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

摘要 HIV-1是人类艾滋病的主要原因，无法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感染恒河猴和 SIVMAC或源自SIVMAC的嵌合体，编码HIV-1包膜(Shiv)。然而，它的有用性 这些模型受到HIV-1和SIVMAC是不同病毒的事实的限制。基于对……的理解 我们在过去几年中获得的特定物种的限制因素，我们产生了一个 重组病毒，命名为喜猴HIV(StHIV)，几乎完全来自HIV-1，但可以 在体外原代恒河猴细胞中非常有效地复制。StHIV只表达两种来自 SIVMAC使其能够在体外在恒河猴细胞中复制，并感染恒河猴并在 体内低水平。这项提议的目的是产生具有增强能力的改良的stHIV衍生物。 在动物身上复制并引起艾滋病。首先，我们将确定额外的SIVMAC辅助蛋白 通过将它们引入stHIV结构，在体内的病毒复制中发挥作用。第二，我们将探索一种 最初的发现表明，对HIV-1的简单操作应该可以避免限制 辫子猕猴的致病因素。第三，我们将通过以下方式减少stHIV构造中存在的SIVMAC序列 产生最小突变的HIV-1蛋白，可以对猕猴限制因子产生抵抗力。 最终，我们将产生与HIV-1毒株非常相似的stHIV，这种毒株在人类体内传播并导致 动物模型中的艾滋病。如果成功，这些研究将彻底改变临床前的探索和 艾滋病治疗和疫苗的发展。与公共卫生的相关性 HIV-1是人类艾滋病的主要原因，不能在大多数非人类灵长类物种中复制 而目前的动物模型是有限的。我们已经开发出基于HIV-1的新型嵌合病毒，并正在 提议在猴子身上测试它们作为HIV-1感染模型的效用，并产生更多的HIV-1- 衍生病毒。如果成功，这项提议将导致改进HIV-1感染的动物模型，并将 极大地便利了药物和疫苗干预措施的开发和测试。

ABSTRACT 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 that encode the HIV-1 envelope (SHIV). 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 that we have acquired during the past few years, we have generated a recombinant virus, named simian tropic HIV (stHIV), that is almost entirely derived from HIV-1 but can replicate very efficiently in primary rhesus macaque cells in vitro. stHIV expresses only two proteins from SIVMAC that enable it to replicate in rhesus macaque cells in vitro and to infect rhesus macaques and replicate at low levels in vivo. The aim of this proposal is to generate improved derivatives of stHIV with enhanced ability to replicate and cause AIDS in animals. First, we will determine whether additional SIVMAC accessory proteins have a role in virus replication in vivo by introducing them into stHIV constructs. Second, we will explore an initial finding which suggests that a simple manipulation of HIV-1 should allow avoidance of restriction factors in pigtailed macaques. Third, we will reduce the SIVMAC sequences present in stHIV constructs by generating minimally mutated HIV-1 proteins that can confer resistance to macaque restriction factors. Ultimately, we will generate stHIVs that closely resemble HIV-1 strains that circulate in humans and cause AIDS in an animal model. If successful, these studies should revolutionize the preclinical exploration and development of AIDS therapeutics and vaccines. Relevance to public health HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most nonhuman primate species and current animal models are limited. We have developed novel chimeric viruses based on HIV-1 and are proposing to test their utility as an HIV-1 infection model in monkeys and to generate additional HIV-1- derived viruses. If successful, this proposal will lead to improved animal models for HIV-1 infection and will considerably facilitate the development and testing of drug and vaccine interventions.