THERAPEUTIC VACCINATION FOR IMMUNODEFICIENCY VIRUSES

免疫缺陷病毒的治疗性疫苗接种

• 批准号: 6603130
• 负责人: MIROSLAV MALKOVSKY
• 金额: $ 32.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603130
• 关键词: AIDS therapy; AIDS vaccines; Macaca mulatta; T lymphocyte; active immunization; cytokine; leukocyte activation /transformation; protein biosynthesis; simian AIDSs; simian immunodeficiency virus; vaccine development

An important feature of infections with immunodeficiency viruses - human (HIV) or simian (SIV) - is the host failure to mount an effective immunological defense against the virus. In some individuals, a status of long-term non-progression is established. It has been suggested that gammadelta T cell- mediated immunity may influence the outcome of HIV/SIV infections. The focus of the first Specific Aim of this proposal is to assess therapeutic vaccination that stimulates gammadelta T cells and its capacity to influence a) the in vivo virus load in SIV-infected animals and b) the pace of SIV disease progression. The second Specific Aim addresses the effect of therapeutic vaccinations with nonpeptidic antigens in the context of discontinuation of highly active antiretroviral therapy (HAART). The presence of strong Vgamma9Vdelta2 T-cell activation by nonpeptidic antigens in vitro results in a potent inhibition of HIV/SIV replication; this will be used to identify the most potent nonpeptidic antigen(s) for Vgamma9Vdelta2 T-cell stimulation. The activation of Vgamma9Vdelta2 T cells will be measured in terms of their cytotoxic activities and their capacity to produce cytokines and antiviral beta-chemokines. The SIV disease progression in SIV-challenged rhesus macaques will be assessed [the immunological parameters (numbers and functions of lymphoid cells) and the in vivo virus load will be monitored using flow cytometry, ELISA and PCR techniques] before and after receiving therapeutic vaccinations with or without HAART and compared with untreated controls. Survival times will be recorded. The efficacy of the testing will be analyzed and the influence of therapeutic vaccinations on prognosis and survival in SIV-infected animals will be determined. Successful outcomes may result in novel therapeutic vaccination strategies for clinical testing in human AIDS.

免疫缺陷病毒感染的一个重要特征--人类（HIV）或猿猴（SIV）--是宿主不能对病毒进行有效的免疫防御。 在一些个体中，建立了长期非进展状态。 已经表明γ δ T细胞介导的免疫可能影响HIV/SIV感染的结果。 本提案的第一个具体目标的重点是评估刺激γ δ T细胞的治疗性疫苗接种及其影响a）SIV感染动物体内病毒载量和B）SIV疾病进展速度的能力。第二个具体目标是在高效抗逆转录病毒治疗（HAART）中止的情况下，非肽抗原治疗性疫苗接种的效果。体外非肽抗原对V γ 9 V δ 2 T细胞的强激活导致对HIV/SIV复制的有效抑制;这将用于鉴定对V γ 9 V δ 2 T细胞刺激最有效的非肽抗原。 V γ 9 V δ 2 T细胞的活化将根据其细胞毒性活性及其产生细胞因子和抗病毒β-趋化因子的能力来测量。 在接受治疗性疫苗接种（含或不含HAART）之前和之后，将评估SIV攻毒恒河猴中的SIV疾病进展[免疫学参数（淋巴细胞的数量和功能）和体内病毒载量将使用流式细胞术、ELISA和PCR技术进行监测]，并与未治疗的对照组进行比较。 将记录存活时间。 将分析试验的有效性，并确定治疗性疫苗接种对SIV感染动物预后和存活率的影响。 成功的结果可能会导致新的治疗性疫苗接种策略，用于人类艾滋病的临床试验。