Autophagy-related protein 5 (ATG5) interacts with bone marrow stromal cell antigen 2 (BST2) to stimulate HBV replication through antagonizing the antiviral activity of BST2.

Hepatitis B virus (HBV) infection is a major global health burden with 820 000 deaths per year. In our previous study, we found that the knockdown of autophagy-related protein 5 (ATG5) significantly upregulated the interferon-stimulated genes (ISGs) expression to exert the anti-HCV effect. However, the regulation of ATG5 on HBV replication and its underlying mechanism remains unclear. In this study, we screened the altered expression of type I interferon (IFN-I) pathway genes using RT² Profiler™ PCR array following ATG5 knock-down and we found the bone marrow stromal cell antigen 2 (BST2) expression was significantly increased. We then verified the upregulation of BST2 by ATG5 knockdown using RT-qPCR and found that the knockdown of ATG5 activated the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway. ATG5 knockdown or BST2 overexpression decreased Hepatitis B core Antigen (HBcAg) protein, HBV DNA levels in cells and supernatants of HepAD38 and HBV-infected NTCP-HepG2. Knockdown of BST2 abrogated the anti-HBV effect of ATG5 knockdown. Furthermore, we found that ATG5 interacted with BST2, and further formed a ternary complex together with HBV-X (HBx). In conclusion, our finding indicates that ATG5 promotes HBV replication through decreasing BST2 expression and interacting with it directly to antagonize its antiviral function.

Analysis of ART effects and drug resistance in adult HIV/AIDS patients in Meigu County, Liangshan Prefecture, China.

BACKGROUND OBJECTIVE: This study aimed to understand the basic situation of adults with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) in Meigu County, Liangshan Yi Autonomous Prefecture. The information of patients who had been on ART for more than 6 months, the effect of ART, the possible reasons for ART failure, knowledge of drug resistance among patients with ART failure and the possible reasons for the emergence of drug resistance were analyzed. METHODS: A total of 2753 people living with HIV (PLWH) were collected for HIV-1 RNA virus nucleic acid testing. Plasma specimens with HIV-1 RNA ≥ 1000 copies/mL were sent to the laboratory for nucleic acid extraction, PCR, electrophoresis and sequencing, and the sequencing results were submitted to the HIV drug resistance database of Stanford University for subtyping to determine the drug resistance mutation sites and drug sensitivity levels. RESULTS: A total of 2753 patients were enrolled in this study. Antiviral therapy failed in 288 patients and was successfully amplified in 245, of which 111 had resistance genes. The resistance rate to failure of viral suppression was 45.3% (111/245). The highest rates of resistance to NNRTIs were found for efavirenz (EFV) and nevirapine (NVP) (42.9%), and the highest rates of resistance to NRTIs were found for 3TC and emtricitabine (FTC) (15.9%). The most common NNRTI resistance mutation site was K103N (20.8%), followed by V179D (9.4%) and V106M (7.8%); the most common NRTI resistance mutation site was M184V/I/MV (14.3%), followed by K65R (6.9%); three PI-associated resistance mutation sites were identified. The subtype of the resistant strain was CRF07-BC in almost all patients (98.9%). CONCLUSIONS: Compared with the previous low ART efficacy in the county, this study showed that the overall virological failure (VF) resistance rate in the county is still low, dominated by resistance to EFV, NVP, 3TC, FTC, and didanosine (DDI). Due to economic constraints, the core regimen is still 3TC + TDF, but before initiating ART, testing for HIV-1 subtypes and resistance should be conducted to avoid resistance that can lead to VF, especially for patients with high risk factors for resistance as shown by epidemiologic investigations.

Fullerenols Mitigate Radiation-Induced Myocardial Injury.

Radiation-induced heart disease is a serious side effect of radiation therapy that can lead to severe consequences. However, effective and safe methods for their prevention and treatment are presently lacking. This study reports the crucial function of fullerenols in protecting cardiomyocytes from radiation injury. First, fullerenols are synthesized using a simple base-catalyzed method. Next, the as-prepared fullerenols are applied as an effective free radical scavenger and broad-spectrum antioxidant to protect against X-ray-induced cardiomyocyte injury. Their ability to reduce apoptosis via the mitochondrial signaling pathway at the cellular level is then verified. Finally, it is observed in animal models that fullerenols accumulate in the heart and alleviate myocardial damage induced by X-rays. This study represents a timely and essential analysis of the prevention and treatment of radiological myocardial injury, providing new insights into the applications of fullerenols for therapeutic strategies.

The whole genome analysis for the first human infection with H10N3 influenza virus in China.

A strain of H10N3 influenza virus, A/Jiangsu/428/2021/H10N3, was isolated from patient in Jiangsu province, eastern China. Phylogenetic analysis illustrated this human H10N3 virus was a low pathogenic avian-origin recombinant virus with HA and NA genes from H10N3 viruses and the other six internal genes from H9N2 viruses. To date, this is the first report of interspecies transmission of an avian H10N3 influenza virus to human.

Dynamics of Plasma EGFR T790M Mutation in Advanced NSCLC: A Multicenter Study.

BACKGROUND: Droplet digital polymerase chain reaction (ddPCR) is an emerging technology for quantitative cell-free DNA oncology applications. However, a ddPCR assay for the epidermal growth factor receptor (EGFR) p.Thr790Met (T790M) mutation suitable for clinical use remains to be established with analytical and clinical validations. OBJECTIVE: We aimed to develop and validate a new ddPCR assay to quantify the T790M mutation in plasma for monitoring and predicting the progression of advanced non-small-cell lung cancer (NSCLC). METHODS: Specificity of the ddPCR assay was evaluated with genomic DNA samples from healthy individuals. The inter- and intraday variations of the assay were evaluated using mixtures of plasmid DNA containing wild-type EGFR and T790M mutation sequences. We assessed the clinical utility of the T790M assay in a multicenter prospective study in patients with advanced NSCLC receiving tyrosine kinase inhibitor (TKI) treatment by analyzing longitudinal plasma DNA samples. RESULTS: We set the criteria for a positive call when the following conditions were satisfied: (1) T790M mutation frequency > 0.098% (3 standard deviations above the background signal); (2) at least two positive droplets in duplicate ddPCR reactions. Among the 62 patients with advanced NSCLC exhibiting resistance to TKI treatment, 15 had one or more serial plasma samples that tested positive for T790M. T790M mutation was detected in the plasma as early as 205 days (median 95 days) before disease progression, determined by imaging analysis. Plasma T790M concentrations also correlated with intervention after disease progression. CONCLUSIONS: We developed a ddPCR assay to quantify the T790M mutation in plasma. Quantification of longitudinal plasma T790M mutation may allow noninvasive assessment of drug resistance and guide follow-up treatment in TKI-treated patients with NSCLC. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT02804100.

Effects of long-term exposure to tenofovir disoproxil fumarate-containing antiretroviral therapy on renal function in HIV-positive Chinese patients.

BACKGROUND: The regimen containing tenofovir disoproxil fumarate (TDF)+lamivudine or emtricitabine + efavirenz remains the recommended first-line antiretroviral therapy (ART) by the WHO. Limited studies, however, have been conducted on the incidence of renal impairment among Chinese patients with long-term exposure to TDF-containing ART regimens. METHODS: We retrospectively analyzed 269 eligible patients who had no comorbidities and received TDF-containing ART from July 2014 to April 2015. TDF-related renal impairment was defined as a decrease of eGFR by >25% from baseline or eGFR <90 ml/min/1.73 m2. Decreased renal function was defined as a decrease of eGFR by > 10 mL/min/1.73 m2 from baseline. RESULTS: 97.0% of study patients were male (median age 29, eGFR 124.0 ml/min/1.73 m2). After 168-week of ART, renal impairment occurred in 7 patients (2.7%). The incidence of decreased renal function was significantly higher at Week 168 compared with that observed at Week 12 (24.8% vs 3.7%, p < 0.001). In generalized estimating equation analysis, patients receiving ART for 144-week (aOR4.1, 95%CI 2.0-8.4) and 168-week (aOR8.4, 95%CI 4.2-16.4) were more likely to develop decreased renal function compared with those receiving ART for 12-week, so were the patients with a weight <58 kg (aOR2.3, 95%CI 1.2-4.3) and 58-66 kg (aOR2.0, 95%CI 1.0-3.8) compared to those with a weight ≥67 kg. At 168-week, 41.0% of 100 patients examined had elevated urine ß2-microglobulin levels, which were negatively correlated with eGFR (r = -0.22, p = 0.02). CONCLUSIONS: TDF-related renal impairment remained rare in HIV-positive Chinese patients with a median age of 29 years who had no comorbidities. A lower weight and duration of ART were associated with decreased renal function.

Association between the HLA-DQB1 polymorphisms and the susceptibility of chronic hepatitis B: A comprehensive meta-analysis.

Single-nucleotide polymorphisms in the human leukocyte antigen (HLA)-DQB1 gene are associated with chronic inflammatory and immunological diseases. Host genetic factors have a key role in the development of chronic hepatitis B (CHB). The aim of the present study was to investigate the association between the HLA-DQB1 polymorphisms and the susceptibility to CHB. PubMed, Embase, CNKI and Wanfang databases were searched for the studies that reported the association of the HLA-DQB1 polymorphisms with CHB between January 1, 1966 and July 30, 2015. HLA-DQB1 polymorphism-specific odds ratio (OR) and 95% confidence intervals (95% CI) were pooled and calculated in the fixed effects model using the Mantel-Haenszel method. Q-test and I2 test were performed to examine the heterogeneity. Begg's funnel test and Egger's test were conducted to assess publication bias. All the statistical tests were two-tailed. Subsequent to searching the databases and screening according to the inclusion criteria, 7 case-control studies were available in the present meta-analysis, including 815 CHB patients and 731 control subjects for the HLA-DQB1 polymorphisms. In conclusion, the statistically significant pooled OR of the HLA-DQB1 polymorphisms were obtained for the HLA-DQB1 loci (*0201, case vs. CONTROL: I2=36.5%; P-value of heterogeneity=0.15; OR, 1.29; 95% CI, 1.02-1.64; P=0.0301; *0301, case vs. CONTROL: I2=0%; P-value of heterogeneity=0.899; OR, 1.37; 95% CI, 1.12-1.69; P=0.002; *0502, case vs. CONTROL: I2=24.9%; P-value of heterogeneity=0.239; OR, 1.50; 95% CI, 1.02-2.20; P=0.04), which were associated with an increased risk of CHB. Similar significant results were observed and acquired in the following HLA-DQB1 loci (*0303, case vs. CONTROL: I2=0%; P-value of heterogeneity=0.986; OR, 0.77; 95% CI, 0.62-0.95; P=0.017; *0604, case vs. CONTROL: I2=0%; P-value of heterogeneity=0.594; OR, 0.38; 95% CI, 0.20-0.74; P=0.003), which were associated with a decreased risk of CHB. No significant association was observed for the other HLA-DQB1 family loci. The present meta-analysis demonstrated that the HLA-DQB1 loci (*0201, *0301 and *0502) polymorphisms were significantly associated with an increased risk of CHB. However, HLA-DQB1 loci polymorphisms (*0303 and *0604) were associated with a decreased risk of CHB. These results support the hypothesis that polymorphisms of the HLA-DQB1 allele families may affect the susceptibility or resistance to CHB.

Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings.

BACKGROUND AND OBJECTIVES: Severe infection with avian influenza A (H5N6) virus in humans was identified first in 2014 in China. Before that, it was unknown or unclear if the disease or the pathogen affected people. This study illustrates the virological and clinical findings of a fatal H5N6 virus infection in a human patient. METHODS: We obtained and analyzed the clinical, epidemiological, and virological data from the patient. Reverse transcription polymerase chain reaction (RT-PCR), viral culture, and sequencing were conducted for determination of the causative pathogen. RESULTS: The patient, who presented with fever, severe pneumonia, leucopenia, and lymphopenia, developed septic shock and acute respiratory distress syndrome (ARDS), and died on day 10 after illness onset. A novel reassortant avian-origin influenza A (H5N6) virus was isolated from the throat swab or trachea aspirate of the patient. The virus was reassorted with the HA gene of clade 2.3.4.4 H5, the internal genes of clade 2.3.2.1 H5, and the NA gene of the H6N6 avian virus. The cleavage site of the HA gene contained multiple basic amino acids, indicating that the novel H5N6 virus was highly pathogenic in chicken. CONCLUSIONS: A novel, highly pathogenic avian influenza H5N6 virus with a backbone of H5N1 virus acquired from the NA gene from the H6N6 virus has been identified. It caused human infection resulting in severe respiratory disease.