THERAPEUTIC VACCINATION FOR IMMUNODEFICIENCY VIRUSES

感染免疫缺陷病毒--人类免疫缺陷病毒(HIV)或猿猴(SIV)--的一个重要特征是宿主未能对该病毒进行有效的免疫防御。在一些个体中，建立了长期无进展的状态。已有研究表明，Gammadelta T细胞免疫可能影响HIV/SIV感染的转归。这项提案的第一个具体目标的重点是评估治疗性疫苗接种，它刺激Gammadelta T细胞及其影响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停止高效抗逆转录病毒疗法(HAART)的背景下，用非肽类抗原进行治疗性疫苗接种的效果。非肽类抗原在体外对T细胞具有很强的激活作用，可以有效抑制HIV/SIV的复制，这将被用来鉴定对VGamma9Vdelta2T细胞刺激最有效的非肽类抗原(S)。VGamma9Vdelta2T细胞的激活将通过它们的细胞毒活性以及它们产生细胞因子和抗病毒β-趋化因子的能力来衡量。在接受或不使用HAART的治疗性疫苗接种之前和之后，将评估SIV攻击恒河猴的SIV疾病进展[将使用流式细胞术、ELISA和PCR技术监测免疫学参数(淋巴样细胞的数量和功能)和体内病毒载量]，并与未经治疗的对照组进行比较。生存时间将被记录下来。将分析测试的效果，并确定治疗性疫苗接种对感染SIV动物的预后和存活率的影响。成功的结果可能会带来新的治疗性疫苗接种策略，用于人类艾滋病的临床测试。

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.