【正文】 virus is a piece of bad news wrapped in protein. — Peter Medawar (191587), Nobel prize winner ? Viruses (from the Latin virus meaning toxin or poison) 1. 體積非常微小，必須用電子顯微鏡才能看到的非細(xì)胞型微生物； 2. 結(jié)構(gòu)簡單，無完整細(xì)胞結(jié)構(gòu)，僅有一種核酸（ RNA或 DNA）； 3. 嚴(yán)格的細(xì)胞內(nèi)寄生性，只能在一定種類的活細(xì)胞中增殖； 4. 對抗生素不敏感，但對干擾素敏感。 Part I ?決定病毒嗜性的因素 病毒受體 1. 細(xì)胞表面的受體，為糖蛋白，糖脂，粘多糖等。 5. 并非所有表達(dá)病毒受體的細(xì)胞均能支持病毒完成增殖。 101(42): 15190–15195. Transcription of host RNAP II genes is repressed following HSV1 infection. (A and B) Nuclear runon transcription analysis of cellular and viral gene transcription in HeLa cells infected with wildtype virus, . (C) Abundance of RNAP II and GTFs in mockinfected and HSV1infected cells. J Virol 1997, 71(3):203140. J Virol 2022,75(20):987284. 細(xì)胞 mRNA↓ 病毒 mRNA↑ Cell molecular responses to viruses ?Responses to viral attachment: activate or block signaling cascade ?Viral modulation of host cell transcription ?Viral modulation of host cell protein synthesis Virusinduced shutoff of host cell protein synthesis. Murine NIH 3T3 cells (lanes 1 to 4) orMadinDarby bovine kidney cells (lanes 5 and 6) were mock infected (U) or infected (I), respectively, with EMCV (lanes 1 and 2), VSV (lanes 3 and 4), or in?uenza virus (lanes 5 and 6). Microbiol Mol Biol Rev 2022, 64(2):23980. 細(xì)胞 蛋白 ↓ 病毒蛋白 ↑ 病毒抑制宿主細(xì)胞蛋白質(zhì)合成的機制 ? 競爭機制 (VSV) ?大量的病毒 mRNA ?病毒 mRNA與核糖復(fù)合體親和力高 ? 抑制宿主細(xì)胞 mRNA從胞核向胞漿轉(zhuǎn)運 (Adenovirus) ? 促進(jìn)宿主細(xì)胞 mRNA降解 (HSV) ? 抑制細(xì)胞 mRNA翻譯的起始和延伸 (Poliovirus) Schematic illustration of eukaryotic mRNA translation and major sites of viral regulation. Microbiol Mol Biol Rev 2022, 64(2):23980. 內(nèi)部核糖體進(jìn)入位點 (IRES, internal ribosome entry site)是 mRNA 5‘端非編碼區(qū)的一段特殊 RNA結(jié)構(gòu)元件，允許核糖體不依賴帽子結(jié)構(gòu)，而是直接與此序列結(jié)合，并啟動翻譯。 ? 病毒誘導(dǎo)的細(xì)胞死亡 : ? 凋亡（ apoptosis） ? 壞死（ necrosis） Virusinduced cell death: apoptosis and necrosis ?Cells may die through two pathways, necrosis or apoptosis. ?Some viral proteins act directly to induce apoptosis while others act indirectly, by neutralizing the effect of a host cell protein that blocks apoptosis. ?Some virus proteins can block the apoptosis pathway, leading to prolonged cell life and increasing the yield of progeny virions. Blocking of apoptosis is also a characteristic of some transforming viruses. Apoptosis signaling pathways. Abbreviations: DD, death domain。 tBID, truncated Bid。 grey boxes: oncogene). Nat Rev Cancer. 2022, 3(7):47788. cis activation trans activation control element disruption geneproduct alteration Retroviral insertional mutagenesis can occur in humans, as illustrated by acute lymphatic leukemia (ALL) as an unwanted plication of retroviralmediated gene therapy. N Engl J Med. 2022, 350(9):91322. IL2R c deficiency Molecular Architecture of the LMO2 Gene and Break Points for Retroviral Insertion or Chromosomal Translocations. N Engl J Med. 2022, 350(9):91322. ?Acutely transforming retroviruses （ 急性轉(zhuǎn)化逆轉(zhuǎn)錄病毒） ?病毒攜帶的病毒癌基因 (vonc)來自宿主細(xì)胞的原癌基因 (conc) ?病毒癌基因致畸性強 ?多為缺陷病毒，需要輔助病毒 (―helper‖ virus)協(xié)助才能完成增殖 Integration of RNA virus genome and host cell genome RNA virus + + + provirus DNA virus RNA host cell conc. vonc. ? 病毒能夠獨立增殖 ? 癌基因不是病毒增殖所必需的 ? 去除病毒癌基因，病毒失去了致畸能力 ? 缺陷病毒，需要輔助病毒協(xié)助才能完成增殖 ? 癌基因與病毒蛋白融合表達(dá) ? 病毒結(jié)構(gòu)基因被破壞 Protooncogene and oncogene ?Transactivating transforming retroviruses （反式激活的逆轉(zhuǎn)錄病毒） ? 通常編碼一個或多個病毒蛋白，它們可以使細(xì)胞