Mucosal transmission and pathogenicity of novel SIVsmm virus strains

新型SIVsmm病毒株的粘膜传播和致病性

• 批准号: 7904663
• 负责人: CRISTIAN APETREI
• 金额: $ 46.22万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904663
• 关键词: AIDS Vaccines; AIDS vaccine development; Animal Model; Animals; Anti-Retroviral Agents; Biological; CD4 Positive T Lymphocytes; Cervical; Characteristics; Clinical; Development; Disease Progression; Dose; Event; Exhibits; Genetic; Genetic Variation; Genome; Goals; HIV; HIV-1; Human; In Vitro; Infection; Intravenous; Kinetics; Macaca; Macaca mulatta; Modeling; Molecular; Molecular Cloning; Monitor; Monkeys; Mucous Membrane; Natural History; Outcome; Pathogenesis; Pathogenicity; Pattern; Peripheral Blood Mononuclear Cell; Plasma; Primates; Property; Ramp; Reagent; Route; SIV; Sampling; T-Cell Depletion; Techniques; Testing; Vaccine Design; Vaccines; Vagina; Variant; Viral; Viremia; Virus; Virus Replication; fitness; follow-up; in vivo; novel; novel vaccines; rectal; research study; tissue culture; transmission process

The development of an effective AIDS vaccine remains one of the highest priorities in HIV research. Studies of HIV pathogenesis, vaccine design and antiretroviral treatments require an appropriate animal model. However, the existing SIV/macaque model has major limitations since (i) prototypic SIVmac strains are too pathogenic, (ii) do not represent mucosally transmitted viruses, and (iii) have been extensively passaged in vitro and in vivo. We have recenfiy identified a large set of new SIVsmm strains which mirror HIV-1 group M viruses in their genetic diversity. Moreover, preliminary in vivo results show that infection of RMs with these SIVsmm strains more closely reproduces the natural history of HIV-1 in humans. Within this HIVRAD consortium, we thus propose to use these new SIVsmm strains to generate new (molecularly cloned) challenge viruses for AIDS vaccine and pathogenesis studies. Project 1 will use a dose-escalafion strategy to infect 21 Indian rhesus macaques (RMs) with genetically diverse SIVsmm strains using intravenous (iv), intrarectal (ir) and intravaginal (ivag) routes. Project 2 will then employ single genome amplificafion (SGA) techniques to infer, and subsequenfiy clone, transmitted/founder (T/F) virus(es) from all of these animals. Following detailed in vitro characterization, a subset of clones will be selected for in vivo competifion (n=18) and pathogenesis (n=8) studies which will be performed by Project 1. Specific Aims include: 1. To generate high titer plasma stocks of genefically divergent SIVsmm strains without in vitro adaptafion for subsequent mucosal and intravenous transmission studies. 2. To infect RMs by intravenous, intrarectal and intravaginal routes with physiologically relevant doses of genetically divergent SIVsmm strains to allow for the identification of transmitted founder (T/F) viruses: 3.; Tp identify SIVsmm clones with, preferenfial mucosal transmissibllity and replication fitness by conducting an in vivo compefition experiment. 4. To characterize the selected SIVsmm clones for in vivo replication kinefics, pathogenicity and suitability as vaccine challenge stocks. We expect these studies to generate new infecfious molecular clones of SIVs with biological properties that more faithfully recapitulate the transmission, pathogenic and diversity of HIV-1 in humans.

有效艾滋病疫苗的开发仍然是HIV研究中最高的优先事项之一。 HIV发病机理，疫苗设计和抗逆转录病毒治疗的研究需要适当的动物 模型。但是，现有的SIV/猕猴模型具有重大局限性，因为（i）原型SIVMAC菌株 太致病了，（ii）不代表粘膜传播病毒，（iii）已广泛 在体外和体内传递。我们已经重新确定了一大批镜像的新SIVSMM菌株 HIV-1组M病毒在其遗传多样性中。此外，初步体内结果表明感染 与这些SIVSMM菌株的RMS更紧密地再现了人类HIV-1的自然历史。在此 因此，Hivrad Consortium，我们建议使用这些新的SIVSMM菌株生成新（分子 克隆）攻击艾滋病疫苗和发病机理研究的病毒。项目1将使用剂量量表 使用遗传多样的SIVSMM菌株感染21种印度恒河猕猴（RMS）的策略 静脉内（IV），直肠内（IR）和阴道（IVAG）路线。然后，项目2将采用单个基因组 从所有 这些动物。按照详细的体外表征，将选择一个子集以进行体内 竞争（n = 18）和发病机理（n = 8）研究将由项目1进行。 包括： 1。产生高滴度的血浆库存基因差异的SIVSMM菌株，而没有体外Adaptafion 用于随后的粘膜和静脉传播研究。 2。通过静脉内，内部和阴道内途径感染RMS，并具有生理相关剂量 遗传上发散的SIVSMM菌株可以识别传播的创始人（T/F）病毒： 3。 TP通过进行挑剔的粘膜透射性和复制适应性识别SIVSMM克隆 体内组合实验。 4。表征所选的SIVSMM克隆用于体内复制动力学，致病性和适合性 作为疫苗挑战股。 我们预计这些研究将产生具有生物学特性的SIV的新的不稳定分子克隆 这更忠实地概括了人类HIV-1的传播，致病性和多样性。