DNA AND PROTEIN IMMUNOGENS FOR SIV/HIV VACCINES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在恒河猴中对GM-CSF作为使用SHIV-89.6 DNA和MVA免疫原以及SHIV-89.6 p攻击的DNA/MVA疫苗的佐剂进行了研究。研究表明，在没有对T细胞进行GM-CSF研究的情况下，与SHIV-89.6 DNA联合施用GM-CSF DNA的动物相比，接种疫苗DNA的动物的峰值和设定点病毒载量降低了10倍。GM-CSF佐剂和非佐剂疫苗引起的Ab反应表明GM-CSF影响了Ab和T细胞反应。这些影响并不表现在反应高度的差异上，而是表现在反应的质量上。GM-CSF佐剂增加了诱导的抗env Ab的亲和力，扩大了反应的中和活性。这种扩大的中和活性扩展到相对容易中和的分离株，但不包括HIV-1的事件株。当分析粘膜和全身反应时，发现了T细胞反应的主要差异。这些分析表明，gm - csf佐剂动物的肠道黏膜中抗病毒CD8 T细胞的频率高于未佐剂动物。这些频率的差异在挑战后持续了8周。研究人员还对接种疫苗的两只猴子的T细胞反应及其与病毒序列突变的关系进行了研究，这两只猴子在4年后失去了对攻击病毒的控制。失去病毒控制的两只猴子在CD8和CD4 T细胞应答的广度和频率上都发生了戏剧性的扩张。最初，这些抗病毒T细胞表达IFN-？，约20%共同生产IL-2。随着时间的推移，产生IL-2的细胞和IFN-？失去了产生细胞，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.