DNA AND PROTEIN IMMUNOGENS FOR SIV/HIV VACCINES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。以SIV-89.6DNA和MVA为免疫原，在恒河猴体内进行了GM-CSF作为DNA/MVA疫苗佐剂的研究。研究表明，在没有对T细胞进行GM-CSF研究的情况下，与接种疫苗DNA的动物相比，联合使用SIV-89.6 DNA的GM-CSF DNA可将峰值和设定点病毒载量降低10倍。GM-CSF佐剂疫苗和非佐剂疫苗诱导的AB反应表明GM-CSF既影响抗体应答又影响T细胞应答。这些影响并不体现在答复的高度上，而是体现在答复的质量上。GM-CSF佐剂增加了抗Env抗体的亲和力，扩大了应答的中和活性。这种中和活性的扩大延伸到相对容易中和的分离株，但不包括艾滋病毒-1的偶发毒株。当分析粘膜反应和全身反应时，发现T细胞反应的主要差异是在攻击后。这些分析表明，GM-CSF佐剂组动物肠道粘膜中抗病毒CD8 T细胞的频率高于非佐剂组动物。这些频率的差异在攻击后持续了长达8周。研究人员还对两只接种疫苗和受到攻击的猴子进行了T细胞反应及其与病毒序列突变的关系的研究，这两只猴子在控制了4年后失去了对挑战病毒的控制。失去病毒控制的两只猴子在反应CD8和CD4T细胞的广度和频率上都经历了戏剧性的扩张。最初，这些抗病毒T细胞表达干扰素-β，其中约20%共同产生IL-2。随着时间的推移，IL-2共同产生的细胞，然后是干扰素？产生细胞丢失，动物患上了艾滋病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies were conducted on the ability of GM-CSF to serve as an adjuvant for a DNA/MVA vaccine using SHIV-89.6 DNA and MVA immunogens and a SHIV-89.6P challenge in rhesus macaques. The studies demonstrated that GM-CSF DNA co-administered with the SHIV-89.6 DNA decreased peak and set point viral loads by 10-fold over those found in animals that received the vaccine DNA in the absence of the GM-CSF studies on the T cell. Ab responses elicited by the GM-CSF-adjuvanted and non-adjuvanted vaccines revealed that the GM-CSF had affected both Ab and T cell responses. These effects were not manifest in differences in the heights of responses but rather in the quality of responses. The GM-CSF adjuvant increased the affinity of the elicited anti-Env Ab broadening the neutralizing activity of the response. This broadening of neutralizing activity extended to isolates that are relatively easy to neutralize, but not to incident strains of HIV-1. The major difference in T cell responses was found post challenge when mucosal as well as systemic responses were analyzed. These analyses revealed that the GM-CSF-adjuvanted animals had higher frequencies of anti-viral CD8 T cells in the gut mucosa than the non-adjuvanted animals. These difference in frequencies persisted for up to 8 weeks post challenge. Studies were also conducted on the T cell responses and their relationship to mutations in viral sequences in two vaccinated and challenged monkeys that lost control of the challenge virus after 4 years of control. Both of the monkeys that lost viral control underwent dramatic expansions in the breadth and frequency of responding CD8 and CD4 T cells. Initially, these anti-viral T cells expressed IFN-?, with about 20% co-producing IL-2. Over time IL-2 co-producing cells and then IFN-? producing cells were lost and the animals developed AIDS.