HIV Neutralizing Antibodies: Isolation, characterization, and interaction with viral variants

HIV 中和抗体：分离、表征以及与病毒变体的相互作用

• 批准号: 10928534
• 负责人: Nicole Doria-Rose
• 金额: $ 152.05万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10928534
• 关键词: Adult; Animals; Antibodies; Antibody Response; Antigens; B-Cell Development; B-Lymphocytes; Binding; Biochemical; Cells; Clinical Research; Development; Donor Selection; Engineering; Epitopes; Glycoproteins; HIV; HIV Antibodies; HIV Infections; HIV envelope protein; HIV vaccine; HIV-1; Immune response; Immunize; Immunoglobulin G; Individual; Infection; Macaca mulatta; Mammalian Cell; Methods; Modeling; Monoclonal Antibodies; Patients; Prevention; Reagent; SIV; Sampling; Serum; Techniques; Testing; Time; Vaccinated; Vaccine Design; Vaccines; Variant; Viral; Virus; Work; antibody test; cross reactivity; deep sequencing; design; glycoprotein structure; high throughput screening; improved; manufacturability; neutralizing antibody; next generation; next generation sequencing; nonhuman primate; novel; pediatric human immunodeficiency virus; simian human immunodeficiency virus; vaccine candidate

Neutralizing antibodies (NAb) against HIV-1 are likely to be a major component of an effective vaccine-induced immune response. Cross-reactive NAbs commonly arise during HIV-1 infection, though only a small subset of infected patients produce NAbs with high breadth and potency. In contrast, the HIV-1 envelope glycoprotein (Env) vaccine immunogens tested to date have failed to elicit cross-reactive neutralizing antibodies. Thus, studying the development of broadly neutralizing antibodies (bNAbs) in infected individuals may provide important lessons for vaccine design. In addition, the isolation of bNAbs from selected donors and vaccinated animals has greatly aided our understanding of HIV-1 Env structure and vulnerability to neutralizing antibodies and such antibodies have potential for prevention or treatment of HIV-1 infection. For several years our lab has been a leader in the field of isolating and characterizing broadly neutralizing antibodies from HIV-infected donors. We have pioneered the development of reagents for isolating epitope-specific B cells, as well as a method for high-throughput screening of unselected B cells. After identification by one of these methods, we recover IgG from the B cells by single-cell PCR, subcloning, and expression in mammalian cells. The resulting antibodies are assayed for virus binding and neutralization, and their breadth, potency, epitopes, and modes of recognition analyzed. We also use next-generation deep sequencing to find clonal relatives of the antibodies and to understand their origins in B cell development. For the latter studies, donors for whom we have longitudinal samples from the time of HIV infection are particularly valuable. In addition, we apply these techniques to the study of animals that were immunized with candidate vaccines. In the past year, our work has included: isolation of monoclonal antibodies from multiple adult and pediatric HIV-infected patients that developed broadly neutralizing serum, including longitudinal samples over several years of infection; isolation and next-generation sequencing analysis of antibodies from rhesus macaques vaccinated with candidate HIV vaccines, some of which were subsequently infected with the model chimeric SIV-HIV virus.

针对HIV-1的中和抗体（NAb）可能是疫苗诱导的有效免疫反应的主要组成部分。交叉反应性抗体通常在HIV-1感染期间产生，尽管只有一小部分感染患者产生具有高广度和效力的抗体。相比之下，迄今为止测试的HIV-1包膜糖蛋白（Env）疫苗免疫原未能引发交叉反应性中和抗体。因此，研究受感染个体中广泛中和抗体（bNAbs）的发展可能为疫苗设计提供重要的经验教训。此外，从选定的供体和接种疫苗的动物中分离bNAbs，极大地帮助我们了解HIV-1 Env结构和对中和抗体的脆弱性，这些抗体具有预防或治疗HIV-1感染的潜力。

项目成果

Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment.

人类免疫缺陷病毒 1 型对有效靶向 CD4 附着位点的单克隆抗体 B12 的抵抗机制。

• DOI: 10.1128/jvi.01142-09
• 发表时间: 2009
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Wu,Xueling;Zhou,Tongqing;O'Dell,Sijy;Wyatt,RichardT;Kwong,PeterD;Mascola,JohnR
• 通讯作者: Mascola,JohnR

Protocol to identify and monitor key mutations of broadly neutralizing antibody lineages following sequential immunization of Ig-humanized mice.

• DOI: 10.1016/j.xpro.2022.101180
• 发表时间: 2022-03-18
• 期刊: STAR protocols
• 作者: Chen X;Schmidt SD;Duan H;Doria-Rose NA;Mascola JR
• 通讯作者: Mascola JR

Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates.

• DOI: 10.1084/jem.20100025
• 发表时间: 2010-08-30
• 期刊: The Journal of experimental medicine
• 作者: Sundling C;Forsell MN;O'Dell S;Feng Y;Chakrabarti B;Rao SS;Loré K;Mascola JR;Wyatt RT;Douagi I;Karlsson Hedestam GB
• 通讯作者: Karlsson Hedestam GB