Overcoming blocks to HIV-1 replication in rhesus macaques.

描述（由申请方提供）：人类HIV-1感染的最实用动物模型由SIX/MAC或编码HIV-1包膜（SHIV）的嵌合体感染恒河猴组成，这两种病毒均可引起动物AIDS。然而，尽管人类的HIV-1感染和猕猴的SIVMAc/SHIV感染之间存在相似之处，但SIVmac与HIV-1相比是一种不同的病毒，这一事实限制了这种动物模型的有用性。HIV-1不能感染恒河猴，至少部分是由于在体外猕猴衍生细胞中已经鉴定出的病毒复制周期的阻断。基于对物种特异性限制因子的理解，我们已经产生了HIV-1和SIVMAc之间的新嵌合体，其中含有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，我们将产生表达具有不同向性的HIV-1包膜蛋白的HIV/SIVMAc嵌合体的版本。将在恒河猴中检测这些病毒的体内复制。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，这些研究可能会导致重要的HIV-1动物模型的推导，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：HIV-1是人类艾滋病的主要原因，它不能在大多数非人灵长类动物中复制，目前的动物模型也很有限。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其作为HIV-1感染模型的实用性，并产生额外的HIV-1衍生病毒。如果成功，这一建议将导致改进HIV-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.