Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo
Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo
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DOI：
10.1128/jvi.00451-16
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发表时间：
2016-07-01
影响因子：
5.4
通讯作者：
Dittmer, Ulf
中科院分区：
文献类型：
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作者：
Lavender, Kerry J.;Gibbert, Kathrin;Dittmer, Ulf
虽然所有12种亚型的人干扰素α（IFN-α）结合相同的受体，最近的结果表明，它们引起独特的宿主反应，并显示不同的病毒感染的控制不同的功效。IFN-α 2亚型目前正在HIV-1临床试验中，但它并没有持续降低HIV-1患者的病毒载量，也不是体外抗HIV-1最有效的亚型。我们现在在人源化小鼠中证明，当以相同的高临床剂量递送时，人IFN-α 14亚型具有非常有效的抗HIV-1活性，而IFN-α 2则没有。在急性感染的预防和治疗中，IFN-α 14而不是IFN-α 2显著抑制HIV-1复制和前病毒载量。此外，HIV-1诱导的免疫过度活化是疾病进展的一个指标，IFN-α 14可以降低，但IFN-α 2不能。尽管无效的IFN-α 2治疗与CD 8（+）T细胞活化相关，但成功的IFN-α 14治疗与内在和先天免疫增加相关，包括显著更高的Tetherin和MX2诱导，HIV-1前病毒DNA中APOBEC 3G特征突变增加，以及TRAIL（+）NK细胞频率更高。这些结果将IFN-α 14确定为一种有效的新治疗药物，其作用机制与抗逆转录病毒药物不同。IFN-α 14在体内减少病毒血症和前病毒载量的能力表明，它具有作为HIV-1感染治愈策略的组成部分的强大潜力。这些结果的广泛意义是，每个人的IFN-α亚型的抗病毒疗效应评估对特定的病毒正在treated.IMPORTANCEThe天然存在的抗病毒蛋白IFN-α 2是用于治疗肝炎病毒，但已被证明是无效的，而对艾滋病毒的三联疗法与抗逆转录病毒（ARV）药物相比。虽然抗逆转录病毒药物抑制艾滋病毒的复制，但它们不能完全清除感染。由于IFN-α通过与ARV不同的机制起作用，并且已被证明可以减少HIV前病毒载量，因此正在进行临床试验以测试IFN-α 2与ARV联合是否可以根除HIV-1感染。IFN-α实际上是一个由12种不同蛋白质组成的家族，每种IFN-α亚型对不同的病毒具有不同的功效。在这里，我们使用含有人类免疫系统的小鼠，因此它们可以感染HIV。通过这个模型，我们证明了虽然IFN-α 2对HIV只有微弱的效果，但IFN-α 14非常有效。这一发现将IFN-α 14确定为更强大的IFN-α亚型，用于旨在治愈HIV的联合治疗试验。
Although all 12 subtypes of human interferon alpha (IFN-alpha) bind the same receptor, recent results have demonstrated that they elicit unique host responses and display distinct efficacies in the control of different viral infections. The IFN-alpha 2 subtype is currently in HIV-1 clinical trials, but it has not consistently reduced viral loads in HIV-1 patients and is not the most effective subtype against HIV-1 in vitro. We now demonstrate in humanized mice that, when delivered at the same high clinical dose, the human IFN-alpha 14 subtype has very potent anti-HIV-1 activity whereas IFN-alpha 2 does not. In both postexposure prophylaxis and treatment of acute infections, IFN-alpha 14, but not IFN-alpha 2, significantly suppressed HIV-1 replication and proviral loads. Furthermore, HIV-1- induced immune hyperactivation, which is a prognosticator of disease progression, was reduced by IFN-alpha 14 but not IFN-alpha 2. Whereas ineffective IFN-alpha 2 therapy was associated with CD8(+) T cell activation, successful IFN-alpha 14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of tetherin and MX2, increased APOBEC3G signature mutations in HIV-1 proviral DNA, and higher frequencies of TRAIL(+) NK cells. These results identify IFN-alpha 14 as a potent new therapeutic that operates via mechanisms distinct from those of antiretroviral drugs. The ability of IFN-alpha 14 to reduce both viremia and proviral loads in vivo suggests that it has strong potential as a component of a cure strategy for HIV-1 infections. The broad implication of these results is that the antiviral efficacy of each individual IFN-alpha subtype should be evaluated against the specific virus being treated.IMPORTANCEThe naturally occurring antiviral protein IFN-alpha 2 is used to treat hepatitis viruses but has proven rather ineffective against HIV in comparison to triple therapy with the antiretroviral (ARV) drugs. Although ARVs suppress the replication of HIV, they fail to completely clear infections. Since IFN-alpha acts by different mechanism than ARVs and has been shown to reduce HIV proviral loads, clinical trials are under way to test whether IFN-alpha 2 combined with ARVs might eradicate HIV-1 infections. IFN-alpha is actually a family of 12 distinct proteins, and each IFN-alpha subtype has different efficacies toward different viruses. Here, we use mice that contain a human immune system, so they can be infected with HIV. With this model, we demonstrate that while IFN-alpha 2 is only weakly effective against HIV, IFN-alpha 14 is extremely potent. This discovery identifies IFN-alpha 14 as a more powerful IFN-alpha subtype for use in combination therapy trials aimed toward an HIV cure.