2015年3月2日 讯 /生物谷BIOON/ --目前治疗个体HIV感染的最大障碍就是病毒可以在许多由休眠免疫细胞组成的细胞库中隐藏起来，而科学家们普遍认为HIV并不会在这些休眠的免疫细胞中复制，因为病毒必须依赖有活性的细胞器才能生存；而近日刊登在国际著名杂志Cell上的两篇文章中，来自美国国家过敏症和传染病研究所的研究人员通过研究发现，HIV可以通过自身来控制病毒是否进行复制，而潜伏期刚好可以给病毒的生存提供基础，相关研究或可揭示为何唤醒潜伏免疫细胞的HIV治疗策略会最终失败。
在第一篇研究中，研究者表示，当细胞从感染阶段过渡到其它阶段时HIV都会抑制处于活性状态，通过利用计算机模型技术，研究者发现名为Tat的HIV蛋白可以作为病毒开关的控制器，而且通过控制Tat蛋白的水平会持续性改变病毒的状态；相反修饰宿主细胞的状态对病毒的潜伏期没有任何影响。
为了证实研究者的发现，他们利用合成生物学技术将病毒和细胞进行了有效分离，从而直接来控制Tat蛋白，结果发现改变Tat蛋白的水平可以有效开启或关闭病毒的活性，但激活或释放宿主细胞活性却对病毒复制没有任何影响。
在第二篇文章中，研究者Leor S. Weinberger表示，我们同哈佛大学的研究者进行联合研究解释了为何HIV在潜伏期依然可以产生活性，HIV通常通过机体内的粘膜表面进入人体中，在那里其感染的靶向细胞较少，如果HIV在粘膜表面感染并杀灭了较少量的靶向细胞，那么其就会死亡；而如果其在部分粘膜组织细胞中潜伏起来，那么其就会随着潜伏的细胞迁移到其它组织中，寻找更多的靶向细胞进行感染，这样一来就会增强其感染成功的概率；研究者表示，利用基于HIV病人数据的数学模型，我们发现潜伏对于病人来说非常有益，其往往会导致HIV高感染率的发生。（生物谷Bioon.com）
doi:10.1016/j.cell.2015.02.009
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A Hardwired HIV Latency Program
Brandon S. Razooky56, Anand Pai5, Katherine Aull, Igor M. Rouzine, Leor S. Weinberger
Biological circuits can be controlled by two general schemes: environmental sensing or autonomous programs. For viruses such as HIV, the prevailing hypothesis is that latent infection is controlled by cellular state (i.e., environment), with latency simply an epiphenomenon of infected cells transitioning from an activated to resting state. However, we find that HIV expression persists despite the activated-to-resting cellular transition. Mathematical modeling indicates that HIV’s Tat positive-feedback circuitry enables this persistence and strongly controls latency. To overcome the inherent crosstalk between viral circuitry and cellular activation and to directly test this hypothesis, we synthetically decouple viral dependence on cellular environment from viral transcription. These circuits enable control of viral transcription without cellular activation and show that Tat feedback is sufficient to regulate latency independent of cellular activation. Overall, synthetic reconstruction demonstrates that a largely autonomous, viral-encoded program underlies HIV latency—potentially explaining why cell-targeted latency-reversing agents exhibit incomplete penetrance.
doi:10.1016/j.cell.2015.02.017
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An Evolutionary Role for HIV Latency in Enhancing Viral Transmission
Igor M. Rouzine, Ariel D. Weinberger, Leor S. Weinberger
HIV latency is the chief obstacle to eradicating HIV but is widely believed to be an evolutionary accident providing no lentiviral fitness advantage. However, findings of latency being “hardwired” into HIV’s gene-regulatory circuitry appear inconsistent with latency being an evolutionary accident, given HIV’s rapid mutation rate. Here, we propose that latency is an evolutionary “bet-hedging” strategy whose frequency has been optimized to maximize lentiviral transmission by reducing viral extinction during mucosal infections. The model quantitatively fits the available patient data, matches observations of high-frequency latency establishment in cell culture and primates, and generates two counterintuitive but testable predictions. The first prediction is that conventional CD8-depletion experiments in SIV-infected macaques increase latent cells more than viremia. The second prediction is that strains engineered to have higher replicative fitness—via reduced latency—will exhibit lower infectivity in animal-model mucosal inoculations. Therapeutically, the theory predicts treatment approaches that may substantially enhance “activate-and-kill” HIV-cure strategies.
本文分享自http://news.bioon.com/article/6666312.html
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