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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.

项目摘要/摘要