRNA-431 and miRNA-448 in IFN-α, IFN-ß and IFN-λ1 treated groups was higher than that in control group (474.5 ± 57.7, 436.0 ± 37.8, 431.3 ± 43.5 vs 99.5 ± 2.4; 389.5 ± 44.0, 416.3 ± 36.7, 284.8 ± 20.9 vs 99.0 ± 0.8; 453.3 ± 51.1, 473.8 ± 24.0, 522.0 ± 40.3 vs 99.5 ± 2.1; 288.3 ± 44.9, 294.3 ± 29.9, 450.0 ± 29.5 vs 100.5 ± 2.4; 319.0 ± 35.4, 357.0 ± 27.5, 446.5 ± 61.2 vs 99.8 ± 1.0; all P < 0.05). The expression of miRNA-196, miRNA-351 and miRNA-448 in IFN-γ-treated group (271.3 ± 29.6, 140.5 ± 27.5, 177.8 ± 23.4) was higher than that in control group (all P < 0.05). But the expression of miRNA-431 and miRNA-296 had no significant difference between IFN-γ treated group and control group (both P > 0.05). The expression of miRNA-122 at difference concentrations (10, 100, 1 000 U/ml) of IFN-α, IFN-ß, IFN-γ and IFN-λ1 (10, 100, 1 000 ng/ml) was lower than that in control group (49.3 ± 4.9, 32.0 ± 3.7, 24.5 ± 3.7 vs 99.5 ± 2.1; 53.5 ± 1.9, 35.5 ± 2.7, 25.8 ± 4.0 vs 98.8 ± 1.3; 60.8 ± 7.1, 43.8 ± 4.0, 33.5 ± 4.2 vs 99.3 ± 2.6; 50.0 ± 2.9, 35.5 ± 3.3, 22.3 ± 3.8 vs 100.3 ± 1.5; all P < 0.01). CONCLUSIONS: Different types of IFN increase the expression of miRNAs that inhibit HCV replication and decrease the expression of miRNA-122 that supports HCV replication. Thus the regulation of HCV replication-related miRNA expression is a general anti-HCV mechanism by different types of IFN. However, the regulation pattern by type II IFN is different from those by other types of IFNs, implying that type II IFN has different anti-HCV mechanisms from other types of IFN at miRNA level.
Subject(s)
Hepatocytes/drug effects , Hepatocytes/metabolism , Interferons/pharmacology , MicroRNAs/metabolism , Cell Line, Tumor , Hepacivirus/physiology , Humans , Interferon-alpha/pharmacology , Interferon-beta/pharmacology , Interferon-gamma/pharmacology , Virus ReplicationABSTRACT
Hypertension remains a major global public health crisis due to various contributing factors, such as age and environmental exposures. This study delves into exploring the intricate association between biological aging, blood lead levels, and hypertension, along with examining the mediating role of blood lead levels in the relationship between biological aging and hypertension. We analyzed data from two cycles of the NHANES, encompassing 4473 individuals aged 18 years and older. Our findings indicate that biological aging potentially escalates the risk of hypertension and the incidences of systolic blood pressure (SBP) and diastolic blood pressure (DBP) abnormalities. Utilizing weighted quantile sum (WQS) and quantile g-computation (QGC) model analyses, we observed that exposure to heavy metal mixtures, particularly lead, may elevate the likelihood of hypertension, SBP, and DBP abnormalities. Further mediation analysis revealed that lead significantly mediated the relationship between biological aging and hypertension and between biological aging and SBP abnormalities, accounting for 64% (95% CI, 49% to 89%) and 64% (95% CI, 44% to 88%) of the effects, respectively. These outcomes emphasize the criticality of implementing environmental health measures.
Subject(s)
Aging , Blood Pressure , Hypertension , Lead , Nutrition Surveys , Humans , Hypertension/blood , Hypertension/epidemiology , Hypertension/etiology , Lead/blood , Aging/blood , Male , Adult , Female , Middle Aged , Environmental Exposure/adverse effects , Aged , Young Adult , Adolescent , United States/epidemiology , Risk Factors , Databases, FactualABSTRACT
The risk of severe condition caused by Corona Virus Disease 2019 (COVID-19) increases with age. However, the underlying mechanisms have not been clearly understood. The dataset GSE157103 was used to perform weighted gene co-expression network analysis on 100 COVID-19 patients in our analysis. Through weighted gene co-expression network analysis, we identified a key module which was significantly related with age. This age-related module could predict Intensive Care Unit status and mechanical-ventilation usage, and enriched with positive regulation of T cell receptor signaling pathway biological progress. Moreover, 10 hub genes were identified as crucial gene of the age-related module. Protein-protein interaction network and transcription factors-gene interactions were established. Lastly, independent data sets and RT-qPCR were used to validate the key module and hub genes. Our conclusion revealed that key genes were associated with the age-related phenotypes in COVID-19 patients, and it would be beneficial for clinical doctors to develop reasonable therapeutic strategies in elderly COVID-19 patients.
Subject(s)
COVID-19 , Physicians , Humans , COVID-19/genetics , Cell Differentiation , Gene Expression Profiling , Phenotype , Gene Regulatory NetworksABSTRACT
OBJECTIVES: Talaromyces marneffei (T. marneffei) is an opportunistic fungal infection (talaromycosis), which is common in subtropical regions and is a leading cause of death in HIV-1-infected patients. This study aimed to determine the characteristics and risk factors associated with hospital readmissions in HIV patients with T. marneffei infection in order to reduce readmissions. METHODS: We conducted a retrospective study of admitted HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China, from 2012 to 2019. Kaplan-Meier analyses and Principal component analysis (PCA) were used to evaluate the effects of T. marneffei infection on patient readmissions. Additionally, univariate and multifactorial analyses, as well as Propensity score matching (PSM) were used to analyze the factors associated with patient readmissions. RESULTS: HIV/AIDS patients with T. marneffei-infected had shorter intervals between admissions and longer lengths of stay than non-T. marneffei-infected patients, despite lower readmission rates. Compared with non-T. marneffei-infected patients, the mortality rate for talaromycosis patients was higher at the first admission. Among HIV/AIDS patients with opportunistic infections, the mortality rate was highest for T. marneffei at 16.2%, followed by cryptococcus at 12.5%. However, the readmission rate was highest for cryptococcus infection (37.5%) and lowest for T. marneffei (10.8%). PSM and Logistic regression analysis identified leukopenia and elevated low-density lipoprotein (LDL) as key factors in T.marneffei-infected patients hospital readmissions. CONCLUSIONS: The first admission represents a critical window to intervene in the prognosis of patients with T. marneffei infection. Leukopenia and elevated LDL may be potential risk factors impacting readmissions. Our findings provide scientific evidence to improve the long-term outcomes of HIV patients with T. marneffei infection.
Subject(s)
Acquired Immunodeficiency Syndrome , HIV Infections , Leukopenia , Mycoses , Opportunistic Infections , Talaromyces , Humans , HIV Infections/complications , HIV Infections/drug therapy , Patient Readmission , Acquired Immunodeficiency Syndrome/complications , Retrospective Studies , China/epidemiology , Mycoses/complications , Mycoses/epidemiology , Mycoses/microbiology , Risk Factors , Antifungal Agents/therapeutic useABSTRACT
The natural process of human immunodeficiency virus type 1(HIV-1) infection is characterized by high viral load, immune cell exhaustion, and immunodeficiency, which eventually leads to the stage of acquired immunodeficiency syndrome (AIDS) and opportunistic infections. Rapidly progressing HIV-1 individuals often die of AIDS several years after infection without treatment. The promotion of ART greatly prolongs the survival time of HIV-infected persons. However, some patients have incomplete immune function reconstruction after ART due to latent storage of HIV-infected cells. Therefore, how to achieve a functional cure has always been the focus and hot spot of global AIDS research. Fortunately, the emergence of ECs/LTNPs who can control virus replication naturally has ignited new hope for realizing a functional cure for AIDS. Recently, a special category of infected individuals has attracted attention that can delay the progression of the disease more rigorously than the natural progression of HIV-1 infection described above. These patients are characterized by years of HIV-1 infection, long-term asymptomatic status, and normal CD4+T cell count without ART, classified as HIV-infected long-term nonprogressors (LTNPs) and elite controllers (ECs). Numerous studies have shown that the host and virus jointly determine the progression of HIV-1 infection, in which the level of innate immunity activation plays an important role. As the first line of defense against pathogen invasion, innate immunity is also a bridge to induce adaptive immunity. Compared with natural progressors, innate immunity plays an antiviral role in HIV-1 infection by inducing or activating many innate immune-related factors in the natural ECs. Learning the regulation of ECs immunity, especially the innate immunity in different characteristics, and thus studying the mechanism of the control of disease progression naturally, will contribute to the realization of the functional cure of AIDS. Therefore, this review will explore the relationship between innate immunity and disease progression in ECs of HIV-1 infection from the aspects of innate immune cells, signaling pathways, cytokines, which is helpful to provide new targets and theoretical references for the functional cure, prevention and control of AIDS, and development of a vaccine.
Subject(s)
Elite Controllers , HIV Infections/immunology , Immunity, Innate , Cytokines , HIV Infections/virology , HIV-1/immunology , Humans , Signal TransductionABSTRACT
Image-based salient object detection has made great progress over the past decades, especially after the revival of deep neural networks. By the aid of attention mechanisms to weight the image features adaptively, recent advanced deep learning-based models encourage the predicted results to approximate the ground-truth masks with as large predictable areas as possible, thus achieving the state-of-the-art performance. However, these methods do not pay enough attention to small areas prone to misprediction. In this way, it is still tough to accurately locate salient objects due to the existence of regions with indistinguishable foreground and background and regions with complex or fine structures. To address these problems, we propose a novel convolutional neural network with purificatory mechanism and structural similarity loss. Specifically, in order to better locate preliminary salient objects, we first introduce the promotion attention, which is based on spatial and channel attention mechanisms to promote attention to salient regions. Subsequently, for the purpose of restoring the indistinguishable regions that can be regarded as error-prone regions of one model, we propose the rectification attention, which is learned from the areas of wrong prediction and guide the network to focus on error-prone regions thus rectifying errors. Through these two attentions, we use the Purificatory Mechanism to impose strict weights with different regions of the whole salient objects and purify results from hard-to-distinguish regions, thus accurately predicting the locations and details of salient objects. In addition to paying different attention to these hard-to-distinguish regions, we also consider the structural constraints on complex regions and propose the Structural Similarity Loss. The proposed loss models the region-level pair-wise relationship between regions to assist these regions to calibrate their own saliency values. In experiments, the proposed purificatory mechanism and structural similarity loss can both effectively improve the performance, and the proposed approach outperforms 19 state-of-the-art methods on six datasets with a notable margin. Also, the proposed method is efficient and runs at over 27FPS on a single NVIDIA 1080Ti GPU.
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has caused many deaths worldwide. To date, the mechanism of viral immune escape remains unclear, which is a great obstacle to developing effective clinical treatment. RNA processing mechanisms, including alternative polyadenylation (APA) and alternative splicing (AS), are crucial in the regulation of most human genes in many types of infectious diseases. Because the role of APA and AS in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown, we performed de novo identification of dynamic APA sites using a public dataset of human peripheral blood mononuclear cell (PBMC) RNA-Seq data in COVID-19 patients. We found that genes with APA were enriched in innate immunity -related gene ontology categories such as neutrophil activation, regulation of the MAPK cascade and cytokine production, response to interferon-gamma and the innate immune response. We also reported genome-wide AS events and enriched viral transcription-related categories upon SARS-CoV-2 infection. Interestingly, we found that APA events may give better predictions than AS in COVID-19 patients, suggesting that APA could act as a potential therapeutic target and novel biomarker in those patients. Our study is the first to annotate genes with APA and AS in COVID-19 patients and highlights the roles of APA variation in SARS-CoV-2 infection.
Subject(s)
COVID-19/genetics , Polyadenylation , SARS-CoV-2 , Alternative Splicing , COVID-19/immunology , Female , Genome, Human , Humans , Immunity, Innate , Leukocytes, Mononuclear , Male , RNA, Messenger , TranscriptomeABSTRACT
To evaluate the mortality risk in the HIV-positive population, we conducted an observational cohort study involving routine data collection of HIV-positive patients who presented at HIV clinics and multiple treatment centers throughout Guangxi province, Southern China in 2011. The patients were screened for tuberculosis (TB) and tested for hepatitis B (HBV) and C (HCV) virus infections yearly. Following the registration, the cohort was followed up for a 60-month period till the end-point (December 31, 2015). Univariable and multivariable Cox proportional hazards regression models were used to analyze the hazard ratio (HR) and 95% confidence interval (95% CI) for mortality after adjusting for confounding factors stratified by patients' sociodemographic and behavioral characteristics. HRs were compared within risk-factor levels. With the median follow-up of 3.7-person years for each individual, 5,398 (37.8%) (of 14,293 patients with HIV/AIDS) died; among whom, 78.4% were antiretroviral therapy (ART)-naïve; 43.6% presented late; and 12.2% and 3.3% of patients had Mycobacterium tuberculosis (MTB) and HBV and HCV co-infection, respectively. Of individuals with CD4 counts, those with CD4 count >350 cells/µL formed 14.0% of those who died. Furthermore, gender [multivariable HR (95% CI):1.94 (1.68-2.25)], Han ethnicity [2.15 (1.07-4.32)], illiteracy [3.28 (1.96-5.5)], elementary education [2.91 (1.8-4.72)], late presentation [2.89 (2.46-3.39)], and MTB co-infection [1.28 (1.10-1.49)] strongly increased the all-cause mortality risk of HIV-positive individuals. The HR for ART-based stratification was 0.08 (0.07-0.09); and for HBV and HCV co-infection, HR was 1.02 (0.86-1.21). The findings emphasized that accessibility to HIV testing among high-risk populations and screening for viral hepatitis and TB co-infection are important for the survival of HIV-positive individuals. Initiating early ART, even for individuals with higher CD4 counts, is advisable to help increase the prolongation of lives within the community.
Subject(s)
Coinfection/mortality , HIV Seropositivity/mortality , Hepatitis B/mortality , Hepatitis C/mortality , Tuberculosis/mortality , Adolescent , Adult , Age Factors , Aged , China/epidemiology , Female , Follow-Up Studies , HIV-1 , Hepacivirus , Hepatitis B virus , Humans , Middle Aged , Mycobacterium tuberculosis , Risk Factors , Sex FactorsABSTRACT
The molecular mechanism of opiate use promoting HIV-1 infection is not fully understood. TLR9 is expressed in many immune cells, including monocytes, macrophages, which can recognize viruses and viral products and consequently induce the production of antiviral factors and initiate immune responses. Previous studies have shown that chronic viral infections can overcome and impair TLR9 pathway. We aimed to explore whether opiate use enhances HIV infection through inhibition of TLR9 pathway via a population-based study. A total of 200 subjects were enrolled and divided into four groups as follows: Opiate+ HIV+ (50), Opiate- HIV+ (50), Opiate+ HIV- (50), and healthy control (Opiate- HIV-, 50). All HIV-infected subjects did not receive antiretroviral therapy while they were enrolled in the study. The results showed that opiate use was associated with higher viral load and lower CD4+ T cell count. Opiate use alone led to lower expression of TLR9, IRF7, and IFN-α at the protein level in PBMCs. Combined with HIV-1 infection, opiate use resulted in lower expression of MyD88, ISG56, and MxA. In addition, morphine treatment promoted HIV-1 replication in macrophages via inhibition of TLR9 pathway. Our data reveal that opiate use plays a cofactor role in pathogenesis of HIV-1 infection through inhibition of TLR9 pathway.
Subject(s)
Antiviral Agents/pharmacology , HIV Infections/metabolism , HIV-1/drug effects , HIV-1/pathogenicity , Signal Transduction/drug effects , Toll-Like Receptor 9/metabolism , Virus Replication/drug effects , Analgesics, Opioid/pharmacology , Blotting, Western , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Humans , Methadone/pharmacology , Real-Time Polymerase Chain Reaction , Viral Load/drug effectsABSTRACT
It is a daunting task to eradicate tuberculosis completely in Heng County due to a large transient population, human immunodeficiency virus/tuberculosis coinfection, and latent infection. Thus, a high-precision forecasting model can be used for the prevention and control of tuberculosis. In this study, four models including a basic autoregressive integrated moving average (ARIMA) model, a traditional ARIMA-generalized regression neural network (GRNN) model, a basic GRNN model, and a new ARIMA-GRNN hybrid model were used to fit and predict the incidence of tuberculosis. Parameters including mean absolute error (MAE), mean absolute percentage error (MAPE), and mean square error (MSE) were used to evaluate and compare the performance of these models for fitting historical and prospective data. The new ARIMA-GRNN model had superior fit relative to both the traditional ARIMA-GRNN model and basic ARIMA model when applied to historical data and when used as a predictive model for forecasting incidence during the subsequent 6 months. Our results suggest that the new ARIMA-GRNN model may be more suitable for forecasting the tuberculosis incidence in Heng County than traditional models.
Subject(s)
Models, Biological , Models, Statistical , Neural Networks, Computer , Tuberculosis/epidemiology , China/epidemiology , Computer Simulation , Humans , IncidenceABSTRACT
Current WHO guidelines recommend initiating ART regardless of CD4+ cell count. In response, we conducted an observational cohort study to assess the effects of pre-ART CD4+ cell count levels on death, attrition, and death or attrition in HIV treated patients. This large HIV treatment cohort study (n = 49,155) from 2010 to 2015 was conducted in Guangxi, China. We used a Cox regression model to analyze associations between pre-ART CD4+ cell counts and death, attrition, and death or attrition. The average mortality and ART attrition rates among all treated patients were 2.63 deaths and 5.32 attritions per 100 person-years, respectively. Compared to HIV patients with <350 CD4+ cells/mm3 at ART initiation, HIV patients with >500 CD4+ cells/mm3 at ART initiation had a significantly lower mortality rate (Adjusted hazard ratio: 0.56, 95% CI: 0.40-0.79), but significantly higher ART attrition rate (AHR: 1.17, 95% CI: 1.03-1.33). Results from this study suggest that HIV patients with high CD4+ cell counts at the time of ART initiation may be at greater risk of treatment attrition. To further reduce ART attrition, it is imperative that patient education and healthcare provider training on ART adherence be enhanced and account for CD4 levels at ART initiation.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , Adult , CD4 Lymphocyte Count , China , Female , HIV Infections/mortality , Humans , Male , Medication Adherence/statistics & numerical data , Mortality , Regression Analysis , Treatment OutcomeABSTRACT
Type-III interferon (IFN-λ), the most recently discovered family of IFNs, shares common features with type I IFNs, but also has many distinctive activities. It is not clear that whether IFN-λ has additional antiviral mechanisms. In this study, we investigated the effects of IFN-λ on autophagy, a cellular process closely related to hepatitis C virus (HCV) infection in human hepatoma Huh7 cells. Our results showed that IFN-λ1 treatment inhibit autophagic activity in Huh7 cells, as evidenced by the decreased expression of microtubule-associated protein 1 light chain 3B (LC3B)-II and conversion of LC3B-I to LC3B-II, decreased formation of GFP-LC3 puncta and accumulation of autophagosomes. IFN-λ1 could also inhibit HCV-induced or tunicamycin (a known inducer of autophagy with similar mechanism to HCV infection) -induced LC3B-II expression and autophagosome formation. Through PCR array, real time RT PCR, and western blot, two autophagy-related genes, ATG5 and GABARAP, were identified and verified to be down-regulated by IFN-λ1 treatment, either in HCV-uninfected Huh7 cells or in HCV JFH-1-infected cells. Overexpression of ATG5 and/or GABARAP could partly recover the IFN-λ1-inhibited HCV replication. Mechanism research demonstrated that IFN-λ1 could induce the expression of miR-181a and miR-214 (targeting ATG5 and GABARAP respectively), by which down-regulates ATG5 and GABARAP expression. Taken together, our results indicate that suppression of the autophagy response by IFN-λ1 contributes to IFN-λ1 anti-HCV activity. The results also provide a theoretical basis for improving the effectiveness of IFN treatment of HCV infection through inhibition of the HCV-induced autophagy response.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Antiviral Agents/pharmacology , Autophagy-Related Protein 5/genetics , Down-Regulation , Hepacivirus/drug effects , Interferons/pharmacology , Microtubule-Associated Proteins/genetics , Apoptosis Regulatory Proteins , Autophagy/drug effects , Cell Line, Tumor , Hepatitis C/drug therapy , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Liver Neoplasms/virology , MicroRNAs/genetics , Signal Transduction , Virus Replication/drug effectsABSTRACT
Previous studies have shown that mycophenolic acid (MPA) has an anti-HCV activity. However, the mechanism of MPA-mediated inhibition of HCV replication remains to be determined. This study investigated whether MPA has an effect on autophagy, a cellular machinery required for HCV replication, thereby, inhibits HCV replication in Huh7 cells. MPA treatment of Huh7 cells could suppress autophagy, evidenced by decreased LC3B-II level and conversion of LC3B-I to LC3B-II, decreased autophagosome formation, and increased p62 level compared to MPA-untreated cells. Tunicamycin treatment or HCV infection could induce cellular autophagy, however, MPA also exhibited its inhibitory effect on tunicamycin- or HCV infection-induced autophagy. The expression of three autophagy-related genes, Atg3, Atg5, and Atg7 were identified to be inhibited by MPA treatment. Over-expression of these genes could partly recover HCV replication inhibited by MPA; however, silencing their expression by siRNAs could enhance the inhibitory effect of MPA on HCV. Collectively, these results reveal that suppression of autophagy by MPA plays a role in its anti-HCV activity. Down-regulating the expression of three autophagy-related genes by MPA involves in its antiviral mechanism.
Subject(s)
Autophagy/drug effects , Carcinoma, Hepatocellular/metabolism , Hepacivirus/physiology , Liver Neoplasms/metabolism , Mycophenolic Acid/pharmacology , Neoplasm Proteins/metabolism , Virus Replication/drug effects , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Cell Line, Tumor , Humans , Liver Neoplasms/pathology , Liver Neoplasms/virologyABSTRACT
Rural-to-urban migrants are at high risk of HIV infection. The goal of this survey was to explore the commercial sexual behavior and condom use among male rural-to-urban migrants in western China. A cross-sectional survey on male rural-to-urban migrants in western China was conducted. Among all the subjects surveyed, 140 (7.4%) had commercial sexual behavior, which is associated with being aged older than 24 years, being of Han or other ethnic minorities, being divorced, separated, or widowed, having experienced drug abuse, having had heterosexual behavior, having had casual sexual partners, having had sex with a homosexual, and being from Xinjiang. A total of 31.4% of them never use condoms when buying sex. Not using condoms is associated with being from Chongqing, having a high school or above education, and having commercial sex monthly. Commercial sexual behavior and not using condoms are common among male rural-to-urban migrants in western China. Strategies and appropriate education should be developed to prevent HIV transmission due to high-risk sexual behaviors.