Mucosal transmission and pathogenicity of novel SIVsmm virus strains
新型SIVsmm病毒株的粘膜传播和致病性
基本信息
- 批准号:7904663
- 负责人:
- 金额:$ 46.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AIDS VaccinesAIDS vaccine developmentAnimal ModelAnimalsAnti-Retroviral AgentsBiologicalCD4 Positive T LymphocytesCervicalCharacteristicsClinicalDevelopmentDisease ProgressionDoseEventExhibitsGeneticGenetic VariationGenomeGoalsHIVHIV-1HumanIn VitroInfectionIntravenousKineticsMacacaMacaca mulattaModelingMolecularMolecular CloningMonitorMonkeysMucous MembraneNatural HistoryOutcomePathogenesisPathogenicityPatternPeripheral Blood Mononuclear CellPlasmaPrimatesPropertyRampReagentRouteSIVSamplingT-Cell DepletionTechniquesTestingVaccine DesignVaccinesVaginaVariantViralViremiaVirusVirus Replicationfitnessfollow-upin vivonovelnovel vaccinesrectalresearch studytissue culturetransmission process
项目摘要
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.
研制有效的艾滋病疫苗仍然是艾滋病毒研究的最高优先事项之一。
研究艾滋病病毒的发病机制,疫苗设计和抗逆转录病毒治疗需要一个合适的动物
模型然而,现有的SIV/猕猴模型具有主要的局限性,因为(i)原型SIVmac株
致病性太强,(ii)不代表粘膜传播的病毒,以及(iii)已广泛
体外和体内传代。我们最近发现了一大批新的SIVsmm毒株,
HIV-1 M组病毒的遗传多样性。此外,初步的体内结果表明,
这些SIVsmm株的RM更接近地再现了HIV-1在人类中的自然史。在这
因此,我们建议使用这些新的SIVsmm株来产生新的(分子水平上)
用于艾滋病疫苗和发病机制研究的攻毒病毒。项目1将使用剂量递增
用遗传多样性SIVsmm株感染21只印度恒河猴(RM)的策略
静脉内(IV)、直肠内(IR)和阴道内(IVAG)途径。项目2将采用单基因组
扩增(SGA)技术,以推断和克隆,传播/创始人(T/F)病毒,从所有
这些动物。在详细的体外表征之后,将选择克隆的子集用于体内研究。
竞争(n=18)和发病机制(n=8)研究,将由项目1进行。具体目标
包括以下步骤:
1.为了产生未经体外适应的遗传上不同的SIVsmm株的高滴度血浆储备液
用于随后的粘膜和静脉内传播研究。
2.通过静脉内、直肠内和阴道内途径感染RM,使用生理相关剂量的
遗传上不同的SIVsmm毒株,以允许鉴定传播的创始者(T/F)病毒:
3. Tp通过以下方法鉴定具有优先粘膜传播性和复制适应性的SIVsmm克隆:
体内竞争实验。
4.描述所选SIVsmm克隆的体内复制动力学、致病性和适用性
作为疫苗攻毒储备。
我们希望这些研究能产生新的具有生物学特性的SIV感染性分子克隆
更真实地再现了HIV-1在人类中的传播、致病性和多样性。
项目成果
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{{ truncateString('CRISTIAN APETREI', 18)}}的其他基金
Impact of metabolic programing of T cells from the GI tract and related tissues on HIV reservoir seeding, maintenance and reactivation
胃肠道和相关组织 T 细胞的代谢编程对 HIV 储存库播种、维持和重新激活的影响
- 批准号:
10361609 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
New Strategy to Improve Gastrointestinal Health in SIV/HIV
改善 SIV/HIV 胃肠道健康的新策略
- 批准号:
10426962 - 财政年份:2018
- 资助金额:
$ 46.22万 - 项目类别:
Impact of a SARS-CoV-2 vaccine on gut integrity, immune activation and efficacy of ART
SARS-CoV-2 疫苗对肠道完整性、免疫激活和 ART 疗效的影响
- 批准号:
10175857 - 财政年份:2018
- 资助金额:
$ 46.22万 - 项目类别:
New Strategy to Improve Gastrointestinal Health in SIV/HIV
改善 SIV/HIV 胃肠道健康的新策略
- 批准号:
10180954 - 财政年份:2018
- 资助金额:
$ 46.22万 - 项目类别:
New Strategy to Improve Gastrointestinal Health in SIV/HIV
改善 SIV/HIV 胃肠道健康的新策略
- 批准号:
10437849 - 财政年份:2018
- 资助金额:
$ 46.22万 - 项目类别:
Assessing the Role of GI Tract Damage to HIV/SIV Disease Progression
评估胃肠道损伤对 HIV/SIV 疾病进展的作用
- 批准号:
9922905 - 财政年份:2017
- 资助金额:
$ 46.22万 - 项目类别:
Assessing the Role of GI Tract Damage to HIV/SIV Disease Progression
评估胃肠道损伤对 HIV/SIV 疾病进展的作用
- 批准号:
9347474 - 财政年份:2017
- 资助金额:
$ 46.22万 - 项目类别:
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:
8497585 - 财政年份:2013
- 资助金额:
$ 46.22万 - 项目类别:
Early Events and Determinants of Oral SIV Transmission in Infant Nonhuman Primate
非人类灵长类婴儿经口 SIV 传播的早期事件和决定因素
- 批准号:
8732835 - 财政年份:2013
- 资助金额:
$ 46.22万 - 项目类别:
SIMIAN IMMUNODEFICIENCY VIRUSES EXPOSURE IN HUMANS IN RURAL CAMEROON
喀麦隆农村地区人类接触猿猴免疫缺陷病毒的情况
- 批准号:
8172971 - 财政年份:2010
- 资助金额:
$ 46.22万 - 项目类别:
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