Novel HIV 1 Envelope immunogens derived from broadly neutralizing plasmas

源自广泛中和血浆的新型 HIV 1 包膜免疫原

• 批准号: 8512894
• 负责人: D. Noah Sather
• 金额: $ 55.36万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512894
• 关键词: Animals; Antibodies; Antibody Formation; Antigens; Autologous; B-Lymphocytes; Binding; Binding Sites; Bone Marrow; CD4 Antigens; Cloning; Communities; Development; Epitope Mapping; Epitopes; Evaluation; Exhibits; Generations; Goals; HIV; HIV-1; Immune response; Immunity; Immunoglobulin G; Infection; Libraries; Monitor; Oryctolagus cuniculus; Phage Display; Phase; Plasma; Process; Protocols documentation; Recombinants; Reporting; Research; Research Personnel; Resources; Specificity; Spleen; Structure; Testing; Tissues; Vaccination; Vaccines; Virus; base; combat; design; env Gene Products; immunogenic; immunogenicity; neutralizing antibody; neutralizing monoclonal antibodies; novel; pandemic disease; prophylactic; receptor binding; response; success; tool; vaccination strategy; vaccine candidate

ABSTRACT The overall aim of our studies is to design novel HIV Envelope immunogens capable of eliciting broadly reactive neutralizing antibodies (NAbs). Although attempts at eliciting broadly neutralizing antibody responses by vaccination have been unsuccessful, exceptionally potent broadly neutralizing antibody responses have been detected in some chronically infected HIV+ subjects. We propose to test new immunogens that are derived from Envelope sequences that were isolated from a well- characterized HIV+ subject whose exceptional broadly neutralizing activity targeted the CD4 receptor binding site (CD4-BS). We hypothesize that HIV-1 Envelope immunogens derived from HIV-1 infected subjects whose plasma exhibits potent, broad cross-neutralizing activity to the CD4-BS will elicit NAbs that are capable of broad cross-neutralization. This proposal is separated into two distinct phases. In the first phase, we propose the following: First, construct and characterize soluble trimeric gp140 Env proteins derived from autologous Env sequences isolated from well-characterized broadly neutralizing plasmas. Second, we will use these trimeric gp140 Envs as immunogens and monitor their ability to elicit broadly neutralizing antibody responses in animals. We will carefully dissect the NAb responses elicited by vaccination to determine both the quality and the epitope targets of the elicited NAb responses. In the second phase, we will isolate new monoclonal neutralizing antibodies from animals that develop broadly neutralizing antibodies in response to vaccinations. We will utilize both phage display libraries and antigen-specific single B cell cloning to isolate antibodies from spleen and bone marrow tissue of immunized animals. Novel antibodies and Fabs will be isolated and extensively characterized for binding and neutralizing activity. Promising Fabs will be made into full immunoglobulin G molecules and extensively characterized for cross-neutralizing potential and binding epitope. Novel anti-HIV neutralizing antibodies from this study will provide valuable new tools to the research community, and help to define new neutralization epitopes on the HIV-1 Envelope spike.

摘要