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探索用重组8型腺相关病毒载体携带1.3拷贝乙型肝炎病毒(rAAV8-1.3HBV)介导的HBV持续感染小鼠模型评价核苷酸类似物抗病毒药物的抗病毒效果。首先,通过将rAAV8-1.3HBV经尾静脉注射到30只C57BL/6小鼠体内,建立HBV持续感染模型并对模型成功率进行检测,将建模成功的27只小鼠随机分成6组。然后采取灌胃的方式给予不同剂量的抗病毒药物恩替卡韦(ETV)及拉米夫定(LAM),每日1次,连续10 d,后停药15 d,同时设置生理盐水及空白对照组。其中ETV分为高剂量(1.0 mg/(kg d))和低剂量(0.1 mg/(kg d))两组;LAM分为高剂量(500 mg/(kg d))和低剂量(100 mg/(kg d))两组。检测给药前后和停药前后小鼠模型血清中HBV DNA、HBeAg和HBsAg表达水平并比较变化情况。结果发现连续给药10 d后,各给药组与生理盐水组相比,血清中HBV DNA水平均显著下降,具有统计学差异(P<0.05)。停药15 d后,低剂量的ETV与LAM两组血清HBV DNA水平出现反弹,差异存在统计学意义(P<0.05)。在整个实验过程中,各组小鼠血清中HBeAg和HBsAg表达水平均未出现明显变化。上述结果表明,ETV和LAM能有效抑制模型小鼠中HBV病毒的复制,而对HBeAg和HBsAg表达水平无明显影响;提示AAV8-1.3HBV介导的HBV持续感染小鼠模型制备简单,成模率高,可有效体现出ETV和LAM抗HBV的作用效果,从而用于核苷酸类似物抗HBV药物的筛查。
To explore the antiviral effect of nucleotide analog anti-virals using a recombinant adenovirus-associated adenovirus vector carrying 1.3 copies of hepatitis B virus (rAAV8-1.3HBV) -mediated persistent HBV infection in mice. First, by injecting rAAV8-1.3HBV into 30 C57BL / 6 mice through the tail vein, the persistent HBV infection model was established and the success rate of the model was tested. The 27 successful mice were randomly divided into 6 groups. ETV and lamivudine (LAM) were administered by gavage at different doses once daily for 10 days and then for 15 days. Meanwhile, normal saline and blank control group were set up. ETV was divided into two groups: high dose (1.0 mg / (kg d)) and low dose (0.1 mg / (kg d)). LAM was divided into high dose (500 mg / / (kg d)) two groups. The levels of HBV DNA, HBeAg and HBsAg in the serum of the mouse model before and after administration and before and after administration were detected and compared. The results showed that after 10 days of continuous administration, the levels of HBV DNA in serum were significantly decreased compared with those in the saline group (P <0.05). Serum HBV DNA level rebounded after low dose of ETV and LAM for 15 days. The difference was statistically significant (P <0.05). Throughout the experiment, no significant changes in the expression levels of HBeAg and HBsAg in serum of each group of mice. The above results show that ETV and LAM can effectively inhibit the replication of HBV virus in model mice, but have no obvious effect on the expression of HBeAg and HBsAg. It is suggested that the AAV8-1.3HBV-mediated HBV persistent infection mouse model is simple and the rate of formation High, can effectively reflect the ETV and LAM anti-HBV effect, which is used for nucleotide analog anti-HBV drug screening.