Overcoming blocks to HIV-1 replication in rhesus macaques.

描述（由申请人提供）：人类HIV-1感染最实用的动物模型是恒河猴被SIX/MAC或嵌合体编码HIV-1包膜（SHIV）感染，这两种方法都会导致动物感染艾滋病。然而，尽管人类HIV-1感染与猕猴SIVMAc/SHIV感染之间存在相似之处，但与HIV-1相比，SIVMAc是一种不同的病毒，这一事实限制了该动物模型的实用性。HIV-1不能感染恒河猴，至少部分原因是在体外恒河猴衍生细胞中发现了病毒复制周期的阻滞。基于对物种特异性限制因子的理解，我们在HIV-1和SIVMAc之间产生了新的嵌合体，其中包含比迄今为止开发的任何SHIV更多的HIV-1衍生序列。这些HIV/SIVMAc嵌合体在恒河猴PBMC中非常有效地复制。在本提案的目标1中，我们将生成表达具有不同向性的HIV-1包膜蛋白的HIV/SIVMAc嵌合体版本。这些病毒将在恒河猴体内进行复制试验。在目标2中，我们将尝试产生尽可能与HIV-1同源但能够在恒河猴细胞中复制的病毒。如果成功，这些研究可能导致衍生出重要的HIV-1动物模型，这将有助于评估新的药物和疫苗疗法。与公共卫生的相关性：艾滋病毒-1是人类艾滋病的主要原因，无法在大多数非人灵长类动物物种中复制，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，并建议在恒河猴中测试它们作为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，这一建议将导致改进艾滋病毒-1感染的动物模型，并将大大促进药物和疫苗干预措施的开发和测试。

DESCRIPTION (provided by applicant): The most practical animal model for HIV-1 infection in humans consists of infection of rhesus macaques by SIX/MAC or chimeras encoding the HIV-1 envelope (SHIV), both of which cause AIDS in animals. However, despite the parallels between HIV-1 infection of humans and SIVMAc/SHIV infection of macaques, the fact that SIVmac is a distinct virus compared to HIV-1 limits the usefulness of this animal model. HIV-1 cannot infect rhesus macaques at least in part due to blocks in the viral replication cycle that have been identified in macaque derived cells in vitro. Based on an understanding of species-specific restriction factors we have generated new chimeras between HIV-1 and SIVMAc containing more HIV-1-derived sequences than any SHIV developed to date. These HIV/SIVMAc chimeras replicate very efficiently in rhesus macaque PBMC. In aim 1 of this proposal we will generate versions of our HIV/SIVMAc chimeras that express HIV-1 envelope proteins with different tropisms. These viruses will be tested for in vivo replication in rhesus macaques. In aim 2 we will attempt to generate viruses that are as homologous to HIV-1 as possible but are capable of replicating in rhesus macaque cells. If successful these studies may lead to the derivation of important HIV-1 animal models that will facilitate the evaluation of new drug and vaccine therapies. 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 rhesus 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.