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

• 批准号: 10401312
• 负责人: Catarina E Hioe
• 金额: $ 81.34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10401312
• 关键词: AIDS/HIV problem; ALVAC; Animals; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Blood; CD34 gene; Case-Control Studies; Cells; Data; Development; Epitopes; Face; Fc Receptor; Future; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Hematopoietic stem cells; Human; Immune; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulin G; Immunologics; In Vitro; Individual; Infection; Lymphoid Tissue; Macaca; Measures; Mediating; Modeling; Molecular Conformation; Monoclonal Antibodies; Mus; Mutation; Passive Transfer of Immunity; Patients; Phase; Plasma; Preventive vaccine; Proteins; Research; Resistance; Risk; SIV; Site; Somatic Mutation; Testing; V3 Loop; Vaccination; Vaccinee; Vaccines; Virion; Virus; Virus Diseases; antibody transfer; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; base; complementarity-determining region 3; cytotoxicity; design; experimental study; human monoclonal antibodies; humanized mouse; immunogenic; in vivo; infection rate; infection risk; mouse model; neutralizing antibody; pandemic disease; protective effect; response; success; transmission process; vaccine development; vaccine evaluation; vaccine trial; vaccine-induced antibodies

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

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: ISCIENCE
• 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: The lancet. HIV
• 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: PLoS pathogens
• 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