Env evolution in humans and RMs
人类和 RM 的环境进化
基本信息
- 批准号:10117175
- 负责人:
- 金额:$ 109.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-07 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:Amino Acid SubstitutionAnimal ModelAnimalsAntibodiesAntibody ResponseAntibody SpecificityAntigensAutologousB-Cell Antigen ReceptorB-LymphocytesBindingBioinformaticsBiological ModelsCD4 Positive T LymphocytesCell Culture TechniquesClinicalDNADataData AnalysesDevelopmentEpitopesEvolutionFingerprintGeneticHIVHIV Envelope Protein gp120HIV-1HIV-1 vaccineHumanImmune systemImmunityImmunizeIn VitroInfectionKineticsLeadLinkMacaca mulattaMapsMolecularMolecular ConformationPathway interactionsPatternPeptidesPolysaccharidesPrimary InfectionReproducibilityRhesusSamplingSite-Directed MutagenesisSpecificityTestingTimeUrsidae FamilyVaccinatedVaccine DesignVaccinesVariantVirusVirus Diseasesdesignenv Gene Productsexpression cloningin vivomonomerneutralizing antibodynovelpre-clinicalresponsesimian human immunodeficiency virustransmission processvaccine candidatevaccine developmentvaccine trialvectorvirtual
项目摘要
SUMMARY
Excluding the great apes, the immune system of Indian rhesus macaques (RMs) most closely approximates
that of humans. Thus, it is widely believed that the RM represents the closest practical animal model for
evaluating protective immunity to HIV-1 and vaccines that might elicit such protection. For the analysis of HIV-1
neutralizing antibodies (NAbs), RMs have in the past been infected with simian-human immunodeficiency
viruses (SHIVs) that bear HIV-1 Envs that were heavily adapted in cell culture or by animal passage, or they
were immunized with any of numerous Env containing candidate vaccines ranging from Env peptides or DNA
vectors to gp120 monomers to soluble stabilized Env trimers (SOSIPs). The findings from all such studies to
date have been the same: Abs can be generated that neutralize heterologous tier 1 viruses, and in some
instances autologous tier 2 viruses, but generally not heterologous tier 2 viruses that constitute virtually all
primary HIV-1 strains and are responsible for clinical HIV-1 transmission. Surprisingly, there is no direct
experimental evidence that RMs have the potential to develop heterologous tier 2 broadly neutralizing
antibodies (bNAbs) even if vaccinated with an appropriate immunogen. Thus, a major roadblock to HIV-1
vaccine development is that there is no animal model system where the elicitation of HIV-1 bNAbs can be
reliably and consistently demonstrated, let alone be studied in an iterative fashion for rational vaccine design.
Project 1 seeks to overcome this roadblock by capitalizing on recent discoveries by the Shaw lab regarding
novel SHIV design strategies. The scientific premise of Project 1 is that since most examples of bNAb
elicitation come from natural human infection by primary strains of HIV-1, the most likely means to elicit bNAbs
in RMs is by infection with SHIVs bearing primary HIV-1 Envs in their native conformations. A key hypothesis
that we will test is that SHIVs bearing primary or transmitted/founder (T/F) Envs will engage rhesus germline
and intermediate ancestor B cell receptors (BCRs) that are orthologous to those engaged by the same Envs in
human infection and that patterns of virus-Ab coevolution leading to the development of neutralizing antibody
specificity, potency and breadth will be similar in both species. Specific Aims of Project 1 are to: (i) analyze in
33 RMs the in vivo replication kinetics and NAb responses of 11 novel SHIVs whose Envs are known to bind to
human bNAb lineage BCRs targeting the V3-glycan supersite (CH848, CH694, CH040), V1V2 supersite
(CAP256SU, ZM233, WITO, Q23, T250-4, CH1012), CD4bs (CH505) or other (BG505), and down-select to
two SHIVs for inoculation into 9 RMs each; (ii) analyze in vivo replication kinetics and env evolutionary
pathways of SHIVs targeting V3-glycan or V1V2 germline and IA BCRs; and (iii) determine the kinetics,
potency and breadth of polyclonal NAb responses and map epitope specificities by a combination of Env
fingerprinting, Env-expression cloning, and site-directed mutagenesis. Project 1 will link closely with Cores B
and C for sequencing and bioinformatics and Projects 2 and 3 for sample provision and data interpretation.
总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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GEORGE M SHAW其他文献
GEORGE M SHAW的其他文献
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{{ truncateString('GEORGE M SHAW', 18)}}的其他基金
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
- 批准号:
10577775 - 财政年份:2021
- 资助金额:
$ 109.37万 - 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
- 批准号:
10624301 - 财政年份:2021
- 资助金额:
$ 109.37万 - 项目类别:
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
- 批准号:
10370383 - 财政年份:2021
- 资助金额:
$ 109.37万 - 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
- 批准号:
10437032 - 财政年份:2021
- 资助金额:
$ 109.37万 - 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
- 批准号:
10326691 - 财政年份:2021
- 资助金额:
$ 109.37万 - 项目类别:
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
- 批准号:
10224528 - 财政年份:2021
- 资助金额:
$ 109.37万 - 项目类别:
SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design
SHIV/HIV 包膜抗体协同进化作为迭代疫苗设计的指南
- 批准号:
9316783 - 财政年份:2017
- 资助金额:
$ 109.37万 - 项目类别:
Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs
SHIV 感染 RM 中的 Env-Ab 共同进化导致 V3 聚糖 bNAb
- 批准号:
10370983 - 财政年份:2017
- 资助金额:
$ 109.37万 - 项目类别:
SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design
SHIV/HIV 包膜抗体协同进化作为迭代疫苗设计的指南
- 批准号:
10117167 - 财政年份:2017
- 资助金额:
$ 109.37万 - 项目类别:
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