抗巨细胞病毒人源化抗体的研究

发布时间：2018-05-28 09:57

本文选题：巨细胞病毒 + 糖蛋白B　；参考：《第三军医大学》2005年博士论文

【摘要】：目的意义人类巨细胞病毒(human cytomegalovirus, HCMV)是Smith等在1956年首先从一名死亡婴儿的颌下腺中分离出来的一种病毒,1964年正式命名为巨细胞病毒。它属β亚科疱疹病毒,为双链DNA病毒,直径约180～250nm,是一种广泛传播的种属特异性病毒。人类感染该病毒后多呈亚临床感染或潜伏感染。在多数免疫功能正常个体中一般不产生明显的临床表现,然而却能持续排放病毒,造成广泛传播。但是,巨细胞病毒对免疫低下患者、育龄妇女及儿童危害极大。在免疫功能低下人群中,潜伏感染的病毒常会被激活,导致严重的甚至是致命性的后果。因此,关于巨细胞病毒的预防和治疗研究日益受到重视(1)。 HCMV也同其它病毒一样,通过吸附、侵入细胞、复制及释放这一循环方式在人体内存活,能逃逸免疫识别并持续感染。病毒吸附到宿主细胞上是病毒感染和扩散的起点,阻断病毒的吸附对于防止病毒感染具有至关重要的意义。HCMV糖蛋白B(gB, glycoprotein B)为HCMV包膜中最丰富的糖蛋白,占包膜蛋白的50 %以上。gB是由跨膜蛋白gp55(glycoprotein 55)和表面蛋白gp116(glycoprotein 116)组成的Ⅰ型膜糖蛋白。gp55位于羧基端,携带占免疫优势的抗原决定簇,gp116位于氨基端,亦携带抗原决定簇,蛋白复合物总长为906个氨基酸。gB的主要致病机制在于提高病毒体穿透力,促进细胞间感染的扩散。研究表明, HCMV gB的中和抗体能阻断病毒感染。吸附抑制和感染力中和实验表明这些抗体能阻止病毒体向细胞穿透。电镜分析显示,抗体能阻断感染的扩散,抗体中和的HCMV病毒体滞留在细胞表面,细胞内的病毒颗粒减少。因此gB是一个非常重要的HCMV治疗靶标。目前HCMVgB抗原性的研究已较为清楚,已发现的三个线性抗体结合位点中,其中两个是病毒中和抗体的靶位。AD1是gB中首要的抗体结合位点,该抗原决定簇由位于552-635氨基酸间的84个氨基酸组成。HCMV感染的病人血清中gB特异性抗体反应中50 %以上直接针对AD1。gB的第二重要的抗体结合位点为AD2,该抗原决定簇由位于50-86氨基酸间的37个氨基酸组成。HCMV感染的病人血清中gB特异性抗体反应中30 %以上针对AD2 (2,3,4)。目前在临床上治疗CMV 的常用药物,如ganciclovir、valganciclovir、
[Abstract]:Purpose meaning Human cytomegalovirus (HCMV) was first isolated from the submandibular gland of a dead infant in 1956 by Smith et al. It was named cytomegalovirus in 1964. It belongs to herpesvirus of 尾 subfamily. It is a double-stranded DNA virus with a diameter of about 180nm. It is a widely spread gene-specific virus. Human infection with the virus is mostly subclinical infection or latent infection. In most normal immune individuals, there is no obvious clinical manifestation, however, the virus can be continuously discharged and spread widely. However, cytomegalovirus (CMV) is harmful to immunocompromised patients, women of childbearing age and children. In people with low immune function, latent viruses are often activated, leading to serious and even fatal consequences. Therefore, more and more attention has been paid to the prevention and treatment of cytomegalovirus. HCMV, like other viruses, can escape immune recognition and continue infection by adsorbing, invading cells, replicating and releasing this cycle in the human body. Virus adsorption on host cells is the starting point for virus infection and spread. Blocking virus adsorption is of vital significance to prevent virus infection. HCMV glycoprotein BngB (glycoprotein B) is the most abundant glycoprotein in HCMV envelope. More than 50% of the envelope protein. GB is a type I membrane glycoprotein, composed of transmembrane protein gp55(glycoprotein 55 and surface protein gp116(glycoprotein 116), which is located at the carboxyl terminal, carrying the dominant antigen determinant, gp116, at the amino end, and also carrying the antigenic determinant. The main pathogenetic mechanism of the total length of 906 amino acids. GB is to improve the penetration of the virus and to promote the spread of intercellular infection. Studies have shown that the neutralizing antibody of, HCMV gB can block the virus infection. Adsorption inhibition and infectivity neutralization experiments show that these antibodies can prevent the virus from penetrating into cells. Electron microscope analysis showed that the antibody could block the spread of the infection, the antibody neutralized HCMV virus remained on the cell surface, and the virus particles in the cells decreased. So GB is a very important target for HCMV therapy. At present, the antigenicity of HCMVgB has been clearly studied. Two of the three linear antibody binding sites have been found, two of which are the target of virus neutralizing antibody. AD1 is the primary antibody binding site in GB. The antigen determinant consists of 84 amino acids located between 552-635 amino acids. The second most important antibody binding site for AD1.gB is more than 50% of the specific antibody response in the sera of patients infected with HCMV. 37 amino acids between 50-86 amino acids. More than 30% of serum GB specific antibody responses in HCMV-infected patients were specific to AD2. Currently commonly used drugs in the treatment of CMV, such as ganciclovirr valganciclovirr,
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R392

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