Overcoming macaque Tetherin to generate an improved animal model for HIV/AIDS

克服猕猴 Tetherin 以产生改进的艾滋病毒/艾滋病动物模型

• 批准号: 209594654
• 负责人: Dr. Julia Bitzegeio
• 金额: --
• 依托单位: Aaron Diamond AIDS Research Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/209594654?language=en
• 关键词: Overcoming; macaque; Tetherin; generate; improved

HIV-1 is the causative agent of AIDS. So far no vaccine is available and due to the high mutability of the virus resistance to available antiretroviral therapies are emerging. For the development of an effective vaccine and new antiretroviral drugs an HIV-1 animal model is necessary. SIV infection in macaques has been studied intensively. However, due to high genetic divergence between HIV-1 and SIV this animal model cannot be used for preclinical studies. HIV-1 is not able to replicate in non-human primates mainly due to the presence of so called restriction factors. In contrast SIVMAC has developed ways to counteract these factors. By studying how these viruses antagonize restriction factors, attempts have been made to develop an HIV-1 variant that is able to replicate in pigtailed macaques. This virus variant called simian tropic HIV (stHIV) contains only the Vif protein of SIVMAC. It is able to replicate to high levels during the acute phase of infection but then does not lead to a sustained high viral load infection with AIDS like symptoms. Preliminary results in vitro indicate that stHIV replication in macaques is limited due to the presence of Interferon (IFN) inducible factors. Recently, an IFN inducible restriction factor called Tetherin that inhibits particle release has been discovered. HIV-1 is not able to counteract macaque Tetherin. Therefore, in this study, we will generate stHIV variants able to counteract macaque Tetherin by either manipulating the Nef or the Vpu protein of HIV-1. Subsequently, we will determine whether overcoming macaque Tetherin is necessary and sufficient to allow stHIV to replicate in vitro in macaque PBMCs in the absence or presence of IFN-¿ or whether additional restriction factors are present limiting stHIV replication. Finally, we will evaluate in vivo if this virus variant is able to induce a chronic infection in pigtailed macaques with persistent high viral loads, leading to an AIDS-like disease in these animals.

HIV-1是艾滋病的病原体。到目前为止还没有疫苗，而且由于病毒的高度变异性，对现有抗逆转录病毒疗法的抗药性正在出现。为了开发有效的疫苗和新的抗逆转录病毒药物，HIV-1动物模型是必要的。SIV在猕猴中的感染已被深入研究。然而，由于HIV-1和SIV之间的高度遗传差异，该动物模型不能用于临床前研究。HIV-1不能在非人类灵长类动物中复制，主要是由于存在所谓的限制因子。与此相反，SIVMAC已开发出抵消这些因素的方法。通过研究这些病毒如何对抗限制性因子，人们试图开发一种能够在长尾猕猴中复制的HIV-1变体。这种被称为嗜猴性HIV（stHIV）的病毒变体只含有SIVMAC的Vif蛋白。它能够在感染的急性期复制到高水平，但不会导致持续的高病毒载量感染，并出现艾滋病样症状。体外试验的初步结果表明，由于干扰素（IFN）诱导因子的存在，stHIV在猕猴中的复制是有限的。最近，已经发现了一种称为Tetherin的抑制颗粒释放的IFN诱导型限制因子。HIV-1不能对抗猕猴的Tetherin。因此，在这项研究中，我们将通过操纵HIV-1的Nef或Vpu蛋白来产生能够抵消猕猴Tetherin的stHIV变体。随后，我们将确定是否克服猕猴Tetherin是必要的和足够的，让stHIV在体外复制猕猴PBMCs在IFN-γ的存在或不存在或是否存在额外的限制因素限制stHIV复制。最后，我们将在体内评估这种病毒变体是否能够在具有持续高病毒载量的短尾猕猴中诱导慢性感染，从而导致这些动物出现艾滋病样疾病。