Conserved Elements Therapeutic DNA Vaccine for HIV

HIV 保守元件治疗性 DNA 疫苗

• 批准号: 9107786
• 负责人: Deborah H. Fuller
• 金额: $ 98.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107786
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Animals; Antigens; Avidity; Blood; CD8B1 gene; Combined Vaccines; Conserved Sequence; Control Animal; DNA; DNA Vaccines; Disease; Drug Combinations; Elements; Epidermis; Epitopes; Evolution; Exhibits; Failure; Frequencies; Goals; Gut associated lymphoid tissue; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Health; Highly Active Antiretroviral Therapy; Immune; Immune Targeting; Immune response; Immunization; Indium; Infection; Inflammatory disease of the intestine; Lead; Macaca; Macaca mulatta; Measures; Mediating; Methods; Mutate; Mutation; Patients; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Proteins; Regimen; Residual state; Role; SIV; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Vaccinated; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Replication; antiretroviral therapy; cost; design; fitness; frontier; gene gun; improved; novel; novel therapeutics; prevent; prototype; response; therapeutic DNA; therapeutic vaccine

DESCRIPTION (provided by applicant): Our previous studies have shown that therapeutic DNA vaccine induction of mucosal responses correlated with significant reduction of virus in the gut of SIV-infected macaques despite the use of a suboptimal ART regimen. This vaccine stimulated T cell responses that suppressed virus to low/undetectable levels and afforded a durable "functional cure" in ~50% of the animals after stopping ART. We propose here to make therapeutic vaccination even more effective by 1) using a more potent combination of drugs (cART) to maximize the effects of the vaccine, 2) using a mucosal adjuvant (LT) to target immune responses to residual virus in gut associated lymphoid tissue, and 3) use of a novel SIV conserved elements (CE) DNA vaccine to focus T cell responses against highly conserved viral sequences that if mutated will impose greater fitness cost. Our overarching hypothesis is that vaccine-induced functional cure is mediated by strong mucosal CD8 responses, and that focusing these responses to the gut in maximally suppressed infections and against more conserved epitopes, which suppress a wider range of possible viral variants and select for more fitness-costing escape mutations, will maximally disable the ability of residual viruses to emerge from the latent reservoir after stopping cART. Operationally, using optimized cART and mucosal targeting we will compare a traditional whole antigen and a CE DNA vaccine for the ability to increase the frequency and strength of mucosal and systemic CD8 responses against conserved viral sequences, and for their impact on viral evolution and fitness, and determine the role of these factors in a functional cure. Our specific aims are to: 1) Determine therapeutic efficacy of an LT-adjuvanted traditional SIV DNA vaccine expressing whole antigens when used with more potent cART. 2) Determine if an SIV CE immunogen will improve therapeutic efficacy. 3) Define immune and virological mechanisms underlying functional cures. Through the proposed studies we will define the virological and immune profile of a vaccine-induced functional cure and determine the feasibility of a novel CE DNA vaccine to induce a functional cure of SIV infection.

描述（由申请人提供）：