Modeling the molecular evolution of SIV to HIV using humanized mice

使用人源化小鼠模拟 SIV 到 HIV 的分子进化

基本信息

批准号：
9979747
负责人：
Ramesh Akkina
金额：
$ 47.8万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979747
关键词：
Acquired Immunodeficiency Syndrome Address Animal Model Area B-Lymphocytes Back Benign CD4 Positive T Lymphocytes Cercocebus atys Cessation of life Chronic Colorado Consensus Data Dendritic Cells Disease Epidemic Evolution Generations Genetic Genome Genomics Genotype Goals HIV HIV Infections HIV-1 HIV-2 Human Immune system In Vitro Infection Laboratories Light Louisiana Modernization Molecular Molecular Evolution Mutation Nucleotides Pan Genus Pathogenesis Pathogenicity Peripheral Blood Mononuclear Cell Phenotype Physiological Population Positioning Attribute Research Institute Retroviridae Role Route Rural SIV Serial Passage Sexual Transmission System T-Lymphocyte Testing Transplantation Universities Vagina Viral Viral Load result Viremia Virulence Virus Wisconsin Work Zoonoses fitness human migration humanized mouse in vivo in vivo Model innovation macrophage molecular modeling nonhuman primate pandemic disease pathogen progenitor theories transmission process viral transmission

项目摘要

Project Summary / Abstract The AIDS pandemic caused by HIV-1 and to a lesser extent by HIV-2 resulted in more than 35 million deaths worldwide, with both these viruses now deeply entrenched in the human population. How these culprits arose during the 20th century from the long-preexisting benign ancient SIV viral strains is still a mystery. Several hypotheses have been put forward that include simple zoonotic transfer followed by spread, modern human migration spreading an otherwise isolated rural disease or inadvertent serial passage of the progenitor viruses in humans resulting in increased virulence. An experimental system that can test some of these hypotheses has been lacking until recently. With the advent of humanized mice (hu-mice) that harbor a transplanted human immune system, it has now become possible to address some key questions surrounding how a retrovirus native to non-human primates that existed through the millennia jumped the species barrier and evolved to give rise to the current human pandemic. Work in our laboratories and others have established a new generation of hu-mice that continuously generate human T cells, B cells, macrophages and dendritic cells de novo, and that are exquisitely sensitive to infection with HIV-1 and HIV- 2 giving rise to chronic viremia and CD4 T cell loss typical of AIDS. Thus, we are now in a unique position to directly evaluate the potential of ancestral SIV strains for human viral transmission, pathogenesis and evolution in a physiologically relevant in vivo human surrogate system. The primary aim of our studies is to exploit this unique in vivo model for serial passage of chimpanzee SIVcpz and sooty mangabey SIVsm viral strains, the progenitors of HIV-1 and HIV-2, respectively, and determine the genetic and phenotypic changes responsible for the emergence of the HIV viral strains. We recently derived promising preliminary data by successfully growing and adapting SIVsm and SIVcpz in hu-mice. Sequence data on the 2nd passage of SIVsm showed fixed mutations in gp41 and the 1st passage SIVcpz has shown sequence changes indicative of viral evolution. These emerging data point to the feasibility of our proposed studies and to reaching the exciting goal of understanding the genetic basis for emergence of both HIV types and thus shedding light on a long-standing mystery. In this work, we will serially passage SIVcpz and SIVsm in vivo in hu-mice to derive human adapted viruses that potentially represent fully evolved strains of HIV-1 and HIV-2 respectively, characterize the key pathogenic attributes, derive sequence data to identify adaptive sequence changes and assess the critical genomic changes in overcoming human restriction factors such as tetherin. To conduct these promising studies, we assembled an accomplished and enthusiastic team of collaborators Drs. Preston Marx (Tulane), Shelby O'Connor and David Evans (University of Wisconsin), Francoise Villinger (New Iberia Research Institute, Louisiana), Brandon Keele (NCI, Frederick), Mark Stenglein and Ramesh Akkina (Colorado State University) involved in complementary areas of work to synergize in this project.

项目概要/摘要由 HIV-1 和较小程度上由 HIV-2 引起的艾滋病大流行导致超过 3500 万人死亡在世界范围内，这两种病毒现已在人群中根深蒂固。这些罪魁祸首是如何产生的 20世纪期间早已存在的良性古代SIV病毒株仍然是一个谜。一些已经提出的假设包括简单的人畜共患病转移随后传播、现代人类迁徙传播了原本孤立的农村疾病或祖先的无意连续传代病毒在人类中导致毒力增加。可以测试其中一些的实验系统直到最近还缺乏假设。随着具有人源化基因的小鼠（hu-mice）的出现移植人体免疫系统，现在已经可以解决一些关键问题围绕一种存在于非人类灵长类动物身上数千年的逆转录病毒如何跨越了物种障碍并进化导致了当前的人类大流行。在我们的实验室和其他实验室工作建立了新一代的 hu-mice，能够持续产生人类 T 细胞、B 细胞、巨噬细胞和树突状细胞从头开始，对 HIV-1 和 HIV- 感染极其敏感 2 引起慢性病毒血症和 CD4 T 细胞丧失，这是艾滋病的典型特征。因此，我们现在处于一个独特的位置直接评估祖先 SIV 毒株在人类病毒传播、发病机制和生理相关的体内人类替代系统的进化。我们研究的主要目的是利用这种独特的体内模型对黑猩猩 SIVcpz 和乌白眉猴 SIVsm 病毒进行连续传代菌株，分别是 HIV-1 和 HIV-2 的祖细胞，并确定遗传和表型变化导致 HIV 病毒株的出现。我们最近得出了有希望的初步数据在 hu-mice 中成功培养和适应 SIVsm 和 SIVcpz。第 2 代的序列数据 SIVsm 显示 gp41 中的固定突变，第 1 代 SIVcpz 显示序列变化表明病毒进化的过程。这些新出现的数据表明了我们提出的研究的可行性并达到了令人兴奋的目标是了解两种艾滋病毒类型出现的遗传基础，从而揭示一个长期存在的谜团。在这项工作中，我们将在 hu-mice 体内连续传代 SIVcpz 和 SIVsm，以获得适应人类的病毒可能分别代表完全进化的 HIV-1 和 HIV-2 菌株，表征了关键致病属性，导出序列数据以识别适应性序列变化并评估关键克服人类限制因素（如系链素）的基因组变化。为了进行这些有前途的研究，我们组建了一支经验丰富且热情的合作团队博士。 Preston Marx（杜兰大学）、Shelby O'Connor 和 David Evans（威斯康星大学）、Francoise Villinger （路易斯安那州新伊比利亚研究所）、Brandon Keele（NCI，弗雷德里克）、Mark Stenglein 和 Ramesh Akkina（科罗拉多州立大学）参与了互补领域的工作，以在该项目中发挥协同作用。