Non-peptidic HIV vaccine

非肽HIV疫苗

• 批准号: 7943969
• 负责人: MIROSLAV MALKOVSKY
• 金额: $ 49.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943969
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animals; Antibody Formation; Antigens; Attenuated; Biological Assay; Blood Cells; Blood specimen; CD4 Positive T Lymphocytes; CD8B1 gene; CXCR4 gene; Cell Count; Cells; Color; Control Groups; Diphosphates; Disease; Effector Cell; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gagging; Genetic Variation; HIV vaccine; HIV-1; Humoral Immunities; Immune; Immune response; Immunity; Immunologic Adjuvants; Infection; Interleukin-2; Intravenous; Lactococcus lactis; Listeria; Lymphoid; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Memory; Methods; Mucous Membrane; Mycobacterium tuberculosis; Outcome; Peptides; Plasma; Recombinants; Resistance; SIV; Staining method; Stains; System; T cell response; T-Lymphocyte; Testing; Time; Vaccinated; Vaccination; Vaccines; Viral Load result; Virus; Virus Replication; cytokine; enzyme linked immunospot assay; immunogenic; improved; mucosal site; novel strategies; novel vaccines; particle; protective effect; public health relevance; receptor; response; simian human immunodeficiency virus; success; trafficking; vaccine delivery; vector vaccine; viral RNA

DESCRIPTION (provided by applicant): HIV-caused AIDS is a potentially lethal disease with no vaccine or cure available at the moment. The obstacles to overcome when developing an effective HIV vaccine include devising a strategy that would generate cellular and humoral immunity with sufficient a) strength to be 'virus- replication-clobbering' and b) breadth to address the extraordinary genetic diversity of the virus. Our proposal is focused specifically on increasing the 'immunizing strength' of HIV vaccines. For this purpose we have developed highly immunogenic recombinant attenuated Listeria vaccine vectors and recombinant Lactococcus lactis vaccine particles. Antigenic priming and boosting with these new vaccine-delivery systems elicits remarkable T-cell and Ab responses. In addition, we have demonstrated that a nonpeptidic phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) together with interleukin-2 stimulate prolonged expansion of V32V42 T effector cells in the lymphoid and mucosal compartments and enhance 12 T-cell and antibody responses. Here we propose studies to ascertain whether or not the strong immunoadjuvant effect of V32V42 T-cell stimulation can be utilized in increasing the 'immunizing strength' of HIV vaccines. Specifically, we propose to test our hypothesis that V32V42 T effector cells generated after HMBPP/IL-2 treatment can readily traffic to the lymphoid tissues and mucosae and upregulate the breadth and magnitude of HIV vaccine-elicited T-cell and antibody responses and ultimately increase the vaccine's protective effects against HIV/AIDS. Thus, our main specific aim is to determine whether the V32V42 T-cell-activating/expanding treatment with HMBPP plus IL-2 can augment the anti-SHIV89.6P potency of our attenuated Listeria ?actA prfA* vaccine vectors expressing HIV-1 Env and SIV gag in SHIV89.6P-challenged rhesus macaques. PUBLIC HEALTH RELEVANCE: There is no vaccine or cure for HIV/AIDS, which is a potentially lethal disease. The main focus of this application is to test a novel strategy for boosting the capacity of HIV vaccines to induce protective responses against HIV/AIDS. Even partial success may have worldwide beneficial effect.

描述(申请人提供)：艾滋病毒引起的艾滋病是一种潜在的致命疾病，目前还没有疫苗或治疗方法。在开发有效的艾滋病毒疫苗时需要克服的障碍包括设计一种战略，该战略将产生足够的细胞和体液免疫，a)具有足够的强度，以“病毒复制-打击”和b)广度，以解决病毒的非凡遗传多样性。我们的建议特别侧重于提高艾滋病毒疫苗的“免疫强度”。为此，我们研制了高度免疫原性的重组减毒李斯特菌疫苗载体和重组乳酸乳球菌疫苗颗粒。用这些新的疫苗递送系统进行抗原启动和增强可引起显著的T细胞和抗体反应。此外，我们还证明了非肽性磷酸抗原(E)-4-羟基-3-甲基-2-烯基焦磷酸(HMBPP)与白细胞介素2(IL-2)共同刺激V32V42T效应细胞在淋巴和粘膜隔间的长时间扩张，并增强12个T细胞和抗体反应。在这里，我们建议进行研究，以确定V32V42T细胞刺激的强大免疫佐剂效应是否可以用于增加HIV疫苗的免疫强度。具体地说，我们建议测试我们的假设，即HMBPP/IL-2治疗后产生的V32V42 T效应细胞可以很容易地运输到淋巴组织和粘膜，并上调艾滋病毒疫苗引发的T细胞和抗体反应的广度和幅度，最终增强疫苗对艾滋病毒/艾滋病的保护作用。因此，我们的主要目的是确定HMBPP和IL-2联合V32V42T细胞激活/扩增处理是否能增强表达HIV-1 env和SIV Gag的减毒李斯特菌疫苗载体在SHIV89.6P攻击猕猴中的抗SHIV89.6P效力。 与公共卫生相关：艾滋病毒/艾滋病是一种潜在的致命性疾病，目前还没有疫苗或治愈方法。这项应用的主要重点是测试一种新的战略，以提高艾滋病毒疫苗诱导对艾滋病毒/艾滋病的保护性反应的能力。即使是部分成功，也可能在全球范围内产生有益影响。