近日,，倫敦大學(xué)一科學(xué)小組最新發(fā)表在《公共科學(xué)圖書(shū)館·病原學(xué)》（Plos Pathogens）期刊上的論文稱,，他們發(fā)現(xiàn)了艾滋病病毒進(jìn)入細(xì)胞核,，進(jìn)而破壞人體免疫系統(tǒng)引發(fā)艾滋病的關(guān)鍵機(jī)理,。這一發(fā)現(xiàn)為科學(xué)家提供了更有效對(duì)抗艾滋病病毒的新標(biāo)靶，為未來(lái)艾滋病的治療帶來(lái)了新希望,。
艾滋病病毒通過(guò)體液,，主要是血液和精液傳播。病毒一旦進(jìn)入血液,，會(huì)感染包括巨噬細(xì)胞在內(nèi)的免疫系統(tǒng)關(guān)鍵部件,。病毒會(huì)進(jìn)入巨噬細(xì)胞的細(xì)胞核，與巨噬細(xì)胞的DNA（脫氧核糖核酸）結(jié)合,，自行復(fù)制并擴(kuò)散到全身各處,。艾滋病病毒要進(jìn)入到細(xì)胞核內(nèi),，必須通過(guò)核孔復(fù)合體（NPC）,，這也是病毒通往細(xì)胞核的大門(mén)。但到目前為止,，艾滋病病毒是如何通過(guò)核孔復(fù)合體的,，其機(jī)制尚不得而知。
包括英國(guó)倫敦大學(xué)學(xué)院研究人員在內(nèi)的一研究小組研究發(fā)現(xiàn),，艾滋病病毒衣殼會(huì)與細(xì)胞核孔復(fù)合體上的Nup358蛋白綁定,，進(jìn)而讓病毒進(jìn)入細(xì)胞核，與DNA結(jié)合,。這個(gè)衣殼蛋白就如同一把鑰匙,，打開(kāi)了核孔復(fù)合體這把鎖，使得艾滋病病毒最終“破門(mén)而入”。
論文第一作者,、倫敦大學(xué)學(xué)院的托爾斯滕·夏勒博士指出,，過(guò)去幾乎所有的艾滋病治療都是瞄準(zhǔn)病毒本身，但艾滋病病毒很容易發(fā)展變化,，從而對(duì)藥物影響免疫，使藥物無(wú)效,。這一新研究表明,，瞄準(zhǔn)宿主體內(nèi)蛋白而不是病毒本身會(huì)更加有效。如果能夠設(shè)計(jì)出一種藥物,，其標(biāo)靶是蛋白,，就會(huì)起到阻止病毒進(jìn)化的效果。
領(lǐng)導(dǎo)該項(xiàng)研究的倫敦大學(xué)學(xué)院格雷格·托爾斯教授指出,，對(duì)于艾滋病的治療來(lái)說(shuō),，能夠領(lǐng)先一步來(lái)開(kāi)發(fā)出新的治療策略非常重要。艾滋病發(fā)現(xiàn)以來(lái),，雖然科學(xué)家在治療艾滋病病毒感染的抗逆轉(zhuǎn)錄病毒藥物的研究開(kāi)發(fā)上已經(jīng)取得了巨大的進(jìn)步,，但病毒對(duì)這些藥物的抵抗力也變得越來(lái)越強(qiáng)，使得該疾病的治療依然難有成效,。在新研究中,，科學(xué)家發(fā)現(xiàn)了允許艾滋病病毒進(jìn)入細(xì)胞核的“鎖和鑰匙”。病毒一旦進(jìn)入細(xì)胞核,，就可以開(kāi)始進(jìn)行自我復(fù)制,，然后幾乎是毫不受限制地在體內(nèi)擴(kuò)散。如果能夠使用藥物阻斷病毒進(jìn)入細(xì)胞核的路徑,，就能夠阻止病毒在體內(nèi)的擴(kuò)散,，這將是一種對(duì)抗艾滋病病毒的新方法。（生物谷Bioon.com）
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doi:10.1371/journal.ppat.1002439
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HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency
Torsten Schaller, Karen E. Ocwieja, Jane Rasaiyaah, Amanda J. Price, Troy L. Brady, Shoshannah L. Roth, Stéphane Hué, Adam J. Fletcher, KyeongEun Lee, Vineet N. KewalRamani, Mahdad Noursadeghi, Richard G. Jenner, Leo C. James, Frederic D. Bushman, Greg J. Towers
Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment.
