Overcoming Host Restriction Factors to Develop Better Animal Models for HIV/AIDS

描述(申请人提供)：HIV-1是人类艾滋病的主要原因，不能在大多数非人类物种中复制。因此，人类艾滋病最实用的动物模型是用SIVMAC感染恒河猴或由SIVMAC衍生的嵌合体。然而，由于HIV-1和SIVMAC是不同的病毒，这些模型的实用性受到限制。基于对物种特异性限制因素的理解，我们产生了重组病毒，称为嗜猴HIV(StHIV)，它几乎完全来自HIV-1，但可以在辫子猕猴中复制。在上一个资助周期中，我们利用动物适应技术开发出了能在小尾猴身上引起艾滋病的stHIV分离株。此外，我们还研究了已知限制因素对stHIV复制的影响，并揭示了由干扰素α诱导并以物种特异性方式限制原代细胞中慢病毒复制的新型、尚未确定的抑制剂的活性。这项提议的目的是通过产生具有感染性的分子克隆来进一步发展stHIV，这些分子克隆在猪尾猕猴和猕猴的黏膜挑战后始终具有致病性，并且基于在人类中传播的HIV-1毒株。为了实现这些目标，我们的研究将包括更详细地描述猕猴中限制因子的多态性和活性，以及这些因素如何推动动物中的病毒进化。此外，我们将确定新型干扰素α诱导的抑制物，以限制stHIV在猕猴细胞中的复制，并产生能够克服它们的stHIV变体。我们的初步数据表明，这些目标是可行的，并将导致stHIV的成功开发，这一进展有可能改变HIV-1药物和疫苗开发的非人类灵长类模型。

DESCRIPTION (provided by applicant): HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most non-human species. Therefore, the most practical animal model of human AIDS consists of infection of rhesus macaques with SIVMAC or chimeras derived from SIVMAC. However, the usefulness of these models is limited by the fact that HIV-1 and SIVMAC are distinct viruses. Based on an understanding of species-specific restriction factors, we have generated recombinant viruses, named simian tropic HIV (stHIV), that are almost entirely derived from HIV-1 but can replicate in pigtailed macaques. During the last funding cycle we have used animal adaptation to develop stHIV isolates that cause AIDS in pigtail macaques. Additionally, we have studied the effects of known restriction factors on stHIV replication and unveiled the activity of novel, as yet unidentified, inhibitors that are induced by IFNα and limit lentiviral replication in a species-specific manner in primary cells. The aims of this proposal are to further develop stHIV by generating infectious molecular clones that are consistently pathogenic following mucosal challenges in both pigtail and rhesus macaques and are based on HIV-1 strains circulating in humans. To achieve these aims our studies will include a more detailed characterization of restriction factor polymorphism and activity in macaques and how these drive virus evolution in animals. Additionally, we will identify novel IFNα-induced inhibitors that limit stHIV replication in macaque cells and generate stHIV variants that can overcome them. Our preliminary data suggest that these goals are feasible and will lead to the successful development of stHIV, an advance that has the potential to transform non- human primate models for HIV-1 drug and vaccine development.