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，在大多数非人类物种中无法复制。因此，人类艾滋病最实用的动物模型是恒河猴感染SIVMAC或由SIVMAC衍生的嵌合体。然而，这些模型的实用性受到HIV-1和SIVMAC是不同病毒这一事实的限制。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，命名为猴热带HIV (stHIV)，它几乎完全来源于HIV-1，但可以在长尾猕猴中复制。在上一个资助周期中，我们利用动物适应技术开发了能在长尾猕猴中引起艾滋病的shiv分离株。此外，我们还研究了已知的限制性因子对stHIV复制的影响，并揭示了由stHIV诱导的尚未鉴定的新型抑制剂的活性

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 IFN? 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 IFN!-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.