Science2014-06-23 3:42 PM

患有AIDS的豚尾猴--一种该疾病的动物模型? HIV-1–induced AIDS in monkeys

论文摘要 

在经过多年的尝试之后,研究人员终于将豚尾猴感染得了一种AIDS样疾病。该进展代表了人们朝着创制某种动物模型所迈出的一大步,有了该模型就可研究活动中的该疾病了。Theodora Hatziioannou及其同事将HIV用一种猴免疫缺陷病毒或SIV的蛋白来修饰,该蛋白熟悉豚尾猴的免疫系统。他们还在他们的许多豚尾猴中耗竭了某种被称作CD8+ T细胞的抗病毒白细胞。研究人员接着将他们修饰的病毒从一个被修饰过的豚尾猴传递或转移给下一个豚尾猴,让该病毒能一路来获得适应性的突变。在第4次传递时,Hatziioannou及她的团队说,该被改变的HIV-1已经获得了克服某种通常会在猴子体内阻断该病毒的被称做束缚因子的重要宿主限制因子的能力,且它开始以进行性增高的水平进行复制。在那一刻,病毒还引起CD4+ T 细胞——这是另外一道重要的防线——数目的剧降,从而导致AIDS样综合症。然而,据研究人员披露,该病毒不会在保留了其CD8+ T细胞的豚尾猴体内进展为AIDS。总而言之,这些发现凸显了HIV在猴子中进行适应所需的特定步骤。但据Hatziioannou及她的团队披露,由于它们涉及豚尾猴体内的CD8+ T细胞的耗竭,因此这些步骤根本不可能会在自然界发生。研究人员希望,进一步研发他们的基于豚尾猴的模型最终可帮助对HIV临床治疗、预防策略及根除病毒的干预措施进行评估。

Abstract 

Primate lentiviruses exhibit narrow host tropism, reducing the occurrence of zoonoses but also impairing the development of optimal animal models of AIDS. To delineate the factors limiting cross-species HIV-1 transmission, we passaged a modified HIV-1 in pigtailed macaques that were transiently depleted of CD8+ cells during acute infection. During adaptation over four passages in macaques, HIV-1 acquired the ability to antagonize the macaque restriction factor tetherin, replicated at progressively higher levels, and ultimately caused marked CD4+ T cell depletion and AIDS-defining conditions. Transient treatment with an antibody to CD8 during acute HIV-1 infection caused rapid progression to AIDS, whereas untreated animals exhibited an elite controller phenotype. Thus, an adapted HIV-1 can cause AIDS in macaques, and stark differences in outcome can be determined by immunological perturbations during early infection.

Editor's Summary

Adapting HIV-1 to infect monkeys, too

HIV-1 replicates well in humans but not in monkeys or mice. On the up side, this reduces the risk of cross-species transmissions, but it makes the study of HIV-1 and AIDS more difficult. Hatziioannou et al. overcame this hurdle by serially passaging HIV-1 in pigtailed macaques. Over time, the HIV-1 acquired mutations that allowed it to adapt to the monkeys. Depleting CD8+ T cells during acute infection resulted in a subset of animals developing an AIDS-like disease by the fourth passage. HIV-1 envelope protein gene selection and the acquisition of mutations in the HIV protein Vpu, which allowed HIV-1 to overcome host restriction by the macaque protein tetherin, accompanied the viral adaptation to the monkeys.

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