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

HIV-1是艾滋病的病原体。到目前为止，还没有疫苗可用，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，艾滋病毒-1动物模型是必要的。SIV在猕猴体内的感染已被广泛研究。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，主要是因为存在所谓的限制因素。相比之下，SIVMAC已经找到了抵消这些因素的方法。通过研究这些病毒如何对抗限制因素，人们试图开发一种能够在辫子猕猴身上复制的HIV-1变种。这种病毒变种称为嗜猴艾滋病毒(StHIV)，只含有SIVMAC的Vif蛋白。它能够在感染的急性期复制到高水平，但随后不会导致持续的高病毒载量感染并出现类似艾滋病的症状。初步的体外实验结果表明，由于干扰素诱导因子的存在，stHIV在猕猴体内的复制受到限制。最近，一种名为Tetherin的干扰素诱导限制因子被发现，它可以抑制颗粒的释放。HIV-1不能中和猕猴Tetherin。因此，在这项研究中，我们将通过操纵HIV-1的Nef或Vpu蛋白来产生能够中和猕猴Tetherin的stHIV变体。随后，我们将确定克服猕猴Tetherin对于允许stHIV在没有或存在干扰素的情况下在猕猴PBMC中体外复制是否必要和充分，或者是否存在限制stHIV复制的其他限制因素。最后，我们将在体内评估这种病毒变体是否能够在持续高病毒载量的辫尾猕猴中诱导慢性感染，从而导致这些动物患上类似艾滋病的疾病。

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.