2008-08-09

[影片] 標的HIV複製



英文聽打:wl ;中文翻譯:kelly, wl ;校稿:豬排飯, wl

The replication of HIV1 is a multiple-step process. Each step is crucial to a successful replication and is therefore a potential target for anti-retrovirus drugs. Step one is the infection of suitable host cells, such as CD4 positive T lymphocytes.

Entry of the HIV into the cells requires the presence of certain receptors on the cell surface: CD4 receptors and co-receptors, such as CCR5 or CXCR4. These receptors interact with protein complexes which are embeded in the virus envelope. These complexes are composed of two glycoproteins and extracellular gp120 and transmembrane gp41.

When HIV approaches the target cells gp120 binds to the CD4 receptors; this process is termed attachment. In promote further binding toward coreceptors, coreceptor binding result in the conformational changes in gp120. This allows gp41 to unfold and insert its hydrophobic terminus into the cell membranes; gp41 then folds back on the cells. This draws the virus toward the cells and facilitates the fusion of the membranes.

The virus nuclear capsid enters the host cells and breaks open releasing two virus RNA strains and three essential replication enzymes: integrase, protease, and reverse transcriptase. Reverse transcriptase begins the reverses transcription of virus RNAs. It has two catalytic domains: the virus nuclearase H active site and the polymerase active site. Here, Single strand virus RNA is transcribed into the RNA-DNA double helixes. Virus nuclearase H breaks down the RNA. The polymerase then completes the remaining DNA strand to form a DNA double helix. Now integrase is the direction. It clicks the di-nucleotides from each 3’ end of the DNA, creating two sticky ends. Integrase then transfers the DNA into the cell nucleus and facilities its integration into the host cell’s genome.

The host cell genome now contains the genetic information of HIV. Activation of the cells induces the transcription of whole virus DNA to messenger RNA. The virus messenger RNA migrates into the cytoplasm where build-in blocks for new virus are synthesized. Some of them have to be processed by the virus protease. Protease clicks longer proteins into smaller core proteins. This step is the crucial to create an infectious virus. Two virus RNA strands and replication enzymes then come together and core proteins assembly around them forming the capsid.

These immature virus particles leave the cell requiring eukaryote envelope coat and virus proteins. The virus matures and becomes ready to infect other cells. HIV replicates millions of times per day destroying the host immune cells and eventually causing diseases for progression. Drugs which interfere with steps of virus replication can stop the fetal process. Entry into the host cells can be blocked by fusion inhibitors, for example. Inhibition of reverse transcripase by nucleoside inhibitors or by non-nucleoside reverse transcriptase inhibitors is parts of standard of antiretrovirus regimens. The action of integratase can be blocked. Protease inhibitors are also parts of standard antiretrovirus therapy. Each blockstep in virus replication is a step toward a better control of HIV diseases.

HIV1的自我複製是一個多步驟的複製過程。每一個單一步驟之於一個成功的複製過程都相當重要,也因此過程中每一個步驟都可以成為抗反轉錄酶病毒藥物(HIV為反轉錄酶病毒)的潛在標的。
HIV1的第一個感染步驟是感染合適的宿主細胞,如CD4陽性T淋巴球。HIV病毒在進入細胞時需要先與細胞表面上特定的受體結合,例如CD4受體及協同受體如CCR5或CXCR4。這些受體再更進一步和嵌入在病毒包膜的蛋白質複合體相互作用。病毒包膜的蛋白質複合體往往由兩個醣蛋白、胞外蛋白gp120及跨膜蛋白gp41組成。

當HIV接近標的細胞時,胞外蛋白gp120會和宿主細胞的CD4受體結合(此過程稱之為附著),另外,在與協同受體進一步結合的過程中,gp120的構形產生了改變。此構形改變允許跨膜蛋白gp41展開並將其親油端插入宿主細胞的細胞膜內;接著,插入宿主細胞並展開的跨膜蛋白gp41重新摺疊。此過程驅使病毒更接近細胞,並促進兩者細胞膜的融合。病毒核衣殼進入宿主細胞後被打開,釋放出兩條病毒RNA及三個必要的複製酶:整合酶、蛋白酶及反轉錄酶。反轉錄酶用來起始病毒RNA的反轉錄作用。此酵素有兩個催化區域:病毒核酸酶H活性區及聚合酶活性區。在這整個複製作用中,單股病毒RNA被轉錄成DNA-RNA雙螺旋。病毒核酸酶H裂解RNA,然後聚合酶完成剩餘的DNA股以形成DNA雙螺旋。

此時上場的整合酶是個關鍵。它從DNA的3’端切下兩個核苷酸,於是在DNA的兩頭創造了黏性端。整合酶接著將DNA轉移至細胞核並促進其和宿主細胞基因體的接合整併。這時宿主細胞基因體包含了HIV的遺傳信息。細胞的活化將誘導整個病毒DNA轉錄成信息RNA。此病毒信息RNA遷移至細胞質中,並在此合成病毒的構件。其中一些病毒蛋白需要經過病毒蛋白酶的處理。蛋白酶將長蛋白分解成小的核心蛋白。此步驟對創造一個具感染性的病毒而言相當重要。兩條病毒RNA及複製酶接著和周圍的核心蛋白組合成衣殼。這些未成熟的病毒顆粒離開細胞時便獲得源自真核宿主細胞膜的套膜及病毒膜蛋白。病毒成熟後便可以感染其他細胞。

HIV一天複製數百萬次,摧毀宿主的免疫細胞,而最終造成疾病的進程。具干擾病毒複製功能的藥物可以阻止此致死的過程。例如,進入宿主細胞的過程可被融合抑制劑阻止。藉由核苷抑制劑或非核苷反轉錄酶抑制劑來阻斷反轉錄酶是標準抗反轉錄病毒療法的一部份。整合酶的活動亦可被阻止。蛋白酶抑制劑也是一種標準的抗反轉錄病毒治療。每一個阻止病毒複製的步驟都可以對HIV疾病產生更好的控制。

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