《病毒学双语版课件Chapter6-2.ppt》由会员分享，可在线阅读，更多相关《病毒学双语版课件Chapter6-2.ppt（38页珍藏版）》请在三一文库上搜索。
1、Chapter 6: Infection Slide 1/38 Infection: Part 2 Part 1 红 录 劝 蘸 取 俩 袱 笛 质 湿 坡 晦 创 恶 瓶 伐 绵 己 港 如 损 尾 馁 爆 搬 栅 混 吊 碾 非 专 袒 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 2/38 Evasion of Immune Responses by Viruses Inhibition of MHC I-Restricted Antig
2、en Presentation:Inhibition of MHC I-Restricted Antigen Presentation: CTLs can only respond to foreign antigens presented by MHC I complexes on the target cell. A number of viruses interfere with MHC I expression or function to disrupt this process virus infections of the eye are also quite common. 块
3、 喳 蓟 瘩 惨 抿 氛 砾 扼 酵 亢 棘 舒 昌 甥 适 朵 俗 录 吵 诫 肝 腮 簇 跟 闯 窘 霜 玛 恢 腑 釜 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 11/38 The Alimentary Canal: Viruses may infect the alimentary canal via the mouth, oropharynx, gut, or rectum, although viruses which infe
4、ct the gut via the oral route must survive passage through the stomach, an extremely hostile environment with a very low pH good medical practice such as the sterilization of surgical instruments) & vaccination, which makes use of the immune system to combat virus infections. Most of the damage to c
5、ells during virus infections occurs very early, often before the clinical symptoms of disease appear. This makes the treatment of virus infection very difficult, & therefore, in addition to being cheaper, prevention of virus infection is undoubtedly better than cure. 法 扦 尝 谱 绝 氯 立 尾 彻 愉 脱 骚 咎 辙 怒 罢
6、幌 咒 绕 拆 甭 糟 滞 盐 侦 形 麓 泥 烈 塑 初 捕 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 25/38 Virus Vaccine Design To design effective vaccines, it is important to understand both the immune response to virus infection & the stages of virus replication that
7、 are appropriate targets for immune intervention. To be effective, vaccines must stimulate as many of the bodys defence mechanisms as possible. In practice, this usually means trying to mimic the disease, without of course causing pathogenesis - for example, the use of nasally administered influenza
8、 vaccines & orally administered poliovirus vaccines. To be effective, it is not necessary to get 100% uptake of vaccine. Herd immunity results from the break in transmission of a virus which occurs when a sufficiently high proportion of a population has been vaccinated. This strategy is most effecti
9、ve where there is no alternative host for the virus, e.g. measles, & in practice is the situation that usually occurs since it is impossible to achieve 100% coverage with any vaccine. 怎 跌 菠 漆 袱 誓 萨 丑 伤 体 接 川 缀 哗 倘 委 坚 效 紧 瘤 公 蝗 努 残 岭 踪 房 用 笑 臻 瓮 株 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件
10、C h a p t e r 6 - 2 Chapter 6: Infection Slide 26/38 DNA Vaccines These are the newest type of vaccine & consist of only a DNA molecule encoding the antigen(s) of interest & possibly, costimulatory molecules such as cytokines. The concept behind these vaccines is that the DNA component will be expre
11、ssed in vivo, creating small amounts of antigenic protein which serve to prime the immune response so that a protective response can be rapidly generated when the real antigen is encountered. In theory, these vaccines could be manufactured quickly & should efficiently induce both humoral & cell- med
12、iated immunity. 貉 橱 担 沛 办 玫 横 朋 搁 树 镰 铸 仙 夯 洲 剁 敌 耽 悲 壳 焊 饶 燕 传 魔 讫 啸 井 譬 碘 魏 厦 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 27/38 Subunit Vaccines These consist of only some components of the virus, sufficient to induce a protective immune respo
13、nse but not enough to allow any danger of infection. In general terms, they are completely safe, except for very rare cases in which adverse immune reactions may occur. Unfortunately, at present, they are also the least effective & most expensive type of vaccines. The major technical problems associ
14、ated with subunit vaccines are their relatively poor antigenicity & the need for new delivery systems, such as improved carriers & adjuvants. There are several categories of such vaccines:There are several categories of such vaccines: Synthetic vaccines, such as short, chemically synthesized peptide
15、s. Recombinant vaccines, produced by genetic engineering. Virus vectors, i.e. recombinant virus genomes genetically manipulated to express protective antigens from (unrelated) pathogenic viruses.舒 茶 乓 薛 扛 时 呢 但 集 误 潮 摘 怠 满 编 数 赂 桐 嚷 掐 剐 侵 勘 塞 铡 抠 啮 和 悬 扔 搀 变 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学
16、 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 28/38 Inactivated Vaccines Produced by exposing the virus to a denaturing agent under precisely controlled conditions. The objective is to cause loss of virus infectivity without loss of antigenicity. Inactivated vaccines have certain advanta
17、ges, such as generally being effective immunogens (if properly inactivated), being relatively stable, & carrying little or no risk of vaccine-associated virus infection (if properly inactivated). It is not possible to produced inactivated vaccines for all viruses, since denaturation of virus protein
18、s may lead to loss of antigenicity, e.g. measles virus. Although relatively effective, killed vaccines are sometimes not as effective at preventing infection as live virus vaccines, often because they fail to stimulate protective mucosal & cell-mediated immunity to the same extent. These vaccines ma
19、y contain virus nucleic acids, which may themselves be a source of infection, either of their own accord (e.g. (+)sense RNA virus genomes) or after recombination with other viruses. 轻 袒 姚 柠 情 韶 悄 忘 啃 阿 互 迷 指 卉 亭 章 麦 肘 吕 臭 纳 辨 亨 由 管 嫡 尧 涝 赴 稼 悟 赣 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C
20、h a p t e r 6 - 2 Chapter 6: Infection Slide 29/38 Live (Attenuated) Virus Vaccines Attenuated viruses with reduced pathogenicity stimulate an immune response without causing disease. The vaccine strain may be a naturally occurring virus (e.g. use of cowpox virus by Edward Jenner to vaccinate agains
21、t smallpox) or artificially attenuated in vitro (e.g. oral poliomyelitis vaccine produced by Albert Sabin). The advantage of attenuated vaccines is that they are good immunogens & induce long-lived, appropriate immunity. These vaccines may be biochemically & genetically unstable & may either lose in
22、fectivity or revert to virulence unexpectedly. Despite intensive study, it is not possible to produce an attenuated vaccine to order, & there is no general mechanism by which all viruses can be reliably & safely attenuated. Inappropriate use of live virus vaccines, for example, in immunocompromised
23、hosts or during pregnancy, may lead to vaccine-associated disease, whereas the same vaccine given to a healthy individual may be perfectly safe. 鸦 粹 溃 摩 垃 尿 版 患 掘 揩 用 盟 虑 眉 蔽 窜 肝 育 瞥 按 穿 剁 谜 盘 印 乎 茅 释 线 哈 诺 摈 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infectio
24、n Slide 30/38 Virus Vectors & Gene Therapy Viruses are being developed as gene delivery systems for the treatment of inherited & also acquired diseases. The first human trial to treat children with immunodeficiency resulting from a lack of the enzyme adenosine deaminase (ADA) began in 1990 & showed
25、encouraging results. Like most of the initial attempts, this trial used recombinant retrovirus genomes as vectors. A variety of different viruses are now being tested as potential vectors & a large number of different trials are underway. Non-virus methods of gene delivery including liposome/DNA com
26、plexes, peptide/DNA complexes & direct injection of recombinant DNA are also under active investigation. 棒 捎 鸭 童 巡 阻 告 瞩 樱 愧 沟 董 讶 肤 症 术 卜 乌 札 少 邯 布 绸 害 汤 囱 小 岁 脱 糖 绸 割 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 31/38 Chemotherapy of Virus Infe
27、ctions The alternative to vaccination is to attempt to treat virus infections using drugs which block virus replication. Historically, discovery of antiviral drugs has been largely fortuitous. Spurred on by successes in the treatment of bacterial infections with antibiotics, drug companies launched
28、huge blind-screening programmes to identify chemical compounds with antiviral activity, with relatively little success. The key to the success of any antiviral drug lies in its specificity. Almost any stage of virus replication can be a target for a drug, but the drug must be more toxic to the virus
29、 than the host. 莫 望 卓 遵 宽 维 恶 饼 懂 囤 辕 肠 泣 移 坏 娜 佣 晓 唇 衬 酱 础 褐 润 缅 胡 素 悦 班 愧 沦 刹 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 32/38 Any of the Stages of Virus Replication can be A Target for Antiviral Intervention. The attachment attachment phase
30、of replication can be inhibited in two ways: by agents which mimic the virus-attachment protein (VAP) & bind to the cellular receptor by agents which mimic the receptor & bind to the VAP It is difficult to target specifically the penetration/ penetration/ uncoatinguncoating stages of virus replicati
31、on as relatively little is known about them. Uncoating in particular is largely mediated by cellular enzymes & is therefore a poor target for intervention, although like penetration, it is often influenced by one or more virus proteins. 祭 给 菠 荫 察 恒 抱 旋 浸 栽 衷 徒 既 浊 缨 早 蛆 眺 结 兴 移 芋 酱 靳 由 饰 栓 硅 趋 绒 采 筑
32、 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 33/38 Amantadine & Rimantadine Amantadine & Rimantadine are active against influenza A viruses. The action of these closely related agents is to block cellular membrane ion channels. The target for bo
33、th drugs is the influenza matrix protein (M2), but resistance to the drug may also map to the hemagglutinin gene. This biphasic action results from the inability of drug- treated cells to lower the pH of the endosomal compartment (a function normally controlled by the M2 gene product), which is esse
34、ntial to induce conformational changes in the HA protein to permit membrane fusion. 友 旦 倔 赊 诽 苏 蜀 转 长 铺 咳 蚕 贴 缴 帛 可 刘 组 哺 渠 稀 欢 窟 存 昭 洽 已 峭 凛 旧 糯 扦 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 34/38 Nucleoside Analogues Many viruses have evolved
35、their own specific enzymes to replicate virus nucleic acids preferentially at the expense of cellular molecules. There is often sufficient specificity in virus polymerases to provide a target for an antiviral agent, & this method has produced the majority of the specific antiviral drugs currently in
36、 use. The majority of these drugs function as polymerase substrates (i.e. nucleoside/nucleotide) analogues, & their toxicity varies considerably from some which are well tolerated (e.g. acyclovir) to others which are quite toxic (e.g. AZT). There is a problem with the pharmacokinetics of these nucle
37、oside analogues - their typical serum half-life is 1-4 h. 哺 电 野 鳖 轮 逝 碉 触 沿 谜 颇 砌 谎 旧 赢 磷 拦 董 怕 谊 络 平 汛 节 趴 躯 踏 箩 说 侣 馅 站 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 35/38 Nucleoside Analogues Nucleoside analogues are, pro-drugs, since they need
38、 to be phosphorylated before becoming effective. This is the key to their selectivity: Acyclovir is phosphorylated by HSV thymidine kinase 200 times more efficiently than by cellular enzymes Ganciclovir is 10 times more effective against CMV than acyclovir, but must be phosphorylated by a kinase enc
39、oded by CMV gene UL97 before it becomes pharmaceutically active A series of other nucleoside analogues derived from these drugs & active against herpesviruses have been developed, e.g. valciclovir & famciclovir. These compounds have improved pharmacokinetic properties such as better oral bioavailabi
40、lity & longer half lives. 川 烛 庶 耐 蹄 愁 泻 博 惰 诱 畔 遗 形 戮 匝 醉 细 疯 刮 照 鞋 埂 周 胰 睹 筏 膛 污 缸 脖 拇 拼 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 36/38 Non-Nucleoside Analogues Foscarnet is an analogue of pyrophosphate which interferes with the binding of i
41、ncoming nucleotide triphosphates by virus DNA polymerases. Ribavirin has a very wide spectrum of activity against many different viruses, especially against many ()sense RNA viruses. The way in which these effects are caused are not entirely clear, but may include mechanisms such as: Ribavirin 5 mon
42、ophosphate inhibits inosine monophosphate dehydrogenase & decreases intracellular pools of guanosine triphosphate Ribavirin 5 triphosphate inhibits guanylyl transferase & the 5 capping of mRNAs Ribavirin 5 triphosphate inhibits initiation & elongation by RNA polymerases Ribavirin is thus quite unlik
43、e the other nucleoside analogues described above & its use is likely to become much more widespread in future. 偷 敝 辰 厌 欣 稳 候 帘 趣 队 晋 登 谜 胚 篱 必 皮 诲 冉 金 南 改 闪 韭 掉 莆 菠 议 糙 逞 伪 亥 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 37/38 Inhibition of Other
44、Stages of Replication Virus gene expressiongene expression is less amenable to chemical intervention than genome replication, because viruses are much more dependent on the cellular machinery for transcription, mRNA splicing, cytoplasmic export, & translation than for replication. To date, no clinic
45、ally useful drugs which discriminate between virus & cellular gene expression have been developed. As with penetration & uncoating, for the majority of viruses, the processes of assembly, maturation & releasematuration & release are poorly understood, & have not yet become targets for antiviral inte
46、rvention. An exception is the anti-influenza drug Relenza, an inhibitor of influenza virus neuraminidase. Neuraminidase is involved in the release of virus particles budding from infected cells & this drug is believed to reduce the spread of virus to other cells. 话 业 氢 瓶 叹 梆 烷 袭 烦 挠 刚 叛 缎 数 疙 沉 副 程
47、掳 嗡 级 湘 埃 奔 养 秸 舒 焰 陕 报 弊 呆 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 Chapter 6: Infection Slide 38/38 Summary Virus infection is a complex, multi-stage interaction between the virus & the host organism. The course & eventual outcome of any infection is the result of a
48、balance between host & virus processes. Host factors involved include exposure to different routes of virus transmission & the control of virus replication by the immune response. Virus processes include the initial infection of the host, spread throughout the host & the regulation of gene expressio
49、n to evade the immune response. Medical intervention against virus infections includes the use of vaccines to stimulate the immune response & drugs to inhibit virus replication. Molecular biology is stimulating the production of a new generation of antiviral drugs & vaccines. 膏 仍 司 剩 璃 更 想 卯 旅 祷 糜 宋 搅 熏 粹 梨 吊 牧 老 纫 壕 地 鸟 诛 阴 揉 令 泪 篆 嘎 谜 藻 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2 病 毒 学 双 语 版 课 件 C h a p t e r 6 - 2