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，它不能在大多数非人类物种中复制。 因此，最实用的人类艾滋病动物模型包括感染恒河猴， SIVMAC或来源于编码HIV-1包膜（SHIV）的SIVMAC的嵌合体。然而， 这些模型受到HIV-1和SIVMAC是不同病毒这一事实的限制。基于对 物种特异性的限制因素，我们已经获得在过去几年中，我们已经产生了一个 重组病毒，命名为嗜猴性HIV（stHIV），几乎完全来源于HIV-1，但可以 在体外在原代恒河猴细胞中非常有效地复制。stHIV只表达两种蛋白质， SIVMAC使其能够在体外恒河猴细胞中复制，并感染恒河猴， 体内低水平。该提案的目的是产生具有增强的能力的stHIV的改进衍生物。 在动物身上复制并导致艾滋病首先，我们将确定是否有额外的SIVMAC辅助蛋白， 通过将它们引入stHIV构建体中在体内病毒复制中起作用。第二，我们将探索 初步发现表明，简单地操纵HIV-1应该可以避免限制 pigtailed macaques短尾猕猴第三，我们将减少stHIV构建体中存在的SIVMAC序列， 产生最低限度突变的HIV-1蛋白，可以赋予对猕猴限制因子的抗性。 最终，我们将生产出与HIV-1病毒株非常相似的stHIV病毒，这种病毒株在人类中传播， 艾滋病的动物模型如果成功，这些研究将彻底改变临床前探索， 艾滋病治疗和疫苗的开发。与公共卫生的相关性 HIV-1是人类艾滋病的主要病因，它不能在大多数非人灵长类动物中复制 目前的动物模型有限。我们已经开发了基于HIV-1的新型嵌合病毒， 计划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。如果成功的话，这一提议将导致改进HIV-1感染的动物模型， 大大促进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.