Harnessing Abs specific for immunogenic and conserved Env epitopes to protect against HIV
利用免疫原性和保守的 Env 表位特异性抗体来预防 HIV
基本信息
- 批准号:10401312
- 负责人:
- 金额:$ 81.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-07 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AIDS/HIV problemALVACAnimalsAntibodiesAntibody ResponseAntibody-Dependent EnhancementBloodCD34 geneCase-Control StudiesCellsDataDevelopmentEpitopesFaceFc ReceptorFutureGenesGoalsHIVHIV Envelope Protein gp120HIV InfectionsHIV vaccineHIV-1Hematopoietic stem cellsHumanImmuneImmunoglobulin AImmunoglobulin Constant RegionImmunoglobulin GImmunologicsIn VitroIndividualInfectionLymphoid TissueMacacaMeasuresMediatingModelingMolecular ConformationMonoclonal AntibodiesMusMutationPassive Transfer of ImmunityPatientsPhasePlasmaPreventive vaccineProteinsResearchResistanceRiskSIVSiteSomatic MutationTestingV3 LoopVaccinationVaccineeVaccinesVirionVirusVirus Diseasesantibody transferantibody-dependent cell cytotoxicityantibody-dependent cellular phagocytosisbasecomplementarity-determining region 3cytotoxicitydesignexperimental studyhuman monoclonal antibodieshumanized mouseimmunogenicin vivoinfection rateinfection riskmouse modelneutralizing antibodypandemic diseaseprotective effectresponsesuccesstransmission processvaccine developmentvaccine evaluationvaccine trialvaccine-induced antibodies
项目摘要
Project Summary/Abstract
Immune effector mechanisms that confer protection against HIV acquisition remain poorly understood.
Immune-correlates analysis of the Phase III RV144 trial of the prime/boost ALVAC+gp120 protein vaccine,
which delivered an overall 31.2% reduction in HIV acquisition, suggested a protective potential in anti-gp120
antibody responses. Specifically, of the 6 primary immunologic parameters evaluated in the RV144 case-
control study, high IgG responses to the V1V2 loop of HIV envelope (Env) gp120 significantly correlated with a
reduced risk of HIV acquisition. This correlate of protection has since been recapitulated in the SIV/macaque
model. Moreover, in a subset of vaccinees with lower levels of neutralizing antibodies and Env-specific plasma
IgA, antibody responses to the V3 loop and antibodies mediating antibody-dependent cellular cytotoxicity
(ADCC) were also associated with protection. However, it remains unclear if and how these V1V2- and V3-
specific antibodies directly mediate their protective effects. These antibodies have no broad neutralizing
activity, but target conserved regions of the V1V2 and V3 loops and are capable of mediating Fc-dependent
antiviral functions in vitro. Nonneutralizing antibodies against conserved conformational epitopes also
synergize to enhance ADCC activity. We propose herein to investigate the protective potential and
mechanisms of action of antibodies targeting V1V2, V3, and other, similarly immunogenic, conserved Env
epitopes by testing passively administered human monoclonal antibodies (mAbs) in a humanized mouse (hu-
mice) model. The proposed study is based on our preliminary findings that a nonneutralizing V1V2 mAb and a
weakly neutralizing V3 mAb were each able to reduce virus infection rate and/or virus burden in hu-mice that
were engrafted with CD34+ human hematopoietic stem cells and challenged with a tier 2 JRFL HIV-1 virus.
The extent to which these and other anti-Env antibodies inducible by vaccination confer protection against
diverse HIV-1 strains has not been determined, and their antiviral mechanisms also have not been defined.
Therefore, we propose experiments to, first, evaluate the ability of anti-V1V2 and anti-V3 human mAbs to
protect against virus infection in hu-mice upon challenge with HIV-1 isolates, particularly transmitted/founder
viruses from subtypes B and C. Second, we propose testing vaccine-induced human mAbs against conserved
epitopes in the V3 and constant regions of Env in hu-mice, using the same mAb transfer/virus challenge
approach. Third, we will investigate the Fab and Fc contributions of these mAbs in protection against HIV. To
this end, we will measure the mAb capacity to target free virions and infected cells, including ex vivo virions
and cells from virus-infected hu-mice, in vitro. We will also prepare mAbs with Fc mutations that abrogate or
enhance Fc-receptor interactions and test their ability to protect hu-mice against virus challenge. Data from this
proposed study will help us understand the types of antibodies and immunogenic Env epitopes that, due to
their protective potential, should be considered in future HIV vaccine development.
项目总结/文摘
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Immune profiles to distinguish hospitalized versus ambulatory COVID-19 cases in older patients.
- DOI:10.1016/j.isci.2022.105608
- 发表时间:2022-12-22
- 期刊:
- 影响因子:5.8
- 作者:Klingler, Jeromine;Lambert, Gregory S.;Bandres, Juan C.;Emami-Gorizi, Rozita;Nadas, Arthur;Oguntuyo, Kasopefoluwa Y.;Amanat, Fatima;Bermudez-Gonzalez, Maria C.;Gleason, Charles;Kleiner, Giulio;Simon, Viviana;Lee, Benhur;Zolla-Pazner, Susan;Upadhyay, Chitra;Hioe, Catarina E.
- 通讯作者:Hioe, Catarina E.
A tale of four studies: HIV vaccine immunogenicity and efficacy in clinical trials.
- DOI:10.1016/s2352-3018(21)00073-4
- 发表时间:2021-07
- 期刊:
- 影响因子:0
- 作者:Zolla-Pazner S;Michael NL;Kim JH
- 通讯作者:Kim JH
Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice.
- DOI:10.1371/journal.ppat.1010183
- 发表时间:2022-01
- 期刊:
- 影响因子:6.7
- 作者:Hioe CE;Li G;Liu X;Tsahouridis O;He X;Funaki M;Klingler J;Tang AF;Feyznezhad R;Heindel DW;Wang XH;Spencer DA;Hu G;Satija N;Prévost J;Finzi A;Hessell AJ;Wang S;Lu S;Chen BK;Zolla-Pazner S;Upadhyay C;Alvarez R;Su L
- 通讯作者:Su L
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Catarina E Hioe其他文献
Catarina E Hioe的其他文献
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{{ truncateString('Catarina E Hioe', 18)}}的其他基金
COVID-19: Significance of Fc properties and functions in antibody responses against SARS-CoV-2
COVID-19:Fc 特性和功能在针对 SARS-CoV-2 的抗体反应中的重要性
- 批准号:
10609822 - 财政年份:2022
- 资助金额:
$ 81.34万 - 项目类别:
COVID-19: Significance of Fc properties and functions in antibody responses against SARS-CoV-2
COVID-19:Fc 特性和功能在针对 SARS-CoV-2 的抗体反应中的重要性
- 批准号:
10365140 - 财政年份:2022
- 资助金额:
$ 81.34万 - 项目类别:
Biologic consequences of HIV-1 interaction with bacteria
HIV-1 与细菌相互作用的生物学后果
- 批准号:
10263148 - 财政年份:2020
- 资助金额:
$ 81.34万 - 项目类别:
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