The potential of signal peptide peptidase as a therapeutic target for hepatitis C

Introduction: Chronic infection with hepatitis C virus (HCV) causes liver steatosis, cirrhosis, metabolic syndrome with inflammation, and eventually leads to hepatocellular carcinoma. HCV core protein is a well-known capsid protein and pathogenic factor related to lipid accumulation, type 2 diabetes mellitus, and carcinogenesis. Cleavage of the C-terminal transmembrane region by signal peptide peptidase (SPP) is required for maturation of the core protein.

Areas covered: Herein, this review details the general aspects of the structure, lifecycle, pathogenesis, and maturation of the HCV core protein, the function of SPP, and clinically available direct-acting antivirals (DAAs). SPP is classified into a group of GXGD-type intramembrane proteases including presenilin-1, which is a component of γ-secretase complex. Several SPP inhibitors were previously identified from γ-secretase inhibitors, but have not yet been improved based on specificity to SPP. Finally, the author discusses the potential of SPP inhibitors for hepatitis C therapy.

Expert opinion: Currently available DAAs therapies are limited because of different viral genotypes and underlying conditions in each patient. DAA-resistant viruses have also been reported. Development of SPP-selective inhibitors may improve current HCV therapies by decreasing in the emergence of DAA-resistant viruses irrespective of viral genotype.     

分析重庆市HIV/AIDS患者合并HBV、HCV感染状况

目的 分析重庆市艾滋病病毒感染者(HIV)和获得性免疫缺陷综合征(acquired immunedeficiency syndrome,AIDS)患者(简称HIV/AIDS患者)合并感染乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)状况.方法 利用《艾滋病综合防治系统——抗病毒治疗管理》数据库,回顾收集重庆市2004-2015年HIV/AIDS治疗患者基本情况和HBsAg、Anti-HCV实验室检测结果,利用SPSS 19.0统计软件进行统计分析.结果 截至2015年12月31日,重庆市HIV/AIDS患者中HBsAg和(或)Anti-HCV总检测率55.1％ (11 231/20 397),其中HBsAg和Anti-HCV都进行检测的患者有9 307例.HIV/HBV、HIV/HBV/HCV、HIV/HCV合并感染的比例分别为9.8％、0.9％、4.5％.HIV/HCV合并感染在30 ～ 45岁年龄段构成比最高;HIV/HBV合并感染在男性中构成比最高,与HIV单纯感染组比较,差异均具有统计学意义(P＜0.05).HIV/HBV合并感染及HIV单纯感染均在性传播中构成比最高,差异无统计学意义(P=0.177);HIV/HCV和HIV/HBV/HCV合并感染在静脉吸毒中构成比最高,与HIV单纯感染比较,差异具有统计学意义(P＜0.05).主城9区中HIV/AIDS患者及合并感染患者比例最高.合并感染组病死率均高于HIV单纯感染组,HIV/HBV/HCV组病死率最高.结论 重庆市HIV/AIDS患者中HBsAg、Anti-HCV检测率较低,不同感染模式具有不同的流行病学特征,且合并感染的病死率较高,需要进一步加强对重庆市HIV/AIDS患者中HBV、HCV合并感染检测率和治疗情况的管理.     

Consolidation of molecular testing in clinical virology

Introduction: The development of quantitative methods for the detection of viral nucleic acids have significantly improved our ability to manage disease progression and to assess the efficacy of antiviral treatment. Moreover, major advances in molecular technologies during the last decade have allowed the identification of new host genetic markers associated with antiviral drug response but have also strongly revolutionized the way we see and perform virus diagnostics in the coming years.

Areas covered: In this review, we describe the history and development of virology diagnostic methods, dedicating particular emphasis on the gradual evolution and recent advances toward the introduction of multiparametric platforms for the syndromic diagnosis. In parallel, we outline the consolidation of viral genome quantification practice in different clinical settings.

Expert commentary: More rapid, accurate and affordable molecular technology can be predictable with particular emphasis on emerging techniques (next generation sequencing, digital PCR, point of care testing and syndromic diagnosis) to simplify viral diagnosis in the next future.     

昆明地区2019年HIV/HCV共感染患者HCV核衣壳蛋白基因分型

目的 基于丙型肝炎病毒（hepatitis C virus, HCV）核衣壳蛋白（nucleocapsid protein）基因序列了解昆明地区人类免疫缺陷病毒（human immunodeficiency virus, HIV）/HCV共感染患者中HCV基因型及基因亚型流行情况。方法 2019年3—8月在云南省传染病医院收集临床诊断为HIV/HCV共感染住院且户籍地为昆明所辖14个县级市、区及县的患者血清,从血清中提取病毒RNA,反转录合成第一链cDNA,采用HCV核衣壳蛋白基因特异性引物进行巢式PCR扩增。结果 共收集到临床诊断疑似HIV/HCV患者样本64例,采用HCV核衣壳蛋白基因特异性引物扩增,其中17例样品扩增阳性。序列分析结果显示,有9例病例的序列与HCV 3b基因亚型序列位于同一个进化分支,核苷酸同源性为93.3%～95.2%;5例病例的序列与HCV 1b基因亚型序列位于同一个进化分支,核苷酸同源性为96.8%～97.6%;1例病例序列与HCV 3a基因亚型序列位于同一个进化分支,核苷酸同源性为95.2%;1例病例序列与HCV 6n基因亚型序列位于同一个进化分支,核苷酸...     

丙肝患者血清 HCV RNA拷贝数与HCV Ab定量和肝脏功能损伤程度的关系

目的 对丙型肝炎患者丙肝病毒RNA（HCV RNA）、丙肝病毒抗体（HCV Ab）和肝功能指标定量结果进行统计分析,并探讨HCV RNA与HCV Ab和肝功能指标间的关系,为丙肝患者诊断和治疗提供参考依据。方法 收集342例丙肝患者血清,采用实时荧光定量PCR技术检测HCV RNA拷贝数,采用化学发光技术检测HCV Ab浓度,分别采用速率法、免疫比浊法、溴甲酚紫法和重氮盐法检测血清ALT、AST,PA,ALB和TBIL、DBIL的活性或浓度。结果 342例研究对象中,HCV RNA拷贝数以N×10⁶ IU/mL为主,占48.7%;而N×10³ IU/mL和N×10⁴ IU/mL最少,分别占4.3%和7.4%。在HCV RNA拷贝数小于1×10³ IU/mL组中,HCV Ab浓度较其他组低,而HCV RNA拷贝数在N×（10³~10⁷）IU/mL组间时,HCV Ab浓度差异无统计学意义（P>0.05）;当HCV Ab浓度大于10 S/CO时,HCV RNA阳性率升高,可达88.7%。与HCV RNA拷贝数小于N×10³ IU/mL相比,大于N×10⁴ IU/mL的丙肝患者血清ALT、AST、ALB和PA异常率增加（P<0.05）,而血清DBIL和IBIL差异无统计学意义（P>0.05）。结论 丙肝病毒主要损伤肝细胞及其合成功能,联合检测HCV Ab和HCV RNA拷贝数对丙型肝炎的诊断和治疗具有重要的意义。     

Lower life expectancy among people with an HCV notification: a population‐based linkage study

Among people with hepatitis C virus (HCV) infection, liver disease‐related deaths have risen over the last 20 years. Life expectancy has not been estimated in this population. HCV notifications (mandatory notification of anti‐HCV‐positive serology since 1991) reported to the New South Wales Health Department from 1992 to 2006 were linked to cause of death data. Abridged life tables were constructed from age‐specific mortality rates. Life expectancy from ages 18–70 years for non‐drug‐related mortality causes was estimated using competing risk methods and compared to the general population of Australia. The cohort comprised 81 644 individuals with an HCV notification, with median follow‐up of 7.6 years. Median age at notification was 34 years [interquartile range (IQR) 28–42] and 63% were male. Between 1992 and 2006, 4607 deaths occurred. Median age at liver‐ and drug‐related death among males was 51 (IQR 45–66) and 36 (IQR 31–42) years, respectively, and among females was 63 (IQR 49–74) and 36 (IQR 30–41) years, respectively. In each year of follow‐up before 2000, 15–21% of deaths were liver‐ and 30–39% were drug‐related. After 2000, liver‐related deaths increased to 20–26% of deaths in each year and drug‐related deaths decreased to 13–19%. Excluding drug‐related causes of death, life expectancy was lowered by an average of 4.2 (SD ± 1.0) and 5.4 (SD ± 0.7) years for males and females, respectively. Among people with an HCV notification, an increasing proportion of deaths are liver‐related. Following removal of drug‐related mortality, life expectancy in this population remained considerably lower, compared with the general population.