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

描述（由申请人提供）：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，最实用的人类AIDS动物模型包括用SIVMAC或来源于SIVMAC的嵌合体感染恒河猴。然而，这些模型的有用性受到HIV-1和SIVMAC是不同病毒的事实的限制。基于对物种特异性限制因子的理解，我们已经产生了重组病毒，命名为猿嗜性HIV（stHIV），几乎完全来自HIV-1，但可以在马尾猕猴中复制。在上一个资助周期中，我们利用动物适应性来开发在猪尾猕猴中引起艾滋病的stHIV分离株。此外，我们还研究了已知限制因子对stHIV复制的影响，并揭示了新的、尚未鉴定的抑制剂的活性，这些抑制剂由IFNα诱导，并以种属特异性方式限制慢病毒在原代细胞中的复制。该提案的目的是通过产生感染性分子克隆来进一步开发stHIV，所述感染性分子克隆在猪尾猕猴和恒河猴的粘膜挑战后始终是致病性的，并且基于在人类中传播的HIV-1菌株。为了实现这些目标，我们的研究将包括对猕猴中限制因子多态性和活性的更详细表征，以及这些如何驱动动物中的病毒进化。此外，我们将确定新的IFNα诱导的抑制剂，限制猕猴细胞中的stHIV复制，并产生stHIV变异体，可以克服他们。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非人灵长类动物模型用于HIV-1药物和疫苗开发。

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.